148 results on '"MAP2K2"'
Search Results
2. Lnc_000048 Promotes Histone H3K4 Methylation of MAP2K2 to Reduce Plaque Stability by Recruiting KDM1A in Carotid Atherosclerosis.
- Author
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Zhang, Shuai, Sun, Yu, Xiao, Qi, Niu, Mengying, Pan, Xudong, and Zhu, Xiaoyan
- Abstract
Stabilizing and inhibiting plaque formation is a key challenge for preventing and treating ischemic stroke. KDM1A-mediated histone modifications, which involved in the development of training immunity, ultimately exacerbate the outcomes of inflammation. Although lncRNAs can recruit KDM1A to participate in histone methylation modification and regulate inflammation, cell proliferation, and other biological processes, little is known about the role of KDM1A-lncRNA interaction during atherosclerosis. The present study sought to delineate the effect of the interaction between lnc_000048 and KDM1A on plaque rupture in carotid atherosclerosis, as well as the potential mechanism. Our results revealed that lnc_000048 reduced the activity of histone demethylase and activated MAP2K2 expression by interacting with KDM1A. Furthermore, upregulated lnc_000048 indirectly regulated ERK phosphorylation by MAP2K2 and eventually activated the inflammatory response through the MAPK pathway, which was involved in atherosclerosis. Importantly, our study using ApoE-/- mice confirmed the regulatory role of lnc_000048 in promoting inflammation and collagen degradation in atherosclerotic plaques. These results suggest that targeting the lnc_000048 /KDM1A/MAP2K2/ERK axis may be a promising strategy for preventing atherosclerosis. [ABSTRACT FROM AUTHOR]
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- 2023
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3. LncRNA SNHG25 Promotes Glioma Progression Through Activating MAPK Signaling.
- Author
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Wu, Zeyu, Lun, Peng, Ji, Tao, Niu, Jiaojiao, Sun, Xiuyan, Liu, Xia, and Xu, Jian
- Abstract
Numerous studies indicated that long non-coding RNAs (lncRNAs) play critical roles in glioma initiation and progression. SNHG25 is a newly identified lncRNA. And the functional role and molecular mechanism of SNHG25 in glioma cells have not been investigated. In this study, we found that SNHG25 was upregulated in glioma cells and tissues. CCK-8, EDU, and colony formation assays demonstrated that SNHG25 knockdown markedly inhibited glioma cell proliferation. In vivo studies showed that SNHG25 knockdown significantly inhibited tumor growth. Further studies indicated that SNHG25 positively regulated MAP2K2 through sponging miR-579-5p. High expression of SNHG25 activated MAPK signaling through MAP2K2. These data suggest that SNHG25 is a potential target and biomarker for glioma. [ABSTRACT FROM AUTHOR]
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- 2022
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4. Myc-associated zinc-finger protein promotes clear cell renal cell carcinoma progression through transcriptional activation of the MAP2K2-dependent ERK pathway
- Author
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Li-Xin Ren, Jin-Chun Qi, An-Ning Zhao, Bei Shi, Hong Zhang, Dan-Dan Wang, and Zhan Yang
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MAZ ,MAP2K2 ,ERK ,Signaling pathway ,Clear cell renal carcinoma ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,RC254-282 ,Cytology ,QH573-671 - Abstract
Abstract Background The dysfunction of myc-related zinc finger protein (MAZ) has been proven to contribute to tumorigenesis and development of multiple cancer types. However, the biological roles and clinical significance of MAZ in clear cell renal carcinoma (ccRCC) remain unclear. Methods MAZ expression was examined in ccRCC and normal kidney tissue by quantitative real-time PCR and Western blot. Statistical analysis was used to evaluate the clinical correlation between MAZ expression and clinicopathological characteristics to determine the relationship between MAZ expression and the survival of ccRCC patients. The biological roles of MAZ in cells were investigated in vitro using MTT and colony assays. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to investigate the relationship between MAZ and its potential downstream signaling molecules. Results MAZ expression is elevated in ccRCC tissues, and higher levels of MAZ were correlated with poor survival of patients with ccRCC. MAZ upregulation elevates the proliferation ability of ccRCC cells in vitro, whereas silencing MAZ represses this ability. Our results further reveal that MAZ promotes cell growth, which is dependent on ERK signaling. Importantly, we found that MAZ positively regulates MAP2K2 expression in ccRCC cells. Mechanistically, MAZ binds to the MAP2K2 promoter and increases MAP2K2 transcription. Furthermore, MAP2K2 levels were shown to be increased in ccRCC tissues and to be associated with a poor prognosis of ccRCC patients. MAP2K2 upregulation activates the ERK signaling pathway and promotes ccRCC progression. Conclusion These results reveal that the MAZ/MAP2K2/ERK signaling axis plays a crucial role in promoting ccRCC progression, which suggests the potential therapeutic utility of MAZ in ccRCC.
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- 2021
- Full Text
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5. Development of a Toll-Like Receptor-Based Gene Signature That Can Predict Prognosis, Tumor Microenvironment, and Chemotherapy Response for Hepatocellular Carcinoma
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Lixia Liu, Bin Liu, Jie Yu, Dongyun Zhang, Jianhong Shi, and Ping Liang
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toll-like receptor signaling pathway ,hepatocellular carcinoma ,prognosis ,tumor microenvironment ,chemotherapy response ,MAP2K2 ,Biology (General) ,QH301-705.5 - Abstract
Objective: Emerging evidence highlights the implications of the toll-like receptor (TLR) signaling pathway in the pathogenesis and therapeutic regimens of hepatocellular carcinoma (HCC). Herein, a prognostic TLR-based gene signature was conducted for HCC.Methods: HCC-specific TLRs were screened in the TCGA cohort. A LASSO model was constructed based on prognosis-related HCC-specific TLRs. The predictive efficacy, sensitivity, and independency of this signature was then evaluated and externally verified in the ICGC, GSE14520, and GSE76427 cohorts. The associations between this signature and tumor microenvironment (stromal/immune score, immune checkpoint expression, and immune cell infiltrations) and chemotherapy response were assessed in HCC specimens. The expression of TLRs in this signature was verified in HCC and normal liver tissues by Western blot. Following si-MAP2K2 transfection, colony formation and apoptosis of Huh7 and HepG2 cells were examined.Results: Herein, we identified 60 HCC-specific TLRs. A TLR-based gene signature (MAP2K2, IRAK1, RAC1, TRAF3, MAP3K7, and SPP1) was conducted for HCC prognosis. High-risk patients exhibited undesirable outcomes. ROC curves confirmed the well prediction performance of this signature. Multivariate Cox regression analysis demonstrated that the signature was an independent prognostic indicator. Also, high-risk HCC was characterized by an increased immune score, immune checkpoint expression, and immune cell infiltration. Meanwhile, high-risk patients displayed higher sensitivity to gemcitabine and cisplatin. The dysregulation of TLRs in the signature was confirmed in HCC. MAP2K2 knockdown weakened colony formation and elevated apoptosis of Huh7 and HepG2 cells.Conclusion: Collectively, this TLR-based gene signature might assist clinicians to select personalized therapy programs for HCC patients.
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- 2021
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6. Myc-associated zinc-finger protein promotes clear cell renal cell carcinoma progression through transcriptional activation of the MAP2K2-dependent ERK pathway.
- Author
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Ren, Li-Xin, Qi, Jin-Chun, Zhao, An-Ning, Shi, Bei, Zhang, Hong, Wang, Dan-Dan, and Yang, Zhan
- Subjects
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ZINC-finger proteins , *RENAL cell carcinoma , *CELL growth , *PROGNOSIS , *WESTERN immunoblotting - Abstract
Background: The dysfunction of myc-related zinc finger protein (MAZ) has been proven to contribute to tumorigenesis and development of multiple cancer types. However, the biological roles and clinical significance of MAZ in clear cell renal carcinoma (ccRCC) remain unclear. Methods: MAZ expression was examined in ccRCC and normal kidney tissue by quantitative real-time PCR and Western blot. Statistical analysis was used to evaluate the clinical correlation between MAZ expression and clinicopathological characteristics to determine the relationship between MAZ expression and the survival of ccRCC patients. The biological roles of MAZ in cells were investigated in vitro using MTT and colony assays. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to investigate the relationship between MAZ and its potential downstream signaling molecules. Results: MAZ expression is elevated in ccRCC tissues, and higher levels of MAZ were correlated with poor survival of patients with ccRCC. MAZ upregulation elevates the proliferation ability of ccRCC cells in vitro, whereas silencing MAZ represses this ability. Our results further reveal that MAZ promotes cell growth, which is dependent on ERK signaling. Importantly, we found that MAZ positively regulates MAP2K2 expression in ccRCC cells. Mechanistically, MAZ binds to the MAP2K2 promoter and increases MAP2K2 transcription. Furthermore, MAP2K2 levels were shown to be increased in ccRCC tissues and to be associated with a poor prognosis of ccRCC patients. MAP2K2 upregulation activates the ERK signaling pathway and promotes ccRCC progression. Conclusion: These results reveal that the MAZ/MAP2K2/ERK signaling axis plays a crucial role in promoting ccRCC progression, which suggests the potential therapeutic utility of MAZ in ccRCC. [ABSTRACT FROM AUTHOR]
- Published
- 2021
- Full Text
- View/download PDF
7. Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype
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Daniel L. Kenney‐Jung, Dante J. Rogers, Samuel J. Kroening, Abigail L. Zatkalik, Ashley E. Whitmarsh, Amy E. Roberts, Martin Zenker, Maria Luigia Gambardella, Ilaria Contaldo, Chiara Leoni, Roberta Onesimo, Giuseppe Zampino, Marco Tartaglia, Domenica I. Battaglia, and Elizabeth I. Pierpont
- Subjects
MAP2K1 ,Settore MED/39 - NEUROPSICHIATRIA INFANTILE ,MAP2K2 ,Genetics ,KRAS ,RASopathies ,Genetics (clinical) ,BRAF ,seizures - Abstract
Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.
- Published
- 2022
8. Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype
- Abstract
Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes.
- Published
- 2022
9. Dysregulation of GSK3β-Target Proteins in Skin Fibroblasts of Myotonic Dystrophy Type 1 (DM1) Patients
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Geneviève Gourdon, Andreas Hentschel, Hanns Lochmüller, Denisa Hathazi, Valentina Grande, Nikoletta Nikolenko, Ulrike Schara-Schmidt, Theo Marteau, Andreas Roos, Emily O'Connor, Universitat Duisberg-Essen, Leibniz-Institut für Analytische Wissenschaften - ISAS - e.V., University of Cambridge School of Clinical Medicine, Université d'Ottawa [Ontario] (uOttawa), Essen University Hospital, Centre de recherche en Myologie – U974 SU-INSERM, Institut National de la Santé et de la Recherche Médicale (INSERM)-Sorbonne Université (SU), University College London Hospitals (UCLH), University Hospital Freiburg, Barcelona Institute of Science and Technology (BIST), University Children's Hospital of Essen [Essen, Germany], HAL UPMC, Gestionnaire, and Centre de Recherche en Myologie
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Male ,Proteomics ,0301 basic medicine ,[SDV]Life Sciences [q-bio] ,Muscle Fibers, Skeletal ,Medizin ,MAP2K2 ,Muscle Development ,CTPS1 ,CAPN1 ,0302 clinical medicine ,Myotonic Dystrophy ,CTNNB1 ,Skin ,Myogenesis ,Kinase ,Middle Aged ,3. Good health ,Cell biology ,[SDV] Life Sciences [q-bio] ,medicine.anatomical_structure ,Neurology ,Female ,Adult ,musculoskeletal diseases ,congenital, hereditary, and neonatal diseases and abnormalities ,Myosin light-chain kinase ,Protein Serine-Threonine Kinases ,Biology ,Myotonic dystrophy ,Myotonin-Protein Kinase ,03 medical and health sciences ,medicine ,Humans ,Muscle Strength ,RNA, Messenger ,Protein kinase A ,GSK3B ,Glycogen Synthase Kinase 3 beta ,Gene Expression Profiling ,Skeletal muscle ,Fibroblasts ,medicine.disease ,HDAC2 ,030104 developmental biology ,fibroblast proteomics ,GSK3 ,Neurology (clinical) ,Trinucleotide Repeat Expansion ,Biomarkers ,030217 neurology & neurosurgery - Abstract
International audience; Myotonic dystrophy type 1 (DM1) is the most common monogenetic muscular disorder of adulthood. This multisystemic disease is caused by CTG repeat expansion in the 3-untranslated region of the DM1 protein kinase gene called DMPK. DMPK encodes a myosin kinase expressed in skeletal muscle cells and other cellular populations such as smooth muscle cells, neurons and fibroblasts. The resultant expanded (CUG)n RNA transcripts sequester RNA binding factors leading to ubiquitous and persistent splicing deregulation. The accumulation of mutant CUG repeats is linked to increased activity of glycogen synthase kinase 3 beta (GSK3), a highly conserved and ubiquitous serine/threonine kinase with functions in pathways regulating inflammation, metabolism, oncogenesis, neurogenesis and myogenesis. As GSK3-inhibition ameliorates defects in myogenesis, muscle strength and myotonia in a DM1 mouse model, this kinase represents a key player of DM1 pathobiochemistry and constitutes a promising therapeutic target. To better characterise DM1 patients, and monitor treatment responses, we aimed to define a set of robust disease and severity markers linked to GSK3by unbiased proteomic profiling utilizing fibroblasts derived from DM1 patients with low (80-150) and high (2600-3600) CTG-repeats. Apart from GSK3 increase, we identified dysregulation of nine proteins (CAPN1, CTNNB1, CTPS1, DNMT1, HDAC2, HNRNPH3, MAP2K2, NR3C1, VDAC2) modulated by GSK3. In silico-based expression studies confirmed expression in neuronal and skeletal muscle cells and revealed a relatively elevated abundance in fibroblasts. The potential impact of each marker in the myopathology of DM1 is discussed based on respective function to inform potential uses as severity markers or for monitoring GSK3 inhibitor treatment responses.
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- 2021
10. Concurrent occurrence of an inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving MAP2K2 in a patient with developmental delay, distinctive facial features, and lambdoid synostosis.
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Shimojima, Keiko, Ondo, Yumiko, Matsufuji, Mayumi, Sano, Nozomi, Tsuru, Hisashi, Oyoshi, Tatsuki, Higa, Nayuta, Tokimura, Hiroshi, Arita, Kazunori, and Yamamoto, Toshiyuki
- Subjects
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DEVELOPMENTAL delay , *CRANIOSYNOSTOSES , *FACIAL abnormalities , *MITOGEN-activated protein kinase kinase , *GENETIC mutation , *CLINICAL trials , *CHROMOSOME abnormalities - Abstract
A female patient presented with developmental delay, distinctive facial features, and congenital anomalies, including a heart defect and premature lambdoid synostosis. The patient showed a paternally inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving the mitogen-activated protein kinase kinase 2 gene ( MAP2K2 ), in which mutations cause the cardio-facio-cutaneous (CFC) syndrome. Reports of patients with overlapping 19p13.3 microdeletions of this region describe similar clinical manifestations including distinctive facial features: prominent forehead, horizontal/down-slanting palpebral fissures, long midface, pointed chin/angular jaw, sparse eyebrows, and underdeveloped cheekbones. Some of these findings overlapped to that of the patients with 16p13.11 microduplications and CFC syndrome. Although craniosynostosis was occasionally observed in patients with dominant-negative mutations in RAS/MAP kinase signaling genes (RASopathies) related to CFC syndrome, it was also reported in two patients with 16p13.11 microduplications. Genetic contributions of both chromosomal aberrations were discussed. [ABSTRACT FROM AUTHOR]
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- 2016
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11. Characterization of Kinase Expression Related to Increased Migration of PC-3M Cells Using Global Comparative Phosphoproteome Analysis
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Sangkyu Lee, Tae Gyun Kwon, Yun-Sok Ha, Yan Gao, Jun Nyung Lee, and Young-Chang Cho
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Male ,Proteomics ,Cancer Research ,MAP2K2 ,Biology ,Proto-Oncogene Mas ,Biochemistry ,Prostate cancer ,Cell Movement ,Cell Line, Tumor ,Genetics ,medicine ,Humans ,Neoplasm Invasiveness ,Phosphorylation ,Molecular Biology ,Kinase ,Prostate ,Prostatic Neoplasms ,Cancer ,Phosphoproteins ,medicine.disease ,Up-Regulation ,Gene Expression Regulation, Neoplastic ,Disease Progression ,Cancer research ,ARAF ,Signal transduction ,Protein Kinases ,Research Article ,Signal Transduction - Abstract
Background/aim Prostate cancer (PCa) is the second-most commonly occurring cancer among men, worldwide. Although the mechanisms associated with the progression of castration-resistant prostate cancer (CRPC) have been widely studied, the mechanism associated with more distant metastases from the bone remains unknown. This study aimed to characterize potential pathogenic kinases associated with highly metastatic PCa, that may regulate phosphorylation in extensively involved and diverse signaling pathways that are associated with the development of various cancers. Materials and methods A mass spectrometry (MS)-based comparative phosphoproteome strategy was utilized to identify differentially expressed kinases between the highly aggressive PCa cell-lines PC-3 and PC-3M. Results Among 2,968 phosphorylation sites in PCa cells, 151 differently expressed phosphoproteins were identified. Seven motifs: -SP-, -SxxE-, -PxS-, -PxSP-, -SxxK-, -SPxK-, and -SxxxxxP- were found to be highly expressed in PC-3M cells. Based on these motifs, the kinases p21-activated kinase (PAK)2, Ste20-like kinase (SLK), mammalian Ste20-like kinase (MST)4, mitogen-activated kinase kinase (MAP2K)2, and A-Raf proto-oncogene serine/threonine kinase (ARAF) were up-regulated in PC-3M cells. Conclusion PAK2, SLK, MST4, MAP2K2, and ARAF are kinases that are potentially associated with the progression of increased migration in PC-3M cells and may represent molecule regulators or drug targets for highly metastatic PCa therapy.
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- 2020
12. De novo ZBTB7A variant in a patient with macrocephaly, intellectual disability, and sleep apnea: implications for the phenotypic development in 19p13.3 microdeletions
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Kaori Yamoto, Tsutomu Ogata, Yohei Masunaga, Akira Ohishi, Shigeo Iijima, Maki Fukami, Fumiko Kato, and Hirotomo Saitsu
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Male ,0301 basic medicine ,Heterozygote ,Candidate gene ,MAP Kinase Kinase 2 ,Mutation, Missense ,MAP2K2 ,030105 genetics & heredity ,03 medical and health sciences ,Sleep Apnea Syndromes ,Intellectual Disability ,Intellectual disability ,Genetics ,Humans ,Medicine ,Missense mutation ,Abnormalities, Multiple ,Child ,Genetics (clinical) ,Zinc finger ,business.industry ,Macrocephaly ,Sleep apnea ,medicine.disease ,Phenotype ,Megalencephaly ,DNA-Binding Proteins ,030104 developmental biology ,Chromosome Deletion ,medicine.symptom ,business ,Chromosomes, Human, Pair 19 ,Transcription Factors - Abstract
Interstitial microdeletions at chromosome 19p13.3 are frequently associated with a constellation of clinical features including macrocephaly, characteristic face, intellectual disability, and sleep apnea. Previous studies in 25 patients with 19p13.3 microdeletions have revealed loss of MAP2K2 in 24 patients and that of PIAS4 and ZBTB7A in 23 patients, suggesting that these three adjacent genes are candidate genes for the phenotypic development in 19p13.3 microdeletions. We identified a de novo likely pathogenic heterozygous missense variant of ZBTB7A (NM_015898.3:c.1152C>G, p.(Cys384Trp)) in a Japanese boy with macrocephaly, intellectual disability, and sleep apnea. This variant affects the conserved cysteine residue forming the coordinate bond with Zn2+ ion at the first zinc finger domain, and is predicted to exert a dominant-negative effect because of the generation of homo- and hetero-dimers with the wild-type and variant ZBTB7A proteins. The results argue for a critical relevance of ZBTB7A to the development of most, but probably not all, of the 19p13.3 microdeletion phenotype.
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- 2019
13. Identification of Hub Genes in Hemifacial Microsomia: Evidence From Bioinformatic Analysis
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Lunkun Ma, Bing-Yang Liu, Xiyuan Li, Zhiyong Zhang, Xi Xu, Pengfei Sun, Shanbaga Zhao, Kai-Yi Shu, Qi-Li Peng, and Yingxiang Liang
- Subjects
MAPK3 ,Databases, Factual ,business.industry ,Computational Biology ,General Medicine ,MAP2K2 ,Computational biology ,medicine.disease ,Hemifacial microsomia ,LMNA ,MicroRNAs ,Goldenhar Syndrome ,Otorhinolaryngology ,Interaction network ,MAP2K1 ,microRNA ,Medicine ,Humans ,Surgery ,Gene Regulatory Networks ,Protein Interaction Maps ,business ,Gene - Abstract
OBJECTIVE This thesis addresses a neglected aspect of bioinformatics research of hemifacial microsomia (HFM). Existing research stops short of prediction based on big data. This study combines multiple databases to explore underlying pathogenesis using bioinformatic approach. METHODS The research consisted of multiple bioinformatic methods, included pathogenic genes analyses, protein-protein interaction network construction, functional enrichment, and mining target genes related miRNA, for studying pathogenic genes of HFM. RESULTS Total of 140 genes were identified as potential genes in the study. The protein-protein interaction networks for pathogenic genes were constructed, which contained 138 nodes and 243 edges with RAF1, MAP2K1, MAP2K2, MAPK3, MAPK1, EGFR, BRAF, LMNA, ESPR1, and SFN as the hub genes. These genes were discovered significantly enriched in MAPK pathway. Besides, the whole of interactions between miRNAs and the top 5 hub genes were revealed. CONCLUSIONS Our results indicated that occurrence of HFM is attributed to a variety of genes. Furthermore, the interactions of pathogenic genes were further elucidated by using bioinformatics approach. It reveals the MAPK pathway play an essential role in its pathogenesis. It may provide a novel perspective on better understanding the pathogenesis and more accurate early screening of HFM.
- Published
- 2021
14. Myc-associated zinc-finger protein promotes clear cell renal cell carcinoma progression through transcriptional activation of the MAP2K2-dependent ERK pathway
- Author
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Dan-Dan Wang, Li-Xin Ren, Zhan Yang, An-Ning Zhao, Bei Shi, Jin-Chun Qi, and Hong Zhang
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MAPK/ERK pathway ,Cancer Research ,Biology ,medicine.disease_cause ,03 medical and health sciences ,0302 clinical medicine ,Downregulation and upregulation ,Genetics ,medicine ,Gene silencing ,Clear cell renal carcinoma ,RC254-282 ,030304 developmental biology ,0303 health sciences ,QH573-671 ,Signaling pathway ,Cell growth ,Neoplasms. Tumors. Oncology. Including cancer and carcinogens ,medicine.disease ,ERK ,Clear cell renal cell carcinoma ,MAP2K2 ,Oncology ,030220 oncology & carcinogenesis ,Cancer research ,MAZ ,Signal transduction ,Cytology ,Primary Research ,Carcinogenesis ,Chromatin immunoprecipitation - Abstract
Background The dysfunction of myc-related zinc finger protein (MAZ) has been proven to contribute to tumorigenesis and development of multiple cancer types. However, the biological roles and clinical significance of MAZ in clear cell renal carcinoma (ccRCC) remain unclear. Methods MAZ expression was examined in ccRCC and normal kidney tissue by quantitative real-time PCR and Western blot. Statistical analysis was used to evaluate the clinical correlation between MAZ expression and clinicopathological characteristics to determine the relationship between MAZ expression and the survival of ccRCC patients. The biological roles of MAZ in cells were investigated in vitro using MTT and colony assays. Luciferase reporter assays and chromatin immunoprecipitation (ChIP) were used to investigate the relationship between MAZ and its potential downstream signaling molecules. Results MAZ expression is elevated in ccRCC tissues, and higher levels of MAZ were correlated with poor survival of patients with ccRCC. MAZ upregulation elevates the proliferation ability of ccRCC cells in vitro, whereas silencing MAZ represses this ability. Our results further reveal that MAZ promotes cell growth, which is dependent on ERK signaling. Importantly, we found that MAZ positively regulates MAP2K2 expression in ccRCC cells. Mechanistically, MAZ binds to the MAP2K2 promoter and increases MAP2K2 transcription. Furthermore, MAP2K2 levels were shown to be increased in ccRCC tissues and to be associated with a poor prognosis of ccRCC patients. MAP2K2 upregulation activates the ERK signaling pathway and promotes ccRCC progression. Conclusion These results reveal that the MAZ/MAP2K2/ERK signaling axis plays a crucial role in promoting ccRCC progression, which suggests the potential therapeutic utility of MAZ in ccRCC.
