Search

Your search keyword '"Solman, Maja"' showing total 29 results
Start Over Author "Solman, Maja"
29 results on '"Solman, Maja"'

1. The sixth international RASopathies symposium: Precision medicine-From promise to practice.

Author

Gripp, Karen W, Schill, Lisa, Schoyer, Lisa, Stronach, Beth, Bennett, Anton M, Blaser, Susan, Brown, Amanda, Burdine, Rebecca, Burkitt-Wright, Emma, Castel, Pau, Darilek, Sandra, Dias, Alwyn, Dyer, Tuesdi, Ellis, Michelle, Erickson, Gregg, Gelb, Bruce D, Green, Tamar, Gross, Andrea, Ho, Alan, Holder, James Lloyd, Inoue, Shin-Ichi, Jelin, Angie C, Kennedy, Annie, Klein, Richard, Kontaridis, Maria I, Magoulas, Pilar, McConnell, Darryl B, McCormick, Frank, Neel, Benjamin G, Prada, Carlos E, Rauen, Katherine A, Roberts, Amy, Rodriguez-Viciana, Pablo, Rosen, Neal, Rumbaugh, Gavin, Sablina, Anna, Solman, Maja, Tartaglia, Marco, Thomas, Angelica, Timmer, William C, Venkatachalam, Kartik, Walsh, Karin S, Wolters, Pamela L, Yi, Jae-Sung, Zenker, Martin, and Ratner, Nancy

Subjects
Humans, Genetic Diseases, Inborn, ras Proteins, Mitogen-Activated Protein Kinase Kinases, Signal Transduction, Germ-Line Mutation, Costello syndrome, Noonan syndrome, RASopathy, cardio-facio-cutaneous syndrome, kinases, neurofibromatosis, Rare Diseases, Genetics, Good Health and Well Being, Clinical Sciences
Abstract

The RASopathies are a group of genetic disorders that result from germline pathogenic variants affecting RAS-mitogen activated protein kinase (MAPK) pathway genes. RASopathies share RAS/MAPK pathway dysregulation and share phenotypic manifestations affecting numerous organ systems, causing lifelong and at times life-limiting medical complications. RASopathies may benefit from precision medicine approaches. For this reason, the Sixth International RASopathies Symposium focused on exploring precision medicine. This meeting brought together basic science researchers, clinicians, clinician scientists, patient advocates, and representatives from pharmaceutical companies and the National Institutes of Health. Novel RASopathy genes, variants, and animal models were discussed in the context of medication trials and drug development. Attempts to define and measure meaningful endpoints for treatment trials were discussed, as was drug availability to patients after trial completion.

Published
2020

4. Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome

Author

Motta, Marialetizia, Solman, Maja, Bonnard, Adeline A, Kuechler, Alma, Pantaleoni, Francesca, Priolo, Manuela, Chandramouli, Balasubramanian, Coppola, Simona, Pizzi, Simone, Zara, Erika, Ferilli, Marco, Kayserili, Hülya, Onesimo, Roberta, Leoni, Chiara, Brinkmann, Julia, Vial, Yoann, Kamphausen, Susanne B, Thomas-Teinturier, Cécile, Guimier, Anne, Cordeddu, Viviana, Mazzanti, Laura, Zampino, Giuseppe, Chillemi, Giovanni, Zenker, Martin, Cavé, Hélène, den Hertog, Jeroen, Tartaglia, Marco, Motta, Marialetizia, Solman, Maja, Bonnard, Adeline A, Kuechler, Alma, Pantaleoni, Francesca, Priolo, Manuela, Chandramouli, Balasubramanian, Coppola, Simona, Pizzi, Simone, Zara, Erika, Ferilli, Marco, Kayserili, Hülya, Onesimo, Roberta, Leoni, Chiara, Brinkmann, Julia, Vial, Yoann, Kamphausen, Susanne B, Thomas-Teinturier, Cécile, Guimier, Anne, Cordeddu, Viviana, Mazzanti, Laura, Zampino, Giuseppe, Chillemi, Giovanni, Zenker, Martin, Cavé, Hélène, den Hertog, Jeroen, and Tartaglia, Marco

Abstract

We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A > G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A > G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here, we provide new data on the clinical spectrum and molecular diversity of this disorder and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge toward an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene and definitively establish a gain-of-function behavior as the mechanism of disease.

Published
2022

5. Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects

Author

Solman, Maja, Blokzijl-Franke, Sasja, Piques, Florian, Yan, Chuan, Yang, Qiqi, Strullu, Marion, Kamel, Sarah M, Ak, Pakize, Bakkers, Jeroen, Langenau, David M, Cavé, Hélène, den Hertog, Jeroen, Solman, Maja, Blokzijl-Franke, Sasja, Piques, Florian, Yan, Chuan, Yang, Qiqi, Strullu, Marion, Kamel, Sarah M, Ak, Pakize, Bakkers, Jeroen, Langenau, David M, Cavé, Hélène, and den Hertog, Jeroen

Abstract

Gain-of-function mutations in the protein-tyrosine phosphatase SHP2 are the most frequently occurring mutations in sporadic juvenile myelomonocytic leukemia (JMML) and JMML-like myeloproliferative neoplasm (MPN) associated with Noonan syndrome (NS). Hematopoietic stem and progenitor cells (HSPCs) are the disease propagating cells of JMML. Here, we explored transcriptomes of HSPCs with SHP2 mutations derived from JMML patients and a novel NS zebrafish model. In addition to major NS traits, CRISPR/Cas9 knock-in Shp2D61G mutant zebrafish recapitulated a JMML-like MPN phenotype, including myeloid lineage hyperproliferation, ex vivo growth of myeloid colonies, and in vivo transplantability of HSPCs. Single-cell mRNA sequencing of HSPCs from Shp2D61G zebrafish embryos and bulk sequencing of HSPCs from JMML patients revealed an overlapping inflammatory gene expression pattern. Strikingly, an anti-inflammatory agent rescued JMML-like MPN in Shp2D61G zebrafish embryos. Our results indicate that a common inflammatory response was triggered in the HSPCs from sporadic JMML patients and syndromic NS zebrafish, which potentiated MPN and may represent a future target for JMML therapies.

Published
2022

6. Modeling (not so) rare developmental disorders associated with mutations in the protein-tyrosine phosphatase SHP2

Author

Solman, Maja, Woutersen, Daniëlle T J, den Hertog, Jeroen, Solman, Maja, Woutersen, Daniëlle T J, and den Hertog, Jeroen

Abstract

Src homology region 2 (SH2)-containing protein tyrosine phosphatase 2 (SHP2) is a highly conserved protein tyrosine phosphatase (PTP), which is encoded by PTPN11 and is indispensable during embryonