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Glomerular epithelial protein-1 (Glepp1), a R3 subtype family of receptor-type protein tyrosine phosphatases, plays important role in the activation of Src family kinases and regulates cellular processes such as cell proliferation, differentiation, and apoptosis. In this study, we firstly examined the functional evaluation of Glepp1 in tooth development and morphogenesis. The precise expression level and developmental function of Glepp1 were examined by RT-qPCR, in situ hybridization, and loss and gain of functional study using a range of in vitro organ cultivation methods. Expression of Glepp1 was detected in the developing tooth germs in cap and bell stage of tooth development. Knocking down Glepp1 at E13 for 2 days showed the altered expression levels of tooth development-related signaling molecules, including Bmps, Dspp, Fgf4, Lef1, and Shh. Moreover, transient knock down of Glepp1 revealed alterations in cellular physiology, examined by the localization patterns of Ki67 and E-cadherin. Similarly, knocking down of Glepp1 showed disrupted enamel rod and interrod formation in 3-week renal transplanted teeth. In addition, due to attrition of odontoblastic layers, the expression signals of Dspp and the localization of NESTIN were almost not detected after knock down of Glepp1; however, their expressions were increased after Glepp1 overexpression. Thus, our results suggested that Glepp1 plays modulating roles during odontogenesis by regulating the expression levels of signaling molecules and cellular events to achieve the proper structural formation of hard tissue matrices in mice molar development. [ABSTRACT FROM AUTHOR]

Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway that eliminates substrate proteins through heat‐shock cognate protein 70 recognition and lysosome‐associated membrane protein type 2A‐assisted translocation. It is distinct from macroautophagy and microautophagy. In recent years, the regulatory mechanisms of CMA have been gradually enriched, including the newly discovered NRF2 and p38–TFEB signaling, as positive and negative regulatory pathways of CMA, respectively. Normal CMA activity is involved in the regulation of metabolism, aging, immunity, cell cycle, and other physiological processes, while CMA dysfunction may be involved in the occurrence of neurodegenerative disorders, tumors, intestinal disorders, atherosclerosis, and so on, which provides potential targets for the treatment and prediction of related diseases. This article describes the general process of CMA and its role in physiological activities and summarizes the connection between CMA and macroautophagy. In addition, human diseases that concern the dysfunction or protective role of CMA are discussed. Our review deepens the understanding of the mechanisms and physiological functions of CMA and provides a summary of past CMA research and a vision of future directions. [ABSTRACT FROM AUTHOR]

Cholesterol, as an important component in mammalian cells, is efficient for viral entry, replication, and assembly. Oxysterols especially hydroxylated cholesterols are recognized as novel regulators of the innate immune response. The antiviral ability of 25HC (25-Hydroxycholesterol) is uncovered due to its role as a metabolic product of the interferon-stimulated gene CH25H (cholesterol-25-hydroxylase). With the advancement of research, the biological functions of 25HC and its structural functions have been interpreted gradually. Furthermore, the underlying mechanisms of antiviral effect of 25HC are not only limited to interferon regulation. Taken up by the special biosynthetic ways and structure, 25HC contributes to modulate not only the cholesterol metabolism but also autophagy and inflammation by regulating signaling pathways. The outcome of modulation by 25HC seems to be largely dependent on the cell types, viruses and context of cell microenvironments. In this paper, we review the recent proceedings on the regulatory effect of 25HC on interferon-independent signaling pathways related to its antiviral capacity and its putative underlying mechanisms. [ABSTRACT FROM AUTHOR]

Abstract Chaperone‐mediated autophagy (CMA) is a lysosomal degradation pathway that eliminates substrate proteins through heat‐shock cognate protein 70 recognition and lysosome‐associated membrane protein type 2A‐assisted translocation. It is distinct from macroautophagy and microautophagy. In recent years, the regulatory mechanisms of CMA have been gradually enriched, including the newly discovered NRF2 and p38–TFEB signaling, as positive and negative regulatory pathways of CMA, respectively. Normal CMA activity is involved in the regulation of metabolism, aging, immunity, cell cycle, and other physiological processes, while CMA dysfunction may be involved in the occurrence of neurodegenerative disorders, tumors, intestinal disorders, atherosclerosis, and so on, which provides potential targets for the treatment and prediction of related diseases. This article describes the general process of CMA and its role in physiological activities and summarizes the connection between CMA and macroautophagy. In addition, human diseases that concern the dysfunction or protective role of CMA are discussed. Our review deepens the understanding of the mechanisms and physiological functions of CMA and provides a summary of past CMA research and a vision of future directions.

To understand the mechanisms underlying tooth morphogenesis, we examined the developmental roles of important posttranslational modification, O‐GlcNAcylation, which regulates protein stability and activity by the addition and removal of a single sugar (O‐GlcNAc) to the serine or threonine residue of the intracellular proteins. Tissue and developmental stage‐specific immunostaining results against O‐GlcNAc and O‐GlcNAc transferase (OGT) in developing tooth germs would suggest that O‐GlcNAcylation is involved in tooth morphogenesis, particularly in the cap and secretory stage. To evaluate the developmental function of OGT‐mediated O‐GlcNAcylation, we employed an in vitro tooth germ culture method at E14.5, cap stage before secretory stage, for 1 and 2 days, with or without OSMI‐1, a small molecule OGT inhibitor. To examine the mineralization levels and morphological changes, we performed renal capsule transplantation for one and three weeks after 2 days of in vitro culture at E14.5 with OSMI‐1 treatment. After OGT inhibition, morphological and molecular alterations were examined using histology, immunohistochemistry, real‐time quantitative polymerase chain reaction, in situ hybridization, scanning electron microscopy, and ground sectioning. Overall, inhibition of OGT resulted in altered cellular physiology, including proliferation, apoptosis, and epithelial rearrangements, with significant changes in the expression patterns of β‐catenin, fibroblast growth factor 4 (fgf4), and sonic hedgehog (Shh). Moreover, renal capsule transplantation and immunolocalizations of Amelogenin and Nestin results revealed that OGT‐inhibited tooth germs at cap stage exhibited with structural changes in cuspal morphogenesis, amelogenesis, and dentinogenesis of the mineralized tooth. Overall, we suggest that OGT‐mediated O‐GlcNAcylation regulates cell signaling and physiology in primary enamel knot during tooth development, thus playing an important role in mouse molar morphogenesis. [ABSTRACT FROM AUTHOR]

Abstract Orthodontic tooth movement relies on bone remodeling and periodontal tissue regeneration in response to the complicated mechanical cues on the compressive and tensive side. In general, mechanical stimulus regulates the expression of mechano-sensitive coding and non-coding genes, which in turn affects how cells are involved in bone remodeling. Growing numbers of non-coding RNAs, particularly mechano-sensitive non-coding RNA, have been verified to be essential for the regulation of osteogenesis and osteoclastogenesis and have revealed how they interact with signaling molecules to do so. This review summarizes recent findings of non-coding RNAs, including microRNAs and long non-coding RNAs, as crucial regulators of gene expression responding to mechanical stimulation, and outlines their roles in bone deposition and resorption. We focused on multiple mechano-sensitive miRNAs such as miR-21, - 29, -34, -103, -494-3p, -1246, -138-5p, -503-5p, and -3198 that play a critical role in osteogenesis function and bone resorption. The emerging roles of force-dependent regulation of lncRNAs in bone remodeling are also discussed extensively. We summarized mechano-sensitive lncRNA XIST, H19, and MALAT1 along with other lncRNAs involved in osteogenesis and osteoclastogenesis. Ultimately, we look forward to the prospects of the novel application of non-coding RNAs as potential therapeutics for tooth movement and periodontal tissue regeneration.

Tea domain transcription factor 4 (TEAD4) plays a pivotal role in tissue development and homeostasis by interacting with Yes-associated protein (YAP) in response to Hippo signaling inactivation. TEAD4 and YAP can also cooperate with transforming growth factor-β (TGF-β)-activated Smad proteins to regulate gene transcription. Yet, it remains unclear whether TEAD4 plays a YAP-independent role in TGF-β signaling. Here, we unveil a novel tumor suppressive function of TEAD4 in liver cancer via mitigating TGF-β signaling. Ectopic TEAD4 inhibited TGF-β-induced signal transduction, Smad transcriptional activity, and target gene transcription, consequently suppressing hepatocellular carcinoma cell proliferation and migration in vitro and xenograft tumor growth in mice. Consistently, depletion of endogenous TEAD4 by siRNAs enhanced TGF-β signaling in cancer cells. Mechanistically, TEAD4 associates with receptor-regulated Smads (Smad2/3) and Smad4 in the nucleus, thereby impairing the binding of Smad2/3 to the histone acetyltransferase p300. Intriguingly, these negative effects of TEAD4 on TGF-β/Smad signaling are independent of YAP, as impairing the TEAD4–YAP interaction through point mutagenesis or depletion of YAP and/or its paralog TAZ has little effect. Together, these results unravel a novel function of TEAD4 in fine tuning TGF-β signaling and liver cancer progression in a YAP-independent manner. [ABSTRACT FROM AUTHOR]

Orthodontic tooth movement relies on bone remodeling and periodontal tissue regeneration in response to the complicated mechanical cues on the compressive and tensive side. In general, mechanical stimulus regulates the expression of mechano-sensitive coding and non-coding genes, which in turn affects how cells are involved in bone remodeling. Growing numbers of non-coding RNAs, particularly mechano-sensitive non-coding RNA, have been verified to be essential for the regulation of osteogenesis and osteoclastogenesis and have revealed how they interact with signaling molecules to do so. This review summarizes recent findings of non-coding RNAs, including microRNAs and long non-coding RNAs, as crucial regulators of gene expression responding to mechanical stimulation, and outlines their roles in bone deposition and resorption. We focused on multiple mechano-sensitive miRNAs such as miR-21, - 29, -34, -103, -494-3p, -1246, -138-5p, -503-5p, and -3198 that play a critical role in osteogenesis function and bone resorption. The emerging roles of force-dependent regulation of lncRNAs in bone remodeling are also discussed extensively. We summarized mechano-sensitive lncRNA XIST, H19, and MALAT1 along with other lncRNAs involved in osteogenesis and osteoclastogenesis. Ultimately, we look forward to the prospects of the novel application of non-coding RNAs as potential therapeutics for tooth movement and periodontal tissue regeneration. [ABSTRACT FROM AUTHOR]