- Published
- 2021
15. A heterozygous missense variant in MAP2K2 in a stillborn romagnola calf with skeletal-cardio-enteric dysplasia
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Cord Drögemüller, Irene M. Häfliger, Arcangelo Gentile, Joana G. P. Jacinto, Jacinto J.G.P., Hafliger I.M., Gentile A., and Drogemuller C.
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Heterotopy ,040301 veterinary sciences ,Veterinary medicine ,610 Medicine & health ,MAP2K2 ,Biology ,RASopathy ,Development ,Genetic analysis ,0403 veterinary science ,03 medical and health sciences ,SF600-1100 ,medicine ,Missense mutation ,Gene ,Cardiac defect ,030304 developmental biology ,Genetics ,0303 health sciences ,General Veterinary ,630 Agriculture ,Precision medicine ,04 agricultural and veterinary sciences ,medicine.disease ,Phenotype ,Short spine ,Protein kinase domain ,QL1-991 ,Dysplasia ,570 Life sciences ,biology ,590 Animals (Zoology) ,Animal Science and Zoology ,Cattle ,Congenital malformation ,Zoology ,congenital malformations - Abstract
RASopathies are a group of developmental disorders caused by dominant mutations in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) cell signaling pathway. The goal of this study was to characterize the pathological phenotype of a Romagnola stillborn calf with skeletal-cardio-enteric dysplasia and to identify a genetic cause by whole-genome sequencing (WGS). The calf showed reduced fetal growth, a short-spine, a long and narrow face, cardiac defects and heterotopy of the spiral colon. Genetic analysis revealed a private heterozygous missense variant in MAP2K2:p.Arg179Trp, located in the protein kinase domain in the calf, and not found in more than 4500 control genomes including its sire. The identified variant affecting a conserved residue was predicted to be deleterious and most likely occurred de novo. This represents the first example of a dominant acting, and most likely pathogenic, variant in MAP2K2 in domestic animals, thereby providing the first MAP2K2-related large animal model, especially in respect to the enteric malformation. In addition, this study demonstrates the utility of WGS-based precise diagnostics for understanding sporadic congenital syndromic anomalies in cattle and the general utility of continuous surveillance for rare hereditary defects in cattle., Skeletal dysplasias encompass a clinical-, pathological- and genetically heterogeneous group of disorders characterized by abnormal cartilage and/or bone formation, growth, and remodeling. They may belong to the so-called RASopathies, congenital conditions caused by heterozygous variants in genes that encode components of the Ras/mitogen-activated protein kinase (MAPK) cell signaling pathway. Herein, an affected calf of the Italian Romagnola breed was reported showing a skeletal-cardio-enteric dysplasia. We identified a most likely disease-causing mutation in the MAP2K2 gene by whole-genome sequencing (WGS). The MAP2K2 gene is known to be related with dominant inherited cardio-facio-cutaneous syndrome in humans, but it was so far unknown to cause a similar disease in domestic animals. We assume that the identified missense variant that was predicted to impair the function of the protein, occurred either within the germline of the dam or post-zygotically in the embryo. Rare lethal diseases such as the skeletal-cardio-enteric dysplasia in livestock are usually not characterized to the molecular level, mainly because of the lack of funds and diagnostic opportunities. Precise WGS-based diagnostics enables the understanding of rare diseases and supports the value of monitoring cattle breeding populations for fatal genetic defects.
- Published
- 2021
16. Infantile epileptic spasms syndrome in children with cardiofaciocutanous syndrome: Clinical presentation and associations with genotype.
- Author
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Kenney-Jung DL, Rogers DJ, Kroening SJ, Zatkalik AL, Whitmarsh AE, Roberts AE, Zenker M, Gambardella ML, Contaldo I, Leoni C, Onesimo R, Zampino G, Tartaglia M, Battaglia DI, and Pierpont EI
- Subjects
- Humans, Proto-Oncogene Proteins B-raf genetics, Proto-Oncogene Proteins B-raf therapeutic use, Genotype, Syndrome, Spasm complications, Spasms, Infantile genetics, Spasms, Infantile complications, Spasms, Infantile drug therapy, Epilepsy genetics
- Abstract
Gene variants that dysregulate signaling through the RAS-MAPK pathway cause cardiofaciocutaneous syndrome (CFCS), a rare multi-system disorder. Infantile epileptic spasms syndrome (IESS) and other forms of epilepsy are among the most serious complications. To investigate clinical presentation, treatment outcomes, and genotype-phenotype associations in CFCS patients with IESS, molecular genetics and clinical neurological history were reviewed across two large clinical research cohorts (n = 180). IESS presented in 18/180 (10%) cases, including 16 patients with BRAF variants and 2 with MAP2K1 variants. Among IESS patients with BRAF variants, 16/16 (100%) had sequence changes affecting the protein kinase domain (exons 11-16), although only 57% of total BRAF variants occurred in this domain. Clinical onset of spasms occurred at a median age of 5.4 months (range: 1-24 months). Among 13/18 patients whose IESS resolved with anti-seizure medications, 10 were treated with ACTH and/or vigabatrin. A substantial majority of CFCS patients with IESS subsequently developed other epilepsy types (16/18; 89%). In terms of neurodevelopmental outcomes, gross motor function and verbal communication were more limited in patients with a history of IESS compared to those without IESS. These findings can inform clinical neurological care guidelines for CFCS and development of relevant pre-clinical models for severe epilepsy phenotypes., (© 2022 The Authors. American Journal of Medical Genetics Part C: Seminars in Medical Genetics published by Wiley Periodicals LLC.)
- Published
- 2022
- Full Text
- View/download PDF
17. The perinatal presentation of cardiofaciocutaneous syndrome.
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Wong Ramsey, Kara N., Loichinger, Matthew H., Slavin, Thomas P., Kuo, Sheree, and Seaver, Laurie H.
- Abstract
There is limited information available related to the perinatal course of cardiofaciocutaneous syndrome (CFC) compared to other syndromes within the Ras-MAP kinase pathway (rasopathies) such as Noonan and Costello syndrome. Retrospective chart review revealed four cases of CFC with molecular confirmation between 2005 and 2012 at Hawaii's largest obstetric and pediatric referral center. We report on details of the prenatal, neonatal, and infancy course and long-term follow-up beyond infancy in two patients. This report includes novel features including systemic hypertension, hyponatremia, and chronic respiratory insufficiency, not previously reported in CFC. We provide pathologic diagnosis of loose anagen hair in one patient. Some of these findings have been reported in the other rasopathies, documenting further clinical overlap among these conditions. Molecular testing can be useful to differentiate CFC from other rasopathies and in counseling families about potential complications and prognosis. We recommend a full phenotypic evaluation including echocardiogram, renal ultrasound, brain imaging, and ophthalmology examination. We additionally recommend close follow-up of blood pressure, pulmonary function, and monitoring for electrolyte disturbance and extra-vascular fluid shifts. © 2014 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
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18. Deletion of MAP2K2/MEK2: a novel mechanism for a RASopathy?
- Author
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Nowaczyk, M.J.M., Thompson, B.A., Zeesman, S., Moog, U., Sanchez‐Lara, P.A., Magoulas, P.L., Falk, R.E., Hoover‐Fong, J.E., Batista, D.A.S., Amudhavalli, S.M., White, S.M., Graham, G.E., and Rauen, K.A.
- Subjects
- *
MITOGEN-activated protein kinase kinase , *MITOGEN-activated protein kinases , *LEOPARD syndrome , *GERM cells , *CRANIOFACIAL abnormalities , *EPIDERMAL growth factor - Abstract
RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/ MAPK) pathway components. Cardio-facio-cutaneous ( CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor-stimulated fibroblasts revealed that P- MEK1/2 was ∼50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
19. Multiple café au lait spots in familial patients with MAP2K2 mutation.
- Author
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Takenouchi, Toshiki, Shimizu, Atsushi, Torii, Chiharu, Kosaki, Rika, Takahashi, Takao, Saya, Hideyuki, and Kosaki, Kenjiro
- Abstract
Recent advances in genetic diagnostic technologies have made the classic disease nosology highly complicated. This situation is exemplified by rasopathies, among which neurofibromatosis type 1 and Noonan syndrome represent prototypic entities. The former condition is characterized by multiple café au lait spots and neurofibromas, while the latter is characterized by distinct facial features, webbed neck, congenital heart disease, and a short stature. On rare occasions, the features of both neurofibromatosis and Noonan syndrome co-exist within an individual; such patients are diagnosed as having neurofibromatosis-Noonan syndrome. Here, we report familial patients with multiple café au lait spots and Noonan syndrome-like facial features. A mutation analysis unexpectedly revealed a mutation in MAP2K2 in both the propositus and his mother. The propositus fulfilled the diagnostic criteria for neurofibromatosis type 1, but his mother did not. Their phenotype was not consistent with that of cardio-facio-cutaneous syndrome, which is classically known to be associated with MAP2K2 mutations. The mother of the propositus had cervical cancer at the age of 23 years, consistent with the oncogenic tendency associated with rasopathies. The phenotypic combination of multiple café au lait spots and Noonan syndrome-like facial features suggested a diagnosis of neurofibromatosis-Noonan syndrome. Whether this condition represents a discrete disease entity or a variable expression of neurofibromatosis type 1 has long been debated. The present observation suggests that some perturbation in the RAS/MAPK signaling cascade results in multiple café au lait spots, a key diagnostic phenotype of rasopathies, although the exact mechanism remains to be elucidated. © 2013 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]
- Published
- 2014
- Full Text
- View/download PDF
20. Personalized and targeted mutational analysis of multiple second primary melanomas under kinase inhibitors
- Author
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Eleonora Cinelli, Giovanni Zelano, Paolo Persichetti, Stefano Calvieri, Valeria Devirgiliis, Martina Verri, Michele Donati, Vincenzo Panasiti, Eleonora Perrella, Anna Crescenzi, and Rosa Coppola
- Subjects
Proto-Oncogene Proteins B-raf ,Skin Neoplasms ,DNA Mutational Analysis ,Dermatology ,MAP2K2 ,medicine.disease_cause ,Germline ,Germline mutation ,Nevus, Epithelioid and Spindle Cell ,Medicine ,Nevus ,Humans ,HRAS ,neoplasms ,Melanoma ,Protein Kinase Inhibitors ,Mutation ,Settore MED/08 - ANATOMIA PATOLOGICA ,business.industry ,Cancer ,Neoplasms, Second Primary ,medicine.disease ,Infectious Diseases ,Cancer research ,business - Abstract
BACKGROUND Second primary melanomas (SPMs) are new developed primary melanomas occurring in a subset of patients affected by BRAF-mutated metastatic melanoma during treatment with BRAF-inhibitors. A drug-induced paradoxical activation of mitogen-activated protein kinase (MAPK) signaling pathway in BRAF-wild type/RAS-mutated cells have been proposed as a possible molecular mechanism but data on the mutational status of SPMs are lacking. In order to better understand genetic alterations affecting the biological mechanism of SPMs, we performed a personalized and targeted next-generation sequencing analysis of a patient affected by metastatic melanoma who developed multiple SPMs during treatment with encorafenib (LGX818). METHODS Using a cancer panel of 50 genes for solid tumors enriched with a custom panel of 10 genes specifically involved in melanoma pathogenesis, we analyzed the primary melanoma, two SPMs, one benign compound nevus and the normal DNA extracted from blood lymphocytes of the patient. RESULTS We identified HRAS Q61 somatic mutation in one SPM developed in a pre-existing nevus. In the primary melanoma, besides the BRAF mutation, we identified the clinically actionable IDH1 R132C somatic mutation. Both SPMs were BRAF wild type. The patient harbors the recently recognized pathogenetic germline variant KDR Q472. We observed that mutations detected in tumor samples involving genes related to melanoma pathogenesis (TP53, PIK3CA, FGFR3, ATF1, KIT, HRAS and MAP2K2) were present in heterozygosis in the germline status of the patient. CONCLUSIONS Our results support the paradoxical mechanism of MAPK pathway for SPMs under BRAF inhibitors. Moreover, they suggest that targeted mutational assessment based on matching somatic and germline analysis represent a promising approach to detect the neoplastic landscape of the tumor and to identify most accurate treatment in metastatic melanoma patient.