Protein kinase A (PKA) is a conserved kinase crucial for fundamental biological processes linked to growth, development, and metabolism. The PKA catalytic subunit is expressed as multiple isoforms in diverse eukaryotes; however, their contribution to ensuring signaling specificity in response to environmental cues remains poorly defined. Catalytic subunit activity is classically moderated via interaction with an inhibitory regulatory subunit. Here, a quantitative mass spectrometry approach is used to examine heat-stress-induced changes in the binding of yeast Tpk1–3 catalytic subunits to the Bcy1 regulatory subunit. We show that Tpk3 is not regulated by Bcy1 binding but, instead, is deactivated upon heat stress via reversible sequestration into cytoplasmic granules. These "Tpk3 granules" are enriched for multiple PKA substrates involved in various metabolic processes, with the Hsp42 sequestrase required for their formation. Hence, regulated sequestration of Tpk3 provides a mechanism to control isoform-specific kinase signaling activity during stress conditions. [Display omitted] • Regulation of PKA C subunits Tpk1–3 by the R subunit Bcy1 is isoform specific • Heat stress induces reversible Tpk3 sequestration and inactivation • The small heat shock protein Hsp42 is required for Tpk3 sequestration • Sequestration provides a non-canonical mechanism to fine-tune PKA signaling Creamer et al. show that a protein kinase A (PKA) catalytic isoform is sequestered into aggregates to regulate PKA kinase activity in response to heat stress. Reversible sequestration requires the Hsp42 chaperone, providing a mechanism to control a key cellular signaling pathway in a catalytic-isoform-specific manner. [ABSTRACT FROM AUTHOR]

Cellular trafficking through the endosomal–lysosomal system is essential for the transport of cargo proteins, receptors and lipids from the plasma membrane inside the cells and across membranous organelles. By acting as sorting stations, vesicle compartments direct the fate of their content for degradation, recycling to the membrane or transport to the trans-Golgi network. To effectively communicate with their neighbors, cells need to regulate their compartmentation and guide their signaling machineries to cortical membranes underlying these contact sites. Endosomal trafficking is indispensable for the polarized distribution of fate determinants, adaptors and junctional proteins. Conversely, endocytic machineries cooperate with polarity and scaffolding components to internalize receptors and target them to discrete membrane domains. Depending on the cell and tissue context, receptor endocytosis can terminate signaling responses but can also activate them within endosomes that act as signaling platforms. Therefore, cell homeostasis and responses to environmental cues rely on the dynamic cooperation of endosomal–lysosomal machineries with polarity and signaling cues. This review aims to address advances and emerging concepts on the cooperative regulation of endocytosis, polarity and signaling, primarily in Drosophila melanogaster and discuss some of the open questions across the different cell and tissue types that have not yet been fully explored. [ABSTRACT FROM AUTHOR]

G protein–coupled receptors (GPCRs) are a protein superfamily comprising >800 members that regulate numerous cellular and physiologic responses. GPCRs represent the largest class of therapeutic targets with implications in various diseases. Although advances in GPCR structural and pharmacological research have significantly improved our knowledge of GPCR signaling mechanisms, mapping diverse post-translational modifications (PTMs) of GPCR proteins and understanding their regulatory roles have received much less attention. Mass spectrometry-based proteomics has become the most popular technology for profiling protein PTMs in a systematic manner. Herein we provide an overview of PTM types, locations, crosstalk and dynamic regulation for different GPCRs that are characterized using proteomic and/or biochemical approaches. Our main focus is on glycosylation, phosphorylation, ubiquitination and palmitoylation that are known to modulate receptor folding, biosynthesis, trafficking, dimerization and signaling. Furthermore, we discuss the locations of specific PTM sites in the structure of a given GPCR and its signaling complex to highlight the importance of PTM regulation in the molecular basis of GPCRs, which may shed new light on structure-based drug discovery.

Aged nonhuman primate (NHP) models are of great value for studying the pathology of metabolic heart diseases and developing therapeutic strategies. In this study, aged male cynomolgus monkeys were fed a regular diet or a high-fat/high-sugar diet (HFSD) for 8 months. Metabolic disorders were diagnosed by 1H-NMR and serum biochemistry, and cardiac function was evaluated by echocardiography. Our results showed that serum metabolic profiles were altered in aged monkeys fed a HFSD, in line with aortic tissue damage, cardiac remodeling, and contractile dysfunction. This aged monkey model significantly increased expression of proinflammatory cytokines and altered expression and phosphorylation of intracellular signaling proteins in the heart, as compared to aged monkeys on a regular diet. Furthermore, the animals demonstrated increased phosphorylation of cardiac myofilament proteins which are causatively associated with decreased myofilament contractility. We conclude that the aged monkey model fed a HFSD exhibits metabolic disorders and cardiac contractile dysfunction. [ABSTRACT FROM AUTHOR]

Circumvallate papilla (CVP) is a distinctively structured with dome-shaped apex, and the surrounding trench which contains over two hundred taste buds on the lateral walls. Although CVP was extensively studied to determine the regulatory mechanisms during organogenesis, it still remains to be elucidated the principle mechanisms of signaling regulations on morphogenesis including taste buds formation. The key role of Yes-associated protein (YAP) in the regulation of organ size and cell proliferation in vertebrates is well understood, but little is known about the role of this signaling pathway in CVP development. We aimed to determine the putative roles of YAP signaling in the epithelial patterning during CVP morphogenesis. To evaluate the precise localization patterns of YAP and other related signaling molecules, including β-catenin, Ki67, cytokeratins, and PGP9.5, in CVP tissue, histology and immunohistochemistry were employed at E16 and adult mice. Our results suggested that there are specific localization patterns of YAP and Wnt signaling molecules in developing and adult CVP. These concrete localization patterns would provide putative involvements of YAP and Wnt signaling for proper epithelial cell differentiation including the formation and maintenance of taste buds. [ABSTRACT FROM AUTHOR]

Cellular trafficking through the endosomal–lysosomal system is essential for the transport of cargo proteins, receptors and lipids from the plasma membrane inside the cells and across membranous organelles. By acting as sorting stations, vesicle compartments direct the fate of their content for degradation, recycling to the membrane or transport to the trans-Golgi network. To effectively communicate with their neighbors, cells need to regulate their compartmentation and guide their signaling machineries to cortical membranes underlying these contact sites. Endosomal trafficking is indispensable for the polarized distribution of fate determinants, adaptors and junctional proteins. Conversely, endocytic machineries cooperate with polarity and scaffolding components to internalize receptors and target them to discrete membrane domains. Depending on the cell and tissue context, receptor endocytosis can terminate signaling responses but can also activate them within endosomes that act as signaling platforms. Therefore, cell homeostasis and responses to environmental cues rely on the dynamic cooperation of endosomal–lysosomal machineries with polarity and signaling cues. This review aims to address advances and emerging concepts on the cooperative regulation of endocytosis, polarity and signaling, primarily in Drosophila melanogaster and discuss some of the open questions across the different cell and tissue types that have not yet been fully explored.