- Published
- 2019
21. Discovery of a First-in-Class Mitogen-Activated Protein Kinase Kinase 1/2 Degrader
- Author
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Xian Chen, Margaret S Jin, Li Wang, Jianping Hu, Ling Xie, Jing Liu, Jian Jin, and Jieli Wei
- Subjects
MAPK/ERK pathway ,MAP Kinase Kinase 1 ,MAP2K2 ,Mitogen-activated protein kinase kinase ,environment and public health ,01 natural sciences ,03 medical and health sciences ,In vivo ,MAP2K1 ,Drug Discovery ,Animals ,Humans ,Enzyme Inhibitors ,030304 developmental biology ,0303 health sciences ,Gene knockdown ,biology ,Molecular Structure ,Chemistry ,Cell growth ,Diphenylamine ,0104 chemical sciences ,Ubiquitin ligase ,Cell biology ,010404 medicinal & biomolecular chemistry ,Benzamides ,biology.protein ,Molecular Medicine ,HT29 Cells - Abstract
MEK1 and MEK2 (also known as MAP2K1 and MAP2K2) are the "gatekeepers" of the ERK signaling output with redundant roles in controlling ERK activity. Numerous inhibitors targeting MEK1/2 have been developed including three FDA-approved drugs. However, acquired resistance to MEK1/2 inhibitors has been observed in patients, and new therapeutic strategies are needed to overcome the resistance. Here, we report a first-in-class degrader of MEK1/2, MS432 (23), which potently and selectively degraded MEK1 and MEK2 in a VHL E3 ligase- and proteasome-dependent manner and suppressed ERK phosphorylation in cells. It inhibited colorectal cancer and melanoma cell proliferation much more effectively than its negative control MS432N (24), and its effect was phenocopied by MEK1/2 knockdown. Compound 23 was highly selective for MEK1/2 in global proteomic profiling studies. It was also bioavailable in mice and can be used for in vivo efficacy studies. We provide two well-characterized chemical tools to the biomedical community.
- Published
- 2019
22. Study of Ras/MAPK pathway gene variants in Chilean patients with Cryptorchidism
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M. T. López, K. Arcos, Nancy Unanue, Carla Vallejos, Diana Ponce, S. Célis, Maria Isabel Hernandez, Fernando Rodríguez, F. Belmar, and Fernando Cassorla
- Subjects
Male ,Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,MAPK/ERK pathway ,Adolescent ,Urology ,Endocrinology, Diabetes and Metabolism ,MAP Kinase Kinase 2 ,MAP2K2 ,030105 genetics & heredity ,Biology ,GTP Phosphohydrolases ,03 medical and health sciences ,Endocrinology ,Cryptorchidism ,Genetic variation ,Humans ,Missense mutation ,Chile ,Child ,Gene ,Genetic Variation ,Infant ,Membrane Proteins ,030104 developmental biology ,Reproductive Medicine ,Child, Preschool ,ras Proteins ,SOS1 ,Cancer research ,Mitogen-Activated Protein Kinases ,SOS1 Protein ,Synonymous substitution ,Signal Transduction - Abstract
Cryptorchidism is one of the most common congenital disorders in boys, and several genetic, hormonal, and environmental factors have been proposed as possible causes for this genitourinary defect. Genetic factors have been intensively searched, but relatively few pathogenic variants have been described. Cryptorchidism is a frequent finding in patients with RASopathies, a group of syndrome caused by mutations in genes of the Ras/MAPK pathway. Our aim was to determine whether patients with isolated cryptorchidism (IC) exhibit Ras/MAPK pathway gene variants associated with RASopathies. Two hundred thirty-nine patients with IC were recruited after orchidopexy. Determination of Ras/MAPK pathway gene variants was performed by high-resolution melting (HRM) analysis followed by sequencing. Restriction or allele-specific amplification assay was applied to (i) variant confirmation; (ii) search in healthy controls; and (iii) segregation analysis. Controls correspond to 100 healthy Chilean adults without a history of cryptorchidism. Molecular analysis showed one synonymous substitution (BRAF_p.Q456Q) in two patients and four missense substitutions (SOS1_ p.R497Q, BRAF_ p.F595L, NRAS_ p.T50I, and MAP2K2_ p.Y134C) in five patients. Our results suggest that some patients with isolated cryptorchidism, but with no evidence of dysmorphic features suggestive of RASopathies, may harbor Ras/MAPK pathway gene alterations.
- Published
- 2018
23. 19p13.3 Aberrations Are Associated with Dysmorphic Features and Deviant Psychomotor Development.
- Author
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Siggberg, L., Olsén, P., Näntö-Salonen, K., and Knuutila, S.
- Subjects
- *
PHENOTYPES , *CHROMOSOMES , *GENETIC recombination , *GENOMICS ,DIAGNOSIS of developmental disabilities - Abstract
Here, we describe 2 patients with de novo genomic imbalances of 19p13.3. Using high-resolution microarray analysis, we detected a 1.25-Mb deletion in one patient and a 0.81- Mb duplication in another. The resulting phenotypes are quite different; one is a 2-year-old boy with macrocephaly and normal growth, while the other is a 9-year-old boy with microcephaly and growth retardation since birth. Both have dysmorphic features and psychomotor developmental delay. This report gives evidence of the effect of small aberrations of chromosome 19 and describes the phenotypes arising from a duplication and deletion of the same location at 19p13.3. Copyright © 2010 S. Karger AG, Basel [ABSTRACT FROM AUTHOR]
- Published
- 2010
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24. Extended-spectrum antiprotozoal bumped kinase inhibitors: A review
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Andrew Hemphill, Dustin J. Maly, Ethan A. Merritt, Marilyn Parsons, Audrey O.T. Lau, Daniel K. Howe, Ryan Choi, Samuel L.M. Arnold, Erkang Fan, Michael W. Riggs, Robert H. Mealey, Kayode K. Ojo, Matthew A. Hulverson, J. Stone Doggett, and Wesley C. Van Voorhis
- Subjects
0301 basic medicine ,Pyridines ,medicine.drug_class ,Immunology ,Antiprotozoal Agents ,MAP2K2 ,Biology ,Article ,Apicomplexa ,03 medical and health sciences ,medicine ,Animals ,Humans ,Protein phosphorylation ,Protein kinase A ,Protein Kinase Inhibitors ,Protozoan Infections ,Kinase ,Imidazoles ,General Medicine ,Protein-Tyrosine Kinases ,biology.organism_classification ,3. Good health ,Cell biology ,030104 developmental biology ,Infectious Diseases ,Biochemistry ,Antiprotozoal ,Benzimidazoles ,Parasitology ,Parasite protein ,Function (biology) - Abstract
Many life-cycle processes in parasites are regulated by protein phosphorylation. Hence, disruption of essential protein kinase function has been explored for therapy of parasitic diseases. However, the difficulty of inhibiting parasite protein kinases to the exclusion of host orthologues poses a practical challenge. A possible path around this difficulty is the use of bumped kinase inhibitors for targeting calcium dependent protein kinases that contain atypically small gatekeeper residues and are crucial for pathogenic apicomplexan parasites’ survival and proliferation. In this review, we review efficacy against the kinase target, the parasite growth in vitro, and in animal infection models, as well as the relevant pharmacokinetic and safety parameters of bumped-kinase inhibitors.
- Published
- 2017
25. DNA Replication Dynamics and Cellular Responses to ATP Competitive CDC7 Kinase Inhibitors
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Huong Quachthithu, David C. A. Gaboriau, Corrado Santocanale, and Michael D. Rainey
- Subjects
DNA Replication ,0301 basic medicine ,DNA replication initiation ,MAPK7 ,Breast Neoplasms ,Pyrimidinones ,MAP2K2 ,Protein Serine-Threonine Kinases ,Biology ,Binding, Competitive ,Biochemistry ,03 medical and health sciences ,Adenosine Triphosphate ,Cell Line, Tumor ,Humans ,Pyrroles ,Phosphorylation ,Kinase activity ,Piperidones ,Cell Proliferation ,MAPK14 ,Cyclin-dependent kinase 1 ,Kinase ,Cell Cycle ,Cyclin-dependent kinase 3 ,General Medicine ,030104 developmental biology ,Molecular Medicine ,Female - Abstract
The CDC7 kinase, by phosphorylating the MCM DNA helicase, is a key switch for DNA replication initiation. ATP competitive CDC7 inhibitors are being developed as potential anticancer agents; however how human cells respond to the selective pharmacological inhibition of this kinase is controversial and not understood. Here we have characterized the mode of action of the two widely used CDC7 inhibitors, PHA-767491 and XL-413, which have become important tool compounds to explore the kinase's cellular functions. We have used a chemical genetics approach to further characterize pharmacological CDC7 inhibition and CRISPR/CAS9 technology to assess the requirement for kinase activity for cell proliferation. We show that, in human breast cells, CDC7 is essential and that CDC7 kinase activity is formally required for proliferation. However, full and sustained inhibition of the kinase, which is required to block the cell-cycle progression with ATP competitor compounds, is problematic to achieve. We establish that MCM2 phosphorylation is highly sensitive to CDC7 inhibition and, as a biomarker, it lacks in dynamic range since it is easily lost at concentrations of inhibitors that only mildly affect DNA synthesis. Furthermore, we find that the cellular effects of selective CDC7 inhibitors can be altered by the concomitant inhibition of cell-cycle and transcriptional CDKs. This work shows that DNA replication and cell proliferation can occur with reduced CDC7 activity for at least 5 days and that the bulk of DNA synthesis is not tightly coupled to MCM2 phosphorylation and provides guidance for the development of next generation CDC7 inhibitors.
- Published
- 2017
26. Kinase Inhibitor Indole Derivatives as Anticancer Agents: A Patent Review
- Author
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Vijay Singh, Rahul V. Patel, Anuj K. Rathi, Riyaz Syed, and Han-Seung Shin
- Subjects
0301 basic medicine ,Cancer Research ,Indoles ,MAPK7 ,Aurora inhibitor ,Antineoplastic Agents ,MAP2K2 ,01 natural sciences ,Receptor tyrosine kinase ,Patents as Topic ,03 medical and health sciences ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Pharmacology (medical) ,Protein Kinase Inhibitors ,biology ,010405 organic chemistry ,Kinase ,General Medicine ,Protein kinase R ,0104 chemical sciences ,030104 developmental biology ,Oncology ,Biochemistry ,biology.protein ,Janus kinase ,Tyrosine kinase - Abstract
Cancer accounts for a number of deaths each year. Consequently, prevention of this deadly disease is more challenging and hence the invention of new anticancer agents is of utmost importance. The current review elaborates the importance of indole designs as patented in the form of anticancer druglike molecules targeting different cites of biological arena. Specific attention was given to kinases such as platelet-derived growth factor receptor, vascular endothelial growth factor receptor and fibroblast growth factor receptor, Bruton's tyrosine kinase, anaplastic lymphoma kinase, Janus kinase, cyclin-dependent kinase aurora kinases A, B and C, checkpoint kinases, protein kinase R, Pim kinases, phosphoinositide 3- kinase, altered proteins kinases, polo-like kinase and many more. Moreover, the article summarizes the mode of action through the particular functions of kinases and the inhibitory potential of indole derivatives toward specific kinase. Certain patents gathered in the existing review article suggest that indole core can be a versatile foundation to discover drug-like kinase inhibitor molecules and modification of substituents existing on the indole moiety may have important impact on the pharmacokinetic and pharmacodynamics aspects of the resultant scaffolds. The information presented here would gather a great deal of interest to identify the new molecular designs bearing indole nucleus presenting novel anticancer drugs with a wide variety of biological targets involved in cancer pathology focusing on the inhibition of tyrosine kinases, serine/threonine-specific protein kinases, cyclin-dependent kinases, lipid kinases and altered protein kinases.