The normal growth and regeneration of feathers is important for improving the welfare and economic value of poultry. Feather follicle stem cells are the basis for driving feather development and are regulated by various molecular signaling pathways in the feather follicle microenvironment. To date, the roles of the Wnt, Bone Morphogenetic Protein (BMP), Notch, and Sonic Hedgehog (SHH) signaling pathways in the regulation of feather growth and regeneration are among the best understood. While these pathways regulate feather morphogenesis in different stages, their dysregulation results in a low feather growth rate, poor quality of plumage, and depilation. Additionally, exogenous nutrient intervention can affect the feather follicle cycle, promote the formation of the feather shaft and feather branches, preventing plumage abnormalities. This review focuses on our understanding of the signaling pathways involved in the transcriptional control of feather morphogenesis and explores the impact of nutritional factors on feather growth and regeneration in poultry. This work may help to develop novel mechanisms by which follicle stem cells can be manipulated to produce superior plumage that enhances poultry carcass quality.

The normal growth and regeneration of feathers is important for improving the welfare and economic value of poultry. Feather follicle stem cells are the basis for driving feather development and are regulated by various molecular signaling pathways in the feather follicle microenvironment. To date, the roles of the Wnt, Bone Morphogenetic Protein (BMP), Notch, and Sonic Hedgehog (SHH) signaling pathways in the regulation of feather growth and regeneration are among the best understood. While these pathways regulate feather morphogenesis in different stages, their dysregulation results in a low feather growth rate, poor quality of plumage, and depilation. Additionally, exogenous nutrient intervention can affect the feather follicle cycle, promote the formation of the feather shaft and feather branches, preventing plumage abnormalities. This review focuses on our understanding of the signaling pathways involved in the transcriptional control of feather morphogenesis and explores the impact of nutritional factors on feather growth and regeneration in poultry. This work may help to develop novel mechanisms by which follicle stem cells can be manipulated to produce superior plumage that enhances poultry carcass quality. [ABSTRACT FROM AUTHOR]

Cholesterol, as an important component in mammalian cells, is efficient for viral entry, replication, and assembly. Oxysterols especially hydroxylated cholesterols are recognized as novel regulators of the innate immune response. The antiviral ability of 25HC (25-Hydroxycholesterol) is uncovered due to its role as a metabolic product of the interferon-stimulated gene CH25H (cholesterol-25-hydroxylase). With the advancement of research, the biological functions of 25HC and its structural functions have been interpreted gradually. Furthermore, the underlying mechanisms of antiviral effect of 25HC are not only limited to interferon regulation. Taken up by the special biosynthetic ways and structure, 25HC contributes to modulate not only the cholesterol metabolism but also autophagy and inflammation by regulating signaling pathways. The outcome of modulation by 25HC seems to be largely dependent on the cell types, viruses and context of cell microenvironments. In this paper, we review the recent proceedings on the regulatory effect of 25HC on interferon-independent signaling pathways related to its antiviral capacity and its putative underlying mechanisms., 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 © 2023 Zhang, Zhu, Wang and Wang.)

Evading TGF-β-mediated growth inhibition is often associated with tumorigenesis in liver, including hepatocellular carcinoma (HCC). To better understand the functions and the underlying molecular mechanisms of TGF-β in HCC initiation and progression, we carried out transcriptome sequencing (RNA-Seq) to identify the target genes of TGF-β. CXXC5, a member of the CXXC-type zinc finger domain-containing protein family, was identified as a novel TGF-β target gene in Hep3B HCC cells. Knockdown of CXXC5 attenuated the expression of a substantial portion of TGF-β target genes and ameliorated TGF-β-induced growth inhibition or apoptosis of Hep3B cells, suggesting that CXXC5 is required for TGF-β-mediated inhibition of HCC progression. Analysis of the TCGA database indicated that CXXC5 expression is reduced in the majority of HCC tissue samples in comparison to that in normal tissues. Furthermore, CXXC5 associates with the histone deacetylase HDAC1 and competes its interaction with Smad2/3, thereby abolishing the inhibitory effect of HDAC1 on TGF-β signaling. These observations together suggest that CXXC5 may act as a tumor suppressor by promoting TGF-β signaling via a positive feedback loop, and reveal a strategy for HCC to bypass TGF-β-mediated cytostasis by disrupting the positive feedback regulation. Our findings shed new light on TGF-β signaling regulation and demonstrate the function of CXXC5 in HCC development. [ABSTRACT FROM AUTHOR]

Brassinosteroids (BRs) play important roles in plant growth, development, and stress responses through the receptor, Brassinosteroid-insensitive 1 (BRI1), which perceives BRs and initiates BR signaling. There is considerable potential agricultural value in regulating BR signaling in crops. In this study, we investigated the effects of overexpressing the tomato (Solanum lycopersicum) BRI1 gene, SlBRI1, on major agronomic traits, such as seed germination, vegetative growth, fruit ethylene production, carotenoid accumulation, yield, and quality attributes. SlBRI1 overexpression enhanced the endogenous BR signaling intensity thereby increasing the seed germination rate, lateral root number, hypocotyl length, CO2 assimilation, plant height, and flower size. The transgenic plants also showed an increase in fruit yield and fruit number per plant, although the mean weight of individual fruit was reduced, compared with wild type. SlBRI1 overexpression also promoted fruit ripening and ethylene production, and caused an increase in levels of carotenoids, ascorbic acid, soluble solids, and soluble sugars during fruit ripening. An increased BR signaling intensity mediated by SlBRI1 overexpression was therefore positively correlated with carotenoid accumulation and fruit nutritional quality. Our results indicate that enhancing BR signaling by overexpression of SlBRI1 in tomato has the potential to improve multiple major agronomic traits.