- Published
- 2017
27. Concurrent occurrence of an inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving MAP2K2 in a patient with developmental delay, distinctive facial features, and lambdoid synostosis
- Author
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Kazunori Arita, Toshiyuki Yamamoto, Nayuta Higa, Keiko Shimojima, Nozomi Sano, Tatsuki Oyoshi, Hisashi Tsuru, Hiroshi Tokimura, Mayumi Matsufuji, and Yumiko Ondo
- Subjects
Heart Defects, Congenital ,0301 basic medicine ,Pathology ,medicine.medical_specialty ,Prominent forehead ,Developmental Disabilities ,Karyotype ,MAP Kinase Kinase 2 ,MAP2K2 ,030105 genetics & heredity ,Biology ,Craniosynostosis ,Craniosynostoses ,03 medical and health sciences ,Ectodermal Dysplasia ,Chromosome Duplication ,Female patient ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,In patient ,Genetics (clinical) ,Facies ,Infant ,General Medicine ,Synostosis ,medicine.disease ,Failure to Thrive ,Phenotype ,Palpebral fissure ,Mutation ,Female ,CFC SYNDROME ,Chromosomes, Human, Pair 19 ,Chromosomes, Human, Pair 16 - Abstract
A female patient presented with developmental delay, distinctive facial features, and congenital anomalies, including a heart defect and premature lambdoid synostosis. The patient showed a paternally inherited 16p13.11 microduplication and a de novo 19p13.3 microdeletion involving the mitogen-activated protein kinase kinase 2 gene (MAP2K2), in which mutations cause the cardio-facio-cutaneous (CFC) syndrome. Reports of patients with overlapping 19p13.3 microdeletions of this region describe similar clinical manifestations including distinctive facial features: prominent forehead, horizontal/down-slanting palpebral fissures, long midface, pointed chin/angular jaw, sparse eyebrows, and underdeveloped cheekbones. Some of these findings overlapped to that of the patients with 16p13.11 microduplications and CFC syndrome. Although craniosynostosis was occasionally observed in patients with dominant-negative mutations in RAS/MAP kinase signaling genes (RASopathies) related to CFC syndrome, it was also reported in two patients with 16p13.11 microduplications. Genetic contributions of both chromosomal aberrations were discussed.
- Published
- 2016
28. Efficacy of MEK inhibition in patients with histiocytic neoplasms
- Author
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Neal Rosen, Ahmet Dogan, Hana Cho, Robert J. Young, Lynn A. Brody, Raajit K. Rampal, Alexia Iasonos, Mario E. Lacouture, Gary A. Ulaner, David M. Hyman, Neval Ozkaya, Esther Drill, Justin Buthorn, Omar Abdel-Wahab, Benjamin H. Durham, Lillian Bitner, Michelle Ki, Eli L. Diamond, and Jasmine H. Francis
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Histiocytic Disorders, Malignant ,Proto-Oncogene Proteins B-raf ,MAP Kinase Signaling System ,MAP Kinase Kinase 2 ,MAP Kinase Kinase 1 ,MAP2K2 ,medicine.disease_cause ,Article ,03 medical and health sciences ,chemistry.chemical_compound ,0302 clinical medicine ,Piperidines ,Medicine ,Humans ,Progression-free survival ,Cobimetinib ,Mitogen-Activated Protein Kinase Kinases ,Multidisciplinary ,business.industry ,medicine.disease ,Progression-Free Survival ,3. Good health ,Proto-Oncogene Proteins c-raf ,Histiocytosis ,030104 developmental biology ,chemistry ,030220 oncology & carcinogenesis ,Histiocytoses ,Mutation ,Cancer research ,Azetidines ,KRAS ,ARAF ,business - Abstract
Histiocytic neoplasms are a heterogeneous group of clonal haematopoietic disorders that are marked by diverse mutations in the mitogen-activated protein kinase (MAPK) pathway1,2. For the 50% of patients with histiocytosis who have BRAFV600 mutations3–5, RAF inhibition is highly efficacious and has markedly altered the natural history of the disease6,7. However, no standard therapy exists for the remaining 50% of patients who lack BRAFV600 mutations. Although ERK dependence has been hypothesized to be a consistent feature across histiocytic neoplasms, this remains clinically unproven and many of the kinase mutations that are found in patients who lack BRAFV600 mutations have not previously been biologically characterized. Here we show ERK dependency in histiocytoses through a proof-of-concept clinical trial of cobimetinib, an oral inhibitor of MEK1 and MEK2, in patients with histiocytoses. Patients were enrolled regardless of their tumour genotype. In parallel, MAPK alterations that were identified in treated patients were characterized for their ability to activate ERK. In the 18 patients that we treated, the overall response rate was 89% (90% confidence interval of 73–100). Responses were durable, with no acquired resistance to date. At one year, 100% of responses were ongoing and 94% of patients remained progression-free. Cobimetinib treatment was efficacious regardless of genotype, and responses were observed in patients with ARAF, BRAF, RAF1, NRAS, KRAS, MEK1 (also known as MAP2K1) and MEK2 (also known as MAP2K2) mutations. Consistent with the observed responses, the characterization of the mutations that we identified in these patients confirmed that the MAPK-pathway mutations were activating. Collectively, these data demonstrate that histiocytic neoplasms are characterized by a notable dependence on MAPK signalling—and that they are consequently responsive to MEK inhibition. These results extend the benefits of molecularly targeted therapy to the entire spectrum of patients with histiocytosis. A proof-of-concept clinical trial of patients with histiocytoses with MAPK-pathway mutations showed durable responses to treatment with the MEK1 and MEK2 inhibitor cobimetinib, which indicates that histiocytic neoplasms are dependent on MAPK signalling.
- Published
- 2018
29. Mixed – Lineage Protein kinases (MLKs) in inflammation, metabolism, and other disease states
- Author
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Michaella M. Reif, Siobhan M. Craige, and Shashi Kant
- Subjects
0301 basic medicine ,MAP Kinase Signaling System ,p38 mitogen-activated protein kinases ,MAP2K2 ,Biology ,MAP2K7 ,03 medical and health sciences ,Metabolic Diseases ,Stress, Physiological ,Neoplasms ,Animals ,Humans ,ASK1 ,Obesity ,Molecular Biology ,MAPK14 ,Inflammation ,Metabolic Syndrome ,MAP kinase kinase kinase ,Kinase ,Liver Diseases ,MAP Kinase Kinase Kinases ,Cell biology ,030104 developmental biology ,Cardiovascular Diseases ,Mitogen-activated protein kinase ,biology.protein ,Cytokines ,Molecular Medicine ,Insulin Resistance ,Nervous System Diseases - Abstract
Mixed lineage kinases, or MLKs, are members of the MAP kinase kinase kinase (MAP3K) family, which were originally identified among the activators of the major stress-dependent mitogen activated protein kinases (MAPKs), JNK and p38. During stress, the activation of JNK and p38 kinases targets several essential downstream substrates that react in a specific manner to the unique stressor and thus determine the fate of the cell in response to a particular challenge. Recently, the MLK family was identified as a specific modulator of JNK and p38 signaling in metabolic syndrome. Moreover, the MLK family of kinases appears to be involved in a very wide spectrum of disorders. This review discusses the newly identified functions of MLKs in multiple diseases including metabolic disorders, inflammation, cancer, and neurological diseases.
- Published
- 2016
30. Clinical Report: Cognitive decline in a patient with Cardiofaciocutaneous syndrome
- Author
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Maria Carmela Tartaglia, Sergio Cabrera, and Chantal F. Morel
- Subjects
Adult ,Heart Defects, Congenital ,Male ,Proto-Oncogene Proteins B-raf ,0301 basic medicine ,Baclofen ,Pediatrics ,medicine.medical_specialty ,MAP2K2 ,Cardiofaciocutaneous syndrome ,medicine.disease_cause ,03 medical and health sciences ,Ectodermal Dysplasia ,Genetics ,medicine ,Humans ,Cognitive Dysfunction ,Cognitive decline ,Genetics (clinical) ,Genetic testing ,medicine.diagnostic_test ,Genetic heterogeneity ,business.industry ,Brain ,Facies ,Cognition ,medicine.disease ,Failure to Thrive ,030104 developmental biology ,Failure to thrive ,KRAS ,medicine.symptom ,business - Abstract
Cardiofaciocutaneous Syndrome (CFCS) is a rare genetic syndrome caused by mutations in one of four genes: BRAF, MAP2K1, MAP2K2, and KRAS. There is tremendous phenotypic heterogeneity in patients with CFCS and so confirmation of diagnosis requires genetic testing. Neurologic and/or cognitive symptoms are present in almost all CFCS individuals. Little is known about cognitive function in older patients with CFCS. In this report, we present the cognitive, neuropsychiatric, and imaging findings of a patient diagnosed with CFCS who after having remained stable developed progressive cognitive/behavioral and motor decline.
- Published
- 2016
31. Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling
- Author
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Melania Parisi, Gabriella Fabbrocini, Maria Carmela Annunziata, Gabriella Esposito, Rosario Ammendola, Fabio Cattaneo, Annunziata, M. C., Parisi, M., Esposito, G., Fabbrocini, G., Ammendola, R., and Cattaneo, F.
- Subjects
FPR2 ,Cell signaling ,phospho-sites ,Amino Acid Motifs ,Phosphatase ,Review ,MAP2K2 ,Protein Serine-Threonine Kinases ,PPP1R14A ,Catalysis ,Receptor tyrosine kinase ,lcsh:Chemistry ,Inorganic Chemistry ,MARK2 ,Phosphoprotein Phosphatases ,Animals ,Humans ,Phospho-site ,PRP4 ,Phosphorylation ,Physical and Theoretical Chemistry ,Protein kinase A ,lcsh:QH301-705.5 ,Molecular Biology ,Spectroscopy ,PKN2 ,G protein-coupled receptor ,biology ,Chemistry ,Kinase ,Organic Chemistry ,STK10 ,Protein phosphatase 1 ,General Medicine ,Receptors, Formyl Peptide ,Computer Science Applications ,Cell biology ,lcsh:Biology (General) ,lcsh:QD1-999 ,PAK4 ,biology.protein ,Protein Processing, Post-Translational ,Signal Transduction - Abstract
FPR1, FPR2, and FPR3 are members of Formyl Peptides Receptors (FPRs) family belonging to the GPCR superfamily. FPR2 is a low affinity receptor for formyl peptides and it is considered the most promiscuous member of this family. Intracellular signaling cascades triggered by FPRs include the activation of different protein kinases and phosphatase, as well as tyrosine kinase receptors transactivation. Protein kinases and phosphatases act coordinately and any impairment of their activation or regulation represents one of the most common causes of several human diseases. Several phospho-sites has been identified in protein kinases and phosphatases, whose role may be to expand the repertoire of molecular mechanisms of regulation or may be necessary for fine-tuning of switch properties. We previously performed a phospho-proteomic analysis in FPR2-stimulated cells that revealed, among other things, not yet identified phospho-sites on six protein kinases and one protein phosphatase. Herein, we discuss on the selective phosphorylation of Serine/Threonine-protein kinase N2, Serine/Threonine-protein kinase PRP4 homolog, Serine/Threonine-protein kinase MARK2, Serine/Threonine-protein kinase PAK4, Serine/Threonine-protein kinase 10, Dual specificity mitogen-activated protein kinase kinase 2, and Protein phosphatase 1 regulatory subunit 14A, triggered by FPR2 stimulation. We also describe the putative FPR2-dependent signaling cascades upstream to these specific phospho-sites.
- Published
- 2020
32. C-type natriuretic peptide improves growth retardation in a mouse model of cardio-facio-cutaneous syndrome
- Author
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Hiroaki Maeda, Kazunori Yoshikiyo, Naomi Morozumi, Yoko Aoki, and Shin Ichi Inoue
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Heart Defects, Congenital ,Proto-Oncogene Proteins B-raf ,medicine.medical_specialty ,medicine.drug_class ,MAP Kinase Signaling System ,medicine.medical_treatment ,MAP Kinase Kinase 2 ,MAP Kinase Kinase 1 ,MAP2K2 ,Biology ,010402 general chemistry ,01 natural sciences ,03 medical and health sciences ,Mice ,Chondrocytes ,Ectodermal Dysplasia ,Internal medicine ,Genetics ,Extracellular ,Natriuretic peptide ,medicine ,Animals ,Humans ,Insulin-Like Growth Factor I ,Molecular Biology ,Genetics (clinical) ,Germ-Line Mutation ,Growth Disorders ,Mice, Inbred ICR ,Kinase ,Growth factor ,Facies ,Natriuretic Peptide, C-Type ,General Medicine ,Chondrogenesis ,Endochondral bone growth ,0104 chemical sciences ,Failure to Thrive ,Disease Models, Animal ,030104 developmental biology ,Endocrinology ,Mutation - Abstract
Cardio-facio-cutaneous (CFC) syndrome, a genetic disorder caused by germline mutations in BRAF, KRAS, MAP2K1 and MAP2K2, is characterized by growth retardation, heart defects, dysmorphic facial appearance and dermatologic abnormalities. We have previously reported that knock-in mice expressing the CFC syndrome-associated mutation, Braf Q241R, showed growth retardation because of gastrointestinal dysfunction. However, other factors associated with growth retardation, including chondrogenesis and endocrinological profile, have not been examined. Here, we show that 3- and 4-week-old BrafQ241R/+ mice have decreased body weight and length, as well as reduced growth plate width in the proximal tibiae. Furthermore, proliferative and hypertrophic chondrocyte zones of the growth plate were reduced in BrafQ241R/+ mice compared with Braf+/+ mice. Immunohistological analysis revealed that extracellular signal-regulated kinase (ERK) activation was enhanced in hypertrophic chondrocytes in BrafQ241R/+ mice. In accordance with growth retardation and reduced growth plate width, decreased serum levels of insulin-like growth factor 1 (IGF-1) and IGF binding protein 3 (IGFBP-3) were observed in BrafQ241R/+ mice at 3 and 4 weeks of age. Treatment with C-type natriuretic peptide (CNP), a stimulator of endochondral bone growth and a potent inhibitor of the FGFR3-RAF1-MEK/ERK signaling, increased body and tail lengths in Braf+/+ and BrafQ241R/+ mice. In conclusion, ERK activation in chondrocytes and low serum IGF-1/IGFBP-3 levels could be associated with the growth retardation observed in BrafQ241R/+ mice. Our data also suggest that CNP is a potential therapeutic target in CFC syndrome.
- Published
- 2018
33. Mek1 Y130C mice recapitulate aspects of the human Cardio-Facio-Cutaneous syndrome
- Author
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Louis Charron, Nicolas Houde, Kévin Jacquet, Nicolas Bisson, Benjamin D. Yu, Kim Landry-Truchon, Rifdat Aoidi, Jason M. Newbern, Suguna Rani Krishnaswami, Katherine A. Rauen, Jean Charron, and Michael C. Holter
- Subjects
0301 basic medicine ,MAPK/ERK pathway ,Neuroscience (miscellaneous) ,lcsh:Medicine ,Medicine (miscellaneous) ,Pulmonary artery stenosis ,MAP2K2 ,Gene mutation ,RASopathy ,Biology ,medicine.disease_cause ,General Biochemistry, Genetics and Molecular Biology ,Mouse model ,03 medical and health sciences ,0302 clinical medicine ,Germline mutation ,Immunology and Microbiology (miscellaneous) ,MAP2K1 ,lcsh:Pathology ,medicine ,Cardio-facio-cutaneous syndrome ,Neurological defects ,Mutation ,lcsh:R ,Wild type ,medicine.disease ,3. Good health ,030104 developmental biology ,MEK1 Y130C mutation ,Cancer research ,RAS/MAPK pathway ,030217 neurology & neurosurgery ,lcsh:RB1-214 ,Research Article - Abstract
The RAS/MAPK signaling pathway is one of the most investigated pathways, owing to its established role in numerous cellular processes and implication in cancer. Germline mutations in genes encoding members of the RAS/MAPK pathway also cause severe developmental syndromes collectively known as RASopathies. These syndromes share overlapping characteristics, including craniofacial dysmorphology, cardiac malformations, cutaneous abnormalities and developmental delay. Cardio-facio-cutaneous syndrome (CFC) is a rare RASopathy associated with mutations in BRAF, KRAS, MEK1 (MAP2K1) and MEK2 (MAP2K2). MEK1 and MEK2 mutations are found in ∼25% of the CFC patients and the MEK1Y130C substitution is the most common one. However, little is known about the origins and mechanisms responsible for the development of CFC. To our knowledge, no mouse model carrying RASopathy-linked Mek1 or Mek2 gene mutations has been reported. To investigate the molecular and developmental consequences of the Mek1Y130C mutation, we generated a mouse line carrying this mutation. Analysis of mice from a Mek1 allelic series revealed that the Mek1Y130C allele expresses both wild-type and Y130C mutant forms of MEK1. However, despite reduced levels of MEK1 protein and the lower abundance of MEK1 Y130C protein than wild type, Mek1Y130C mutants showed increased ERK (MAPK) protein activation in response to growth factors, supporting a role for MEK1 Y130C in hyperactivation of the RAS/MAPK pathway, leading to CFC. Mek1Y130C mutant mice exhibited pulmonary artery stenosis, cranial dysmorphia and neurological anomalies, including increased numbers of GFAP+ astrocytes and Olig2+ oligodendrocytes in regions of the cerebral cortex. These data indicate that the Mek1Y130C mutation recapitulates major aspects of CFC, providing a new animal model to investigate the physiopathology of this RASopathy. This article has an associated First Person interview with the first author of the paper., Summary: A mouse model for cardio-facio-cutaneous syndrome caused by MEK1 Y130C mutant protein reveals the role of hyperactivation of the RAS/MAPK pathway in the development of the syndrome.
- Published
- 2018
34. Development of a Toll-Like Receptor-Based Gene Signature That Can Predict Prognosis, Tumor Microenvironment, and Chemotherapy Response for Hepatocellular Carcinoma.
- Author
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Liu L, Liu B, Yu J, Zhang D, Shi J, and Liang P
- Abstract
Objective: Emerging evidence highlights the implications of the toll-like receptor (TLR) signaling pathway in the pathogenesis and therapeutic regimens of hepatocellular carcinoma (HCC). Herein, a prognostic TLR-based gene signature was conducted for HCC. Methods: HCC-specific TLRs were screened in the TCGA cohort. A LASSO model was constructed based on prognosis-related HCC-specific TLRs. The predictive efficacy, sensitivity, and independency of this signature was then evaluated and externally verified in the ICGC, GSE14520, and GSE76427 cohorts. The associations between this signature and tumor microenvironment (stromal/immune score, immune checkpoint expression, and immune cell infiltrations) and chemotherapy response were assessed in HCC specimens. The expression of TLRs in this signature was verified in HCC and normal liver tissues by Western blot. Following si-MAP2K2 transfection, colony formation and apoptosis of Huh7 and HepG2 cells were examined. Results: Herein, we identified 60 HCC-specific TLRs. A TLR-based gene signature (MAP2K2, IRAK1, RAC1, TRAF3, MAP3K7, and SPP1) was conducted for HCC prognosis. High-risk patients exhibited undesirable outcomes. ROC curves confirmed the well prediction performance of this signature. Multivariate Cox regression analysis demonstrated that the signature was an independent prognostic indicator. Also, high-risk HCC was characterized by an increased immune score, immune checkpoint expression, and immune cell infiltration. Meanwhile, high-risk patients displayed higher sensitivity to gemcitabine and cisplatin. The dysregulation of TLRs in the signature was confirmed in HCC. MAP2K2 knockdown weakened colony formation and elevated apoptosis of Huh7 and HepG2 cells. Conclusion: Collectively, this TLR-based gene signature might assist clinicians to select personalized therapy programs for HCC patients., Competing Interests: The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest., (Copyright © 2021 Liu, Liu, Yu, Zhang, Shi and Liang.)
- Published
- 2021
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35. The Kinase Activity-deficient Isoform of the Protein Araf Antagonizes Ras/Mitogen-activated Protein Kinase (Ras/MAPK) Signaling in the Zebrafish Embryo*
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Anming Meng, Xingfeng Liu, and Cong Xiong
- Subjects
MAPK/ERK pathway ,animal structures ,transcript variant ,embryo ,Embryonic Development ,MAP2K2 ,Biochemistry ,Araf ,Cell Line ,mesoderm ,Animals ,Humans ,c-Raf ,mitogen-activated protein kinase (MAPK) ,Kinase activity ,Molecular Biology ,patterning ,biology ,fungi ,Cell Biology ,zebrafish ,Molecular biology ,Cell biology ,Fibroblast Growth Factors ,Isoenzymes ,Proto-Oncogene Proteins c-raf ,Mitogen-activated protein kinase ,fibroblast growth factor (FGF) ,embryonic structures ,biology.protein ,ARAF ,Signal transduction ,Mitogen-Activated Protein Kinases ,Ras protein ,Developmental Biology ,Signal Transduction - Abstract
Background: The full-length Araf (Araf-tv1) inhibits Nodal/Smad2-induced mesendodermal induction in zebrafish embryos. Results: Araf-tv2, a kinase-deficient isoform of zebrafish Araf, can inhibit developmental functions of Fgf/Ras signaling. Conclusion: Araf-tv1 and Araf-tv2 regulate distinct signaling pathways in zebrafish embryos. Significance: The zebrafish araf gene is expressed to produce different variants with distinct functions during embryogenesis., Raf kinases are important components of the Ras-Raf-Mek-Erk pathway and also cross-talk with other signaling pathways. Araf kinase has been demonstrated to inhibit TGF-β/Smad2 signaling by directly phosphorylating and accelerating degradation of activated Smad2. In this study, we show that the araf gene expresses in zebrafish embryos to produce a shorter transcript variant, araf-tv2, in addition to the full-length variant araf-tv1. araf-tv2 is predicted to encode a C-terminally truncated peptide without the kinase activity domain. Araf-tv2 can physically associate with Araf-tv1 but does not antagonize the inhibitory effect of Araf-tv1 on TGF-β/Smad2 signaling. Instead, Araf-tv2 interacts strongly with Kras and Nras, ultimately blocking MAPK activation by these Ras proteins. In zebrafish embryos, overexpression of araf-tv2 is sufficient to inhibit Fgf/Ras-promoted Erk activation, mesodermal induction, dorsal development, and neuroectodermal posteriorization. Therefore, different isoforms of Araf may participate in similar developmental processes but by regulating different signaling pathways.
- Published
- 2015
36. Global analysis of specificity determinants in eukaryotic protein kinases
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Cristina Viéitez, Pedro Beltrao, Vinothini Rajeeve, David Bradley, and Pedro R. Cutillas
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Genetics ,Cell signaling ,Kinase Family ,Kinase ,Mutant ,Gene duplication ,MAP2K2 ,Biology ,Receptor ,SH3 domain - Abstract
Protein kinases lie at the heart of cell signalling processes, constitute one of the largest human domain families and are often mutated in disease. Kinase target recognition at the active site is in part determined by a few amino acids around the phosphoacceptor residue. These preferences vary across kinases and despite the increased knowledge of target substrates little is known about how most preferences are encoded in the kinase sequence and how these preferences evolve. Here, we used alignment-based approaches to identify 30 putative specificity determinant residues (SDRs) for 16 preferences. These were studied using structural models and were validated by activity assays of mutant kinases. Mutation data from patient cancer samples revealed that kinase specificity is often targeted in cancer to a greater extent than catalytic residues. Throughout evolution we observed that kinase specificity is strongly conserved across orthologs but can diverge after gene duplication as illustrated by the evolution of the G-protein coupled receptor kinase family. The identified SDRs can be used to predict kinase specificity from sequence and aid in the interpretation of evolutionary or disease-related genomic variants.