The advent of high-throughput genomics techniques, along with the completion of genome sequencing projects, identification of protein--protein interactions and reconstruction of genome-scale pathways, has accelerated the development of systems biology research in the yeast organism Saccharomyces cerevisiae. In particular, discovery of biological pathways in yeast has become an important forefront in systems biology, which aims to understand the interactions among molecules within a cell leading to certain cellular processes in response to a specific environment. While the existing theoretical and experimental approaches enable the investigation of well-known pathways involved in metabolism, gene regulation and signal transduction, bioinformatics methods offer new insights into computational modeling of biological pathways. A wide range of computational approaches has been proposed in the past for reconstructing biological pathways from high-throughput datasets. Here we review selected bioinformatics approaches for modeling biological pathways in S. cerevisiae, including metabolic pathways, gene-regulatory pathways and signaling pathways. We start with reviewing the research on biological pathways followed by discussing key biological databases. In addition, several representative computational approaches for modeling biological pathways in yeast are discussed. [ABSTRACT FROM AUTHOR]

Teraspanin transmembrane protein, Perp (P53 apoptosis effector related to PMP22), which is found in the plasma membrane as a component of the desmosome, is reported to be involved in the morphogenesis of the epithelium and the enamel formation of the incisor. However, its expression pattern and signaling regulation during molar development have not been elucidated in detail. We have examined the precise expression patterns of Perp in developing lower molars and employed the knock-down of Perp by antisense oligodeoxynucleotide treatment during in vitro organ cultivation at embryonic day 13 to define the precise developmental function of Perp. Perp was expressed mainly in the dental lamina and stellate reticulum regions at the bud and cap stages. After Perp knock-down, the tooth germ showed disruption of the dental lamina and stellate reticulum with altered apoptosis and proliferation. The changed expression levels of related signaling molecules from the enamel knot and desmosome were evaluated by real-time quantitative polymerase chain reaction. A renal capsule transplantation method was employed to examine the effects of Perp knock-down on molar crown development. Ultrastructural observations revealed that enamel was deposited more densely in an irregular pattern in the cusp region, and that dentin was hypo-mineralized after Perp knock-down at the cap stage. Thus, Perp might play important roles in the formation and integration of stellate reticulum, dental lamina structure and enamel formation through signaling interactions with the enamel knot and desmosome-related signaling molecules at the cap stage of lower molar development. [ABSTRACT FROM AUTHOR]

Wnt/β-catenin signaling has a great and diverse influence on the formation, development, and vital activity of a great number of vertebrate tissues, including heart tissue. The role of Wnt/β-catenin signaling and β-catenin itself in the processes of cardiogenesis and adult myocardium functioning is not fully elucidated to date. The current review regards the attempt to generalize contemporary literature data on participation of this signaling pathway in embryogenesis and postnatal heart development, as well as in adult myocardium functioning in normal conditions and during stress adaptation, and aging, resulting in hypertrophy and heart remodeling. Based on the experimental articles and reviews, we can assume that Wnt/β-catenin signaling pathway is involved not only in controlling the cardiogenesis but also in processes of adaptation and remodeling of the adult organ. This control can be characterized as complicated and multistep and β-catenin appears to be a prospective candidate as a target for development of new approaches to adult myocardium pathologies therapy. [ABSTRACT FROM AUTHOR]

Abstract: mGlu7 receptors are coupled to Gi/Go-proteins and activate multiple transduction pathways, including inhibition of adenylyl cyclase activity and stimulation of ERK1/2 and JNK pathways. mGlu7 receptors play an important role in cognition and emotion and are involved in stress-related disorders such as anxiety and depression and in susceptibility to convulsive seizures. In spite of these potential clinical implications, little is known on the mechanisms that regulate mGlu7-receptor signaling. Here we show that mGlu7 receptor-dependent signaling pathways were regulated in a complementary manner by different GRK subtypes, with GRK4 affecting the adenylyl cyclase and the JNK pathways, and GRK2 selectively affecting the ERK1/2 pathway. Additionally we found that the two isoforms of non-visual arrestins, i.e. β-arrestin1 and β-arrestin2, exerted opposite effects on mGlu7-receptor signaling, with β-arrestin1 positively modulating ERK1/2 and inhibiting JNK, and β-arrestin2 doing the opposite. This represents a remarkable example of “reciprocal regulation” of receptor signaling by the two isoforms of β-arrestin. Finally we found that β-arrestin1 amplified mGlu7 receptor-dependent ERK1/2 activation in response to L-AP4 (an orthosteric agonist), but not in response to AMN082 (an atypical mGlu7-receptor allosteric agonist). The different effect of β-arrestin1 on L-AP4- and AMN082-stimulated ERK1/2 phosphorylation is in line with the emerging concept of β-arrestin-biased agonists. The present study may open new perspectives in elucidating the physio-pathological roles of the mGlu7 receptor and may provide new insights for the possibility to develop specific (biased) agonists that can selectively activate different signaling pathways. [Copyright &y& Elsevier]

The constitutive androstane receptor (CAR, NR1I3) plays a crucial role in the regulation of drug metabolism, energy homeostasis, and cancer development through modulating the transcription of its numerous target genes. Different from prototypical nuclear receptors, CAR can be activated by either direct ligand binding or ligand-independent (indirect) mechanisms both initiated with nuclear translocation of CAR from the cytoplasm. In comparison to the well-defined ligand-based activation, indirect activation of CAR appears to be exclusively involved in the nuclear translocation through mechanisms yet to be fully understood. Accumulating evidence reveals that without activation, CAR forms a protein complex in the cytoplasm where it can be functionally affected by multiple signaling pathways. In this review, we discuss recent progresses in our understanding of the signaling regulation of CAR nuclear accumulation and activation. We expect that this review will also provide greater insight into the similarity and difference between the mechanisms of direct vs. indirect human CAR activation. [ABSTRACT FROM AUTHOR]

As a prototype of the TGF-β superfamily cytokines, TGF-β is well known for its diverse roles in embryogenesis and adult tissue homeostasis. TGF-β evokes cellular responses by signaling mainly through cell membrane receptors and transcription factor R-Smads and Co-Smad (Smad4), while an inhibitory Smad, Smad7, acts as a critical negative regulator of TGF-β signaling. Smad7 antagonizes TGF-β signaling by regulating the stability or activity of the receptors or blocking the DNA binding of the functional R-Smad-Smad4 complex in the nucleus. However, the function of Smad7 in the nucleus is not fully understood. Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor with multiple functions. It has been reported that YY1 can inhibit Smad-dependent transcriptional responses and TGF-β/BMP-induced cell differentiation independently of its DNA binding ability. In this study, we found that Smad7 interacts with YY1 and the interaction is attenuated by TGF-β signaling. Reporter assays and target gene expression analyses revealed that Smad7 and YY1 act in concert to inhibit TGF-β-induced transcription in the nucleus. Furthermore, Smad7 could enhance the interaction of YY1 with the histone deacetylase HDAC1. Consistently, YY1 and HDAC1 augmented the transcription repression activity of Smad7 in Gal4-luciferase reporter analysis. Therefore, our findings define a novel mechanism of Smad7 and YY1 to antagonize TGF-β signaling. [ABSTRACT FROM AUTHOR]

Using RACE method, a DREB-like gene- CkDREB, which contains a conserved AP2/ERF domain, was isolated from Caragana korshinskii. Full length of CkDREB cDNA was 1743 bp, including an ORF of 1038 bp and encoding a polypeptide of 345 amino acids. CkDREB protein shared high identification with other homologs from other plants. The KR-rich motif at the N-terminal region played an essential role in nuclear localization of CkDREB. Yeast one-hybrid experiments testified that CkDREB possess specific DRE element-binding activity and transcriptional activation. A variety of abiotic stress, including high salt, dehydration, low temperature all significantly induced the expression of CkDREB gene. Exogenous phytohormone ABA also slightly up-regulated the mRNA accumulation of CkDREB. Overexpression of CkDREB in transgenic tobacco plants resulted in enhanced tolerance to high salinity and osmotic stresses and induction of downstream target genes under normal conditions. These results suggested that CkDREB may play an essential role as a DREB transcription factor in regulation of stress-responsive signaling in C. korshinskii. [ABSTRACT FROM AUTHOR]

The dehydration-responsive element-binding (DREB) protein specifically binds the dehydration-responsive element and is part of a plant-specific family of transcription factors that play important roles in regulating the expression of genes in response to a variety of abiotic stresses, including drought, high salt, and low temperature. In this study, a DREB-like gene containing a conserved APETLA2 (AP2)/ethylene responsive element binding factor (ERF) domain, termed DRE binding factor (CkDBF), was isolated from Caragana korshinskii. The K, R-rich motif in the N-terminal region was shown to play an essential role in nuclear localization of CkDBF. DNA-binding specificity and transactivation activity of CkDBF were verified by yeast one-hybrid experiments. Expression of CkDBF was shown to be upregulated by high salt, dehydration, low temperature, and the phytohormone abscisic acid (ABA). Overexpression of CkDBF in transgenic tobacco plants resulted in higher tolerance to high salinity and osmotic stresses and induction of a downstream target gene under normal conditions. These results suggest that CkDBF may play an essential role as a DREB transcription factor in regulation of stress-responsive signaling in C. korshinskii. [ABSTRACT FROM AUTHOR]

Translation, a process of generating a peptide from the codons present in messenger RNA, can be a site of independent regulation of protein synthesis; it has not been well studied in the kidney. Translation occurs in three stages (initiation, elongation, and termination), each with its own set of regulatory factors. Mechanisms controlling translation include small inhibitory RNAs such as microRNAs, binding proteins, and signaling reactions. Role of translation in renal injury in diabetes, endoplasmic reticulum stress, acute kidney injury, and, in physiological adaptation to loss of nephrons is reviewed here. Contribution of mRNA translation to physiology and disease is not well understood. Because it is involved in such diverse areas as development and cancer, it should prove a fertile field for investigation in renal science. [ABSTRACT FROM AUTHOR]

G protein-coupled receptors (GPCRs) are a protein superfamily comprising >800 members that regulate numerous cellular and physiologic responses. GPCRs represent the largest class of therapeutic targets with implications in various diseases. Although advances in GPCR structural and pharmacological research have significantly improved our knowledge of GPCR signaling mechanisms, mapping diverse post-translational modifications (PTMs) of GPCR proteins and understanding their regulatory roles have received much less attention. Mass spectrometry-based proteomics has become the most popular technology for profiling protein PTMs in a systematic manner. Herein we provide an overview of PTM types, locations, crosstalk and dynamic regulation for different GPCRs that are characterized using proteomic and/or biochemical approaches. Our main focus is on glycosylation, phosphorylation, ubiquitination and palmitoylation that are known to modulate receptor folding, biosynthesis, trafficking, dimerization and signaling. Furthermore, we discuss the locations of specific PTM sites in the structure of a given GPCR and its signaling complex to highlight the importance of PTM regulation in the molecular basis of GPCRs, which may shed new light on structure-based drug discovery., 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 © 2022 Zhang, Li and Shui.)