- Published
- 2017
37. A computational protocol to evaluate the effects of protein mutants in the kinase gatekeeper position on the binding of ATP substrate analogues
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Valentina Romano, Tjaart A. P. de Beer, and Torsten Schwede
- Subjects
Models, Molecular ,0301 basic medicine ,Plasma protein binding ,MAP2K2 ,Biology ,General Biochemistry, Genetics and Molecular Biology ,SH3 domain ,03 medical and health sciences ,chemistry.chemical_compound ,Adenosine Triphosphate ,Clinical Protocols ,Protein kinases ,Humans ,Tyrosine ,Binding site ,Computational protein modelling ,Medicine(all) ,chemistry.chemical_classification ,Binding Sites ,030102 biochemistry & molecular biology ,Biochemistry, Genetics and Molecular Biology(all) ,Kinase ,General Medicine ,Gatekeeper residue ,030104 developmental biology ,Enzyme ,Biochemistry ,chemistry ,Shokat’s method ,Mutation ,Adenosine triphosphate ,Research Article ,Protein Binding - Abstract
Background The determination of specific kinase substrates in vivo is challenging due to the large number of protein kinases in cells, their substrate specificity overlap, and the lack of highly specific inhibitors. In the late 90s, Shokat and coworkers developed a protein engineering-based method addressing the question of identification of substrates of protein kinases. The approach was based on the mutagenesis of the gatekeeper residue within the binding site of a protein kinase to change the co-substrate specificity from ATP to ATP analogues. One of the challenges in applying this method to other kinase systems is to identify the optimal combination of mutation in the enzyme and chemical derivative such that the ATP analogue acts as substrate for the engineered, but not the native kinase enzyme. In this study, we developed a computational protocol for estimating the effect of mutations at the gatekeeper position on the accessibility of ATP analogues within the binding site of engineered kinases. Results We tested the protocol on a dataset of tyrosine and serine/threonine protein kinases from the scientific literature where Shokat’s method was applied and experimental data were available. Our protocol correctly identified gatekeeper residues as the positions to mutate within the binding site of the studied kinase enzymes. Furthermore, the approach well reproduced the experimental data available in literature. Conclusions We have presented a computational protocol that scores how different mutations at the gatekeeper position influence the accommodation of various ATP analogues within the binding site of protein kinases. We have assessed our approach on protein kinases from the scientific literature and have verified the ability of the approach to well reproduce the available experimental data and identify suitable combinations of engineered kinases and ATP analogues.
- Published
- 2017
38. Glycogen Synthase Kinase 3
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Prital Patel and James R. Woodgett
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0301 basic medicine ,Kinase ,Cyclin-dependent kinase 2 ,MAP2K2 ,Biology ,MAP2K7 ,Cell biology ,03 medical and health sciences ,030104 developmental biology ,Biochemistry ,GSK-3 ,biology.protein ,ASK1 ,Signal transduction ,Glycogen synthase - Abstract
Glycogen synthase kinase-3 (GSK-3) is an unusual protein-serine kinase in that it is primarily regulated by inhibition and lies downstream of multiple cell signaling pathways. This raises a variety of questions in terms of its physiological role(s), how signaling specificity is maintained and why so many eggs have been placed into one basket. There are actually two baskets, as there are two isoforms, GSK-3α and β, that are highly related and largely redundant. Their many substrates range from regulators of cellular metabolism to molecules that control growth and differentiation. In this chapter, we review the characteristics of GSK-3, update progress in understanding the kinase, and try to answer some of the questions raised by its unusual properties. Indeed, the kinase may trigger transformation in our thinking of how cellular signals are organized and controlled.
- Published
- 2017
39. Bivalent inhibitors of protein kinases
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Carrie M. Gower, Dustin J. Maly, and Matthew E. K. Chang
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Models, Molecular ,Cell signaling ,Kinase ,MAPK7 ,Computational biology ,MAP2K2 ,Biology ,MAP3K7 ,Biochemistry ,Article ,SNAP-tag ,Adenosine Triphosphate ,Drug Discovery ,Animals ,Humans ,Kinase activity ,Protein kinase A ,Protein Kinase Inhibitors ,Protein Kinases ,Molecular Biology ,Signal Transduction - Abstract
Protein kinases are key players in a large number of cellular signaling pathways. Dysregulated kinase activity has been implicated in a number of diseases, and members of this enzyme family are of therapeutic interest. However, due to the fact that most inhibitors interact with the highly conserved ATP-binding sites of kinases, it is a significant challenge to develop pharmacological agents that target only one of the greater than 500 kinases present in humans. A potential solution to this problem is the development of bisubstrate and bivalent kinase inhibitors, in which an active site-directed moiety is tethered to another ligand that targets a location outside of the ATP-binding cleft. Because kinase signaling specificity is modulated by regions outside of the ATP-binding site, strategies that exploit these interactions have the potential to provide reagents with high target selectivity. This review highlights examples of kinase interaction sites that can potentially be exploited by bisubstrate and bivalent inhibitors. Furthermore, an overview of efforts to target these interactions with bisubstrate and bivalent inhibitors is provided. Finally, several examples of the successful application of these reagents in a cellular setting are described.
- Published
- 2014
40. Reprogramming protein kinase substrate specificity through synthetic mutations
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George M. Church, Joshua M. Lubner, Mike Chou, and Daniel Schwartz
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Genetics ,0303 health sciences ,Mutation ,DYRK1A ,Kinase ,Computational biology ,MAP2K2 ,Biology ,medicine.disease_cause ,MAP3K7 ,MAP3K8 ,03 medical and health sciences ,0302 clinical medicine ,medicine ,Peptide library ,Protein kinase A ,030217 neurology & neurosurgery ,030304 developmental biology - Abstract
Protein kinase specificity is largely imparted through substrate binding pocket motifs. Missense mutations in these regions are frequently associated with human disease, and in some cases can alter substrate specificity. However, current efforts at decoding the influence of mutations on substrate specificity have been focused on disease-associated mutations. Here, we adapted the Proteomic Peptide Library (ProPeL) approach for determining kinase specificity to the task of exploring structure-function relationships in kinase specificity by interrogating the effects of synthetic mutation. We established a specificity model for the wild-type DYRK1A kinase with unprecedented resolution. Using existing crystallographic and sequence homology data, we rationally designed mutations that precisely reprogrammed the DYRK1A kinase at the P+1 position to mimic the substrate preferences of a related kinase, CK II. This study illustrates a new synthetic biological approach to reprogram kinase specificity by design, and a powerful new paradigm to investigate structure-function relationships underpinning kinase substrate specificity.
- Published
- 2016
41. Targeting Catalytic and Non-Catalytic Functions of Protein Kinases
- Author
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Stefan Knapp and Susanne Müller
- Subjects
Atp competitive ,Kinase ,Kinase Family ,Structural plasticity ,Allosteric regulation ,Non catalytic ,MAP2K2 ,Biology ,SH3 domain ,Cell biology - Abstract
Protein kinases have developed into a major target family for the development of novel therapeutics. With currently more than 30 approved drugs and several hundred ongoing clinical studies, the kinase family has emerged as one of the most successful and established target families. The high degree of structural plasticity of the kinase catalytic domain revealed a multitude of diverse and sometimes target-specific cavities and binding modes, which has enabled the development of highly specific inhibitors. However, recent studies revealed additional essential non-catalytic functions of protein kinases usually associated with the kinase active state. Thus, allosteric kinase inhibitors that stabilize a variety of kinase inactive states modulating both catalytic as well as non-catalytic kinase functions, result in different cellular responses and clinical outcomes when compared with ATP competitive inhibitors that target the active state. These findings indicate that allosteric inhibitors could also be developed targeting scaffolding functions of catalytically inert pseudokinases that often play key roles in disease development. Here we review the main inhibitor classes that have been developed to date and the structural and functional consequences of their distinct binding modes to the kinase catalytic domain.
- Published
- 2016
42. Phosphorylation Sites in Protein Kinases and Phosphatases Regulated by Formyl Peptide Receptor 2 Signaling.
- Author
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Annunziata, Maria Carmela, Parisi, Melania, Esposito, Gabriella, Fabbrocini, Gabriella, Ammendola, Rosario, and Cattaneo, Fabio
- Subjects
- *
MITOGEN-activated protein kinase phosphatases , *PROTEIN kinases , *PHOSPHOPROTEIN phosphatases , *PEPTIDE receptors , *MITOGEN-activated protein kinases , *PROTEIN-tyrosine kinases , *PROTEIN-tyrosine phosphatase - Abstract
FPR1, FPR2, and FPR3 are members of Formyl Peptides Receptors (FPRs) family belonging to the GPCR superfamily. FPR2 is a low affinity receptor for formyl peptides and it is considered the most promiscuous member of this family. Intracellular signaling cascades triggered by FPRs include the activation of different protein kinases and phosphatase, as well as tyrosine kinase receptors transactivation. Protein kinases and phosphatases act coordinately and any impairment of their activation or regulation represents one of the most common causes of several human diseases. Several phospho-sites has been identified in protein kinases and phosphatases, whose role may be to expand the repertoire of molecular mechanisms of regulation or may be necessary for fine-tuning of switch properties. We previously performed a phospho-proteomic analysis in FPR2-stimulated cells that revealed, among other things, not yet identified phospho-sites on six protein kinases and one protein phosphatase. Herein, we discuss on the selective phosphorylation of Serine/Threonine-protein kinase N2, Serine/Threonine-protein kinase PRP4 homolog, Serine/Threonine-protein kinase MARK2, Serine/Threonine-protein kinase PAK4, Serine/Threonine-protein kinase 10, Dual specificity mitogen-activated protein kinase kinase 2, and Protein phosphatase 1 regulatory subunit 14A, triggered by FPR2 stimulation. We also describe the putative FPR2-dependent signaling cascades upstream to these specific phospho-sites. [ABSTRACT FROM AUTHOR]
- Published
- 2020
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43. Clinical Comparison of Overlapping Deletions of 19p13.3
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Jim Tepperberg, LaDonna Immken, David J. Amor, Stuart Schwartz, Virginia K. Proud, Peter Papenhausen, Joris Andrieux, Romela Pasion, Ghislaine Plessis, Tiong Yang Tan, Hiba Risheg, Elisabeth A. Keitges, and Stephanie Sacharow
- Subjects
Male ,Heart malformation ,Developmental Disabilities ,MAP2K2 ,Biology ,Polymorphism, Single Nucleotide ,Young Adult ,Intellectual Disability ,Genetics ,medicine ,Humans ,Abnormalities, Multiple ,Copy-number variation ,Child ,In Situ Hybridization, Fluorescence ,Genetics (clinical) ,Sequence Deletion ,Microarray analysis techniques ,Macrocephaly ,Microarray Analysis ,Phenotype ,Child, Preschool ,Female ,medicine.symptom ,Haploinsufficiency ,Chromosomes, Human, Pair 19 ,SNP array - Abstract
We present three patients with overlapping interstitial deletions of 19p13.3 identified by high resolution SNP microarray analysis. All three had a similar phenotype characterized by intellectual disability or developmental delay, structural heart abnormalities, large head relative to height and weight or macrocephaly, and minor facial anomalies. Deletion sizes ranged from 792 Kb to 1.0 Mb and included a common region arr [hg19] 19p13.3 (3,814,392–4,136,989), containing eight genes: ZFR2, ATCAY, NMRK2, DAPK3, EEF2, PIAS4, ZBTB7A, MAP2K2, and two non-coding RNA's MIR637 and SNORDU37. The patient phenotypes were compared with three previous single patient reports with similar interstitial 19p13.3 deletions and six additional patients from the DECIPHER and ISCA databases to determine if a common haploinsufficient phenotype for the region can be established. © 2013 Wiley Periodicals, Inc.