Protein kinases are essential for signal transduction and control of most cellular processes, including metabolism, membrane transport, motility, and cell cycle. Despite the critical role of kinases in cells and their strong association with diseases, good coverage of their interactions is available for only a fraction of the 535 human kinases. Here, we present a comprehensive mass-spectrometry-based analysis of a human kinase interaction network covering more than 300 kinases. The interaction dataset is a high-quality resource with more than 5,000 previously unreported interactions. We extensively characterized the obtained network and were able to identify previously described, as well as predict new, kinase functional associations, including those of the less well-studied kinases PIM3 and protein O-mannose kinase (POMK). Importantly, the presented interaction map is a valuable resource for assisting biomedical studies. We uncover dozens of kinase-disease associations spanning from genetic disorders to complex diseases, including cancer. • AP-MS confirms over 1,300 known and reveals over 5,000 kinase protein interactions • Functional contexts and regulatory circuits for poorly studied kinases • Kinases are biochemically linked to a broad range of Mendelian disease modules • Biochemical context for kinase complexes containing human cancer proteins In this issue of Molecular Cell, Buljan et al. present a comprehensive account of human kinase complexes for inferring new kinase functions, kinase signaling modules, and kinase complexes linked to genetic diseases. [ABSTRACT FROM AUTHOR]

In the present manuscript it was builded a model for IL-1 interactions with IL-1Rs in both solution and cell membrane format to study the extracellular regulation of IL-1. With the calibrated model we made the following highlights predictions: • IL-1α is more potent to induce IL-1Rs signaling than IL-1β independently on the cell type. • IL-1R2 do not controls IL-1 signaling at the cell membrane level but is the better IL-1 system component for the controlling of IL-1β at the soluble format. • IL-1R3 has the lowest capacity to prevent IL-1 signaling but is the only sIL-1R that has specificity for certain type of cells. IL-1 system is involved in the induction and maintenance of chronic inflammation associated with several autoimmune diseases and cancer, mainly due to its capacity to promote the secretion of inflammatory mediators. For this reason, several intracellular and extracellular mechanisms for this system have been fixed during the evolution. In spite of the large description of molecular interactions between IL-1 ligands and receptors, little is known about the relevance and limits of the extracellular regulatory mechanims in different scenarios. To tackle this problem, we developed and calibrated a mathematical model including all the known interactions between IL-1 ligands and IL-1Rs and calibrate it with experimental data of IL-1 binding to different cells. The model predicts that, independently on the IL-1Rs expression, IL-1α has more ability than IL-1β to induce IL-1 signaling, which suggests that both ligands can be equally relevant for the IL-1 related inflammation. On the other hand, at the cell level, IL-1 signaling is mainly controlled by IL-1R1 and IL-1R3 and not by IL-1R2. Moreover, the soluble form of IL-1R1 and IL-1RA have the highest capacity to prevent IL-1α while IL-1R2 and IL-1R1 and IL-1RA have a similar capacity to prevent IL-1β signaling. The soluble IL-1R3 has the lowest capacity to prevent IL-1 signaling and preferentially inhibits cells with low number of IL-1R3. In general, model predictions suggest several ways in which IL-1 controlling system may fail, developing IL-1 related inflammation. [ABSTRACT FROM AUTHOR]

Hepatocellular carcinoma (HCC) is the major form of primary liver cancer and one of the most prevalent and life-threatening malignancies globally. One of the hallmarks in HCC is the sustained cell survival and proliferative signals, which are determined by the balance between oncogenes and tumor suppressors. Transforming growth factor beta (TGF-β) is an effective growth inhibitor of epithelial cells including hepatocytes, through induction of cell cycle arrest, apoptosis, cellular senescence, or autophagy. The antitumorigenic effects of TGF-β are bypassed during liver tumorigenesis via multiple mechanisms. Furthermore, along with malignant progression, TGF-β switches to promote cancer cell survival and proliferation. This dichotomous nature of TGF-β is one of the barriers to therapeutic targeting in liver cancer. Thereafter, understanding the underlying molecular mechanisms is a prerequisite for discovering novel antitumor drugs that may specifically disable the growth-promoting branch of TGF-β signaling or restore its tumor-suppressive arm. This review summarizes how TGF-β inhibits or promotes liver cancer cell survival and proliferation, highlighting the functional switch mechanisms during the process., (Copyright © 2020 The Authors. Published by Elsevier Ltd.. All rights reserved.)