- Published
- 2013
44. Deletion ofMAP2K2/MEK2: a novel mechanism for a RASopathy?
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Julie Hoover-Fong, B. A. Thompson, Ute Moog, Gail E. Graham, S. M. Amudhavalli, R. E. Falk, Susan Zeesman, Denise A.S. Batista, Małgorzata J.M. Nowaczyk, Pedro A. Sanchez-Lara, Katherine A. Rauen, Susan M. White, and Pilar L. Magoulas
- Subjects
Genetics ,Pathology ,medicine.medical_specialty ,Heart malformation ,MAP2K2 ,RASopathy ,Biology ,medicine.disease_cause ,medicine.disease ,Phenotype ,Hypotonia ,Germline mutation ,medicine ,KRAS ,medicine.symptom ,Haploinsufficiency ,Genetics (clinical) - Abstract
RASopathies are a class of genetic syndromes caused by germline mutations in genes encoding Ras/mitogen-activated protein kinase (Ras/MAPK) pathway components. Cardio-facio-cutaneous (CFC) syndrome is a RASopathy characterized by distinctive craniofacial features, skin and hair abnormalities, and congenital heart defects caused by activating mutations of BRAF, MEK1, MEK2, and KRAS. We define the phenotype of seven patients with de novo deletions of chromosome 19p13.3 including MEK2; they present with a distinct phenotype but have overlapping features with CFC syndrome. Phenotypic features of all seven patients include tall forehead, thick nasal tip, underdeveloped cheekbones, long midface, sinuous upper vermilion border, tall chin, angular jaw, and facial asymmetry. Patients also have developmental delay, hypotonia, heart abnormalities, failure to thrive, obstructive sleep apnea, gastroesophageal reflux and integument abnormalities. Analysis of epidermal growth factor-stimulated fibroblasts revealed that P-MEK1/2 was ∼50% less abundant in cells carrying the MEK2 deletion compared to the control. Significant differences in total MEK2 and Sprouty1 abundance were also observed. Our cohort of seven individuals with MEK2 deletions has overlapping features associated with RASopathies. This is the first report suggesting that, in addition to activating mutations, MEK2 haploinsufficiency can lead to dysregulation of the MAPK pathway.
- Published
- 2013
45. Selective 3-Phosphoinositide-Dependent Kinase 1 (PDK1) Inhibitors: Dissecting the Function and Pharmacology of PDK1
- Author
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Jesus R. Medina
- Subjects
G protein-coupled receptor kinase ,animal structures ,Chemistry ,Kinase ,MAPK7 ,MAP2K2 ,Cell biology ,Biochemistry ,Drug Discovery ,Molecular Medicine ,ASK1 ,Protein kinase A ,Protein kinase B ,Phosphoinositide-dependent kinase-1 - Abstract
3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a protein target that has generated considerable interest in both academia and the pharmaceutical industry. PDK1 is responsible for regulating the activity of related kinases in the AGC kinase family, including AKT, by phosphorylating a specific threonine or serine residue within the activation loop which is critical for kinase activation. Many of the kinases activated by PDK1 regulate cellular process such as cell survival, differentiation, growth, and protein expression. Although significant work has been done to understand the role of PDK1 function in cells, recently discovered potent and selective small molecule PDK1 inhibitors are providing a unique opportunity to further dissect PDK1 function and predict the pharmacological consequences of PDK1 inhibition. This Miniperspective reviews the discovery of these selective PDK1 inhibitors and highlights their value in cellular studies, the understanding of PDK1 biology, and the impact on the therapeutic potential of PDK1 inhibition in cancer.
- Published
- 2013
46. 1p13.2 deletion displays clinical features overlapping Noonan syndrome, likely related to NRAS gene haploinsufficiency
- Author
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Heloísa B. Pena, Carlos A. Bacino, Sérgio D.J. Pena, Natália D. Linhares, Raony Guimaraes Corrêa Do Carmo Lisboa Cardenas, Bruno Delobel, Katherine Lachlan, Göran Annerén, Bruno Dallapiccola, Ann-Charlotte Thuresson, Paul A. James, and Maíra C.M. Freire
- Subjects
0301 basic medicine ,Neuroblastoma RAS viral oncogene homolog ,lcsh:QH426-470 ,Medicinska och farmaceutiska grundvetenskaper ,Hemizygosity ,MAP2K2 ,Biology ,RASopathy ,03 medical and health sciences ,Noonan syndrome type 6 ,Genetics ,medicine ,Molecular Biology ,Exome sequencing ,unmasking heterozygosity ,1p13.2 deletion ,Basic Medicine ,medicine.disease ,NRAS gene ,3. Good health ,PTPN11 ,lcsh:Genetics ,030104 developmental biology ,Special Series of Articles - 60 Years of The Brazilian Society of Genetics ,Noonan syndrome ,Haploinsufficiency - Abstract
Deletion-induced hemizygosity may unmask deleterious autosomal recessive variants and be a cause of the phenotypic variability observed in microdeletion syndromes. We performed complete exome sequencing (WES) analysis to examine this possibility in a patient with 1p13.2 microdeletion. Since the patient displayed clinical features suggestive of Noonan Syndrome (NS), we also used WES to rule out the presence of pathogenic variants in any of the genes associated with the different types of NS. We concluded that the clinical findings could be attributed solely to the 1p13.2 haploinsufficiency. Retrospective analysis of other nine reported patients with 1p13.2 microdeletions showed that six of them also presented some characteristics of NS. In all these cases, the deleted segment included the NRAS gene. Gain-of-function mutations of NRAS gene are causally related to NS type 6. Thus, it is conceivable that NRAS haploinsufficiency and gain-of-function mutations may have similar clinical consequences. The same phenomenon has been described for two other genes belonging to the Ras/MAPK pathway: MAP2K2 and SHOC2. In conclusion, we here report genotype-phenotype correlations in patients with chromosome 1p13.2 microdeletions and we propose that NRAS may be a critical gene for the NS characteristics in the patients.
- Published
- 2016
47. ARAF acts as a scaffold to stabilize BRAF:CRAF heterodimers
- Author
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Richard Marais and Ana Paula Rebocho
- Subjects
Proto-Oncogene Proteins B-raf ,MAPK/ERK pathway ,Cancer Research ,Cell signaling ,MAP Kinase Signaling System ,MAP2K2 ,Biology ,Cell Line, Tumor ,Neoplasms ,Genetics ,Humans ,Protein Isoforms ,Molecular Biology ,Kinase ,Cell biology ,Enzyme Activation ,Proto-Oncogene Proteins c-raf ,Cancer research ,raf Kinases ,Mitogen-Activated Protein Kinases ,Protein Multimerization ,ARAF ,Signal transduction ,Signal Transduction - Abstract
The RAF proteins are cytosolic protein kinases that regulate cell responses to extracellular signals. There are three RAF proteins in cells, ARAF, BRAF and CRAF, and recent studies have shown that the formation of complexes by these different isoforms has an important role in their activation, particularly in response to RAF inhibitors. Here, we investigated the role of ARAF in cancer cell signaling and examined the role of ARAF in mediating paradoxical activation of the MAPK pathway in cells treated with RAF inhibitors. We show that two mutations that occur in ARAF in cancer inactivate the kinase. We also show that ARAF is not functionally redundant with CRAF and cannot substitute for CRAF downstream of RAS. We further show that ARAF binds to and is activated by BRAF and that ARAF also forms complexes with CRAF. Critically, ARAF seems to stabilize BRAF:CRAF complexes in cells treated with RAF inhibitors and thereby regulate cell signaling in a subtle manner to ensure signaling efficiency.
- Published
- 2012
48. Evidence for elevated (LIMK2 and CFL1) and suppressed (ICAM1, EZR, MAP2K2, and NOS3) gene expressions in metabolic syndrome
- Author
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Serdar Oztuzcu, Elif Oguz, Hasan Dagli, Mesut Ozkaya, Abdullah T. Demiryürek, Seniz Demiryürek, Suzan Tabur, and Belgin Alasehirli
- Subjects
0301 basic medicine ,Adult ,Cofilin 1 ,Male ,medicine.medical_specialty ,Nitric Oxide Synthase Type III ,Endocrinology, Diabetes and Metabolism ,MAP Kinase Kinase 2 ,Down-Regulation ,Gene Expression ,MAP2K2 ,030204 cardiovascular system & hematology ,Biology ,Lim kinase ,03 medical and health sciences ,0302 clinical medicine ,Endocrinology ,Ezrin ,Internal medicine ,Gene expression ,medicine ,Humans ,Abdominal obesity ,Metabolic Syndrome ,Kinase ,Lim Kinases ,Middle Aged ,medicine.disease ,Intercellular Adhesion Molecule-1 ,Up-Regulation ,Cytoskeletal Proteins ,030104 developmental biology ,Female ,medicine.symptom ,Metabolic syndrome ,Dyslipidemia - Abstract
The metabolic syndrome (MetS) is a common multicomponent condition including abdominal obesity, dyslipidemia, hypertension, and hyperglycaemia. The aim of this study was to investigate the associations of the expression of a panel of signalling genes with the MetS in a Turkish population. A total of 54 MetS patients and 42 healthy controls with similar age and sex were included to this study. mRNA from blood samples was extracted, and real-time polymerase chain reaction was performed for gene expressions using a BioMark 96.96 dynamic array system. We observed marked increases in LIM kinase 2 (LIMK2) and cofilin 1 (CFL1) gene expressions in MetS patients. However, there were significant decreases in intercellular adhesion molecules 1 (ICAM1), ezrin (EZR), mitogen-activated protein kinase kinase 2 (MAP2K2), and nitric oxide synthase 3 (NOS3) gene expressions in MetS patients. Additionally, no marked changes were noted in other 15 genes studied. This is the first study to provide evidence that activation of LIMK2/CFL1 pathway may play an important role in MetS.
- Published
- 2015
49. The Evolution of Protein Kinase Inhibitors from Antagonists to Agonists of Cellular Signaling
- Author
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Arvin C. Dar and Kevan M. Shokat
- Subjects
Models, Molecular ,Protein Conformation ,Molecular Sequence Data ,MAPK7 ,MAP2K2 ,Biology ,Biochemistry ,Adenosine Triphosphate ,Neoplasms ,Drug Discovery ,Animals ,Humans ,Amino Acid Sequence ,Protein kinase A ,Protein Kinase Inhibitors ,MAPK14 ,G protein-coupled receptor kinase ,Binding Sites ,Molecular Structure ,Kinase ,Drug discovery ,Computational Biology ,Cell biology ,Mutation ,Signal transduction ,Protein Kinases ,Sequence Alignment ,Signal Transduction - Abstract
Kinases are highly regulated enzymes with diverse mechanisms controlling their catalytic output. Over time, chemical discovery efforts for kinases have produced ATP-competitive compounds, allosteric regulators, irreversible binders, and highly specific inhibitors. These distinct classes of small molecules have revealed many novel aspects about kinase-mediated signaling, and some have progressed from simple tool compounds into clinically validated therapeutics. This review explores several small-molecule inhibitors for kinases highlighting elaborate mechanisms by which kinase function is modulated. A complete surprise of targeted kinase drug discovery has been the finding of ATP-competitive inhibitors that behave as agonists, rather than antagonists, of their direct kinase target. These studies hint at a connection between ATP-binding site occupancy and networks of communication that are independent of kinase catalysis. Indeed, kinase inhibitors that induce changes in protein localization, protein-protein interactions, and even enhancement of catalytic activity of the target kinase have been found. The relevance of these findings to the therapeutic efficacy of kinase inhibitors and to the future identification of new classes of drug targets is discussed.
- Published
- 2011
50. Manipulation of kinase signaling by bacterial pathogens
- Author
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Kim Orth, Anne Marie Krachler, and Andrew R. Woolery
- Subjects
0303 health sciences ,Bacteria ,030306 microbiology ,Effector ,Kinase ,Reviews ,Cell Biology ,MAP2K2 ,Review ,Biology ,Cell biology ,03 medical and health sciences ,Humans ,ASK1 ,Signal transduction ,Protein kinase A ,Protein kinase B ,Protein Kinases ,PI3K/AKT/mTOR pathway ,030304 developmental biology ,Signal Transduction - Abstract
Bacterial pathogens use effector proteins to manipulate their hosts to propagate infection. These effectors divert host cell signaling pathways to the benefit of the pathogen and frequently target kinase signaling cascades. Notable pathways that are usurped include the nuclear factor κB (NF-κB), mitogen-activated protein kinase (MAPK), phosphatidylinositol 3-kinase (PI3K)/Akt, and p21-activated kinase (PAK) pathways. Analyzing the functions of pathogenic effectors and their intersection with host kinase pathways has provided interesting insights into both the mechanisms of virulence and eukaryotic signaling.
- Published
- 2011
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