Porphyromonas ( P.) gingivalis associates tightly with periodontal diseases and it is also a dominant pathogen of periapical periodontitis. However, the influence of P. gingivalis on cementoblasts, root surface cells pivotal in the apical areas, and the possible involvement of other molecules remain largely elusive. CXXC5 is a nuclear protein that regulates gene expression as well as cell growth, differentiation, and apoptosis. In this study, P. gingivalis repressed the mineralization capacity of cementoblasts by inducing inflammatory reactions and inhibiting cell differentiation. Intriguingly, the expression of CXXC5 decreased in P. gingivalis -treated OCCM-30 cells and apical periodontitis models but gradually increased during mineralization. Furthermore, RNA interference of CXXC5 significantly inhibited cementoblast differentiation, represented by decline of bone-associated markers Osterix, osteocalcin (OCN), and alkaline phosphatase (ALP). CXXC5 overexpression facilitated differentiation, and therefore attenuated the P. gingivalis -repressed effects on OCCM-30 cells. In addition, Erk1/2, p38, and PI3K-Akt were inactivated by silencing CXXC5 and activated upon its overexpression, whereas Wnt/β-catenin exhibited an opposite trend. The employment of specific inhibitors revealed that the CXXC5-dependent promotions of cementoblast differentiation were partially abrogated by p38 and PI3K-Akt inhibitors but were exacerbated by inhibiting Erk1/2. Overall, our experiment demonstrated a novel function of CXXC5 in the regeneration of impaired cementum caused by P. gingivalis invasion and suggested that MAPK signaling network balances the facilitation effects of CXXC5 in cementoblast differentiation., Competing Interests: Competing Interests: The authors have declared that no competing interest exists.

Transforming growth factor beta (TGF-β) is a multi-functional polypeptide that plays a critical role in regulating a broad range of cellular functions and physiological processes. Signaling is initiated when TGF-β ligands bind to two types of cell membrane receptors with intrinsic Ser/Thr kinase activity and transmitted by the intracellular Smad proteins, which act as transcription factors to regulate gene expression in the nucleus. Although it is relatively simple and straight-forward, this TGF-β/Smad pathway is regulated by various feedback loops at different levels, including the ligand, the receptor, Smads and transcription, and is thus fine-tuned in terms of signaling robustness, duration, specificity, and plasticity. The precise control gives rise to versatile and context-dependent pathophysiological functions. In this review, we firstly give an overview of TGF-β signaling, and then discuss how each step of TGF-β signaling is finely controlled by distinct modes of feedback mechanisms, involving both protein regulators and miRNAs., (© The Author 2017. Published by Oxford University Press on behalf of the Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.)

Brassinosteroids (BRs) play important roles in plant growth, development, and stress responses through the receptor, Brassinosteroid-insensitive 1 (BRI1), which perceives BRs and initiates BR signaling. There is considerable potential agricultural value in regulating BR signaling in crops. In this study, we investigated the effects of overexpressing the tomato ( Solanum lycopersicum ) BRI1 gene, SlBRI1 , on major agronomic traits, such as seed germination, vegetative growth, fruit ethylene production, carotenoid accumulation, yield, and quality attributes. SlBRI1 overexpression enhanced the endogenous BR signaling intensity thereby increasing the seed germination rate, lateral root number, hypocotyl length, CO 2 assimilation, plant height, and flower size. The transgenic plants also showed an increase in fruit yield and fruit number per plant, although the mean weight of individual fruit was reduced, compared with wild type. SlBRI1 overexpression also promoted fruit ripening and ethylene production, and caused an increase in levels of carotenoids, ascorbic acid, soluble solids, and soluble sugars during fruit ripening. An increased BR signaling intensity mediated by SlBRI1 overexpression was therefore positively correlated with carotenoid accumulation and fruit nutritional quality. Our results indicate that enhancing BR signaling by overexpression of SlBRI1 in tomato has the potential to improve multiple major agronomic traits.

The advent of high-throughput genomics techniques, along with the completion of genome sequencing projects, identification of protein-protein interactions and reconstruction of genome-scale pathways, has accelerated the development of systems biology research in the yeast organism Saccharomyces cerevisiae In particular, discovery of biological pathways in yeast has become an important forefront in systems biology, which aims to understand the interactions among molecules within a cell leading to certain cellular processes in response to a specific environment. While the existing theoretical and experimental approaches enable the investigation of well-known pathways involved in metabolism, gene regulation and signal transduction, bioinformatics methods offer new insights into computational modeling of biological pathways. A wide range of computational approaches has been proposed in the past for reconstructing biological pathways from high-throughput datasets. Here we review selected bioinformatics approaches for modeling biological pathways inS. cerevisiae, including metabolic pathways, gene-regulatory pathways and signaling pathways. We start with reviewing the research on biological pathways followed by discussing key biological databases. In addition, several representative computational approaches for modeling biological pathways in yeast are discussed., (© The Author 2015. Published by Oxford University Press. All rights reserved. For permissions, please email: journals.permissions@oup.com.)

TGF-β is a pleiotropic cytokine that regulates a wide range of cellular actions and pathophysiological processes. TGF-β signaling is spatiotemporally fine-tuned. As a key negative regulator of TGF-β signaling, Smad7 exerts its inhibitory effects by blocking receptor activity, inducing receptor degradation or interfering with Smad-DNA binding. However, the functions and the molecular mechanisms underlying the actions of Smad7 in TGF-β signaling are still not fully understood. In this study we report a novel mechanism whereby Smad7 antagonizes TGF-β signaling at the Smad level. Smad7 oligomerized with R-Smad proteins upon TGF-β signaling and directly inhibited R-Smad activity, as assessed by Gal4-luciferase reporter assays. Mechanistically, Smad7 competes with Smad4 to associate with R-Smads and recruits the E3 ubiquitin ligase NEDD4L to activated R-Smads, leading to their polyubiquitination and proteasomal degradation. Similar to the R-Smad-Smad4 oligomerization, the interaction between R-Smads and Smad7 is mediated by their mad homology 2 (MH2) domains. A positive-charged basic region including the L3/β8 loop-strand module and adjacent amino acids in the MH2 domain of Smad7 is essential for the interaction. These results shed new light on the regulation of TGF-β signaling by Smad7., (© 2016 by The American Society for Biochemistry and Molecular Biology, Inc.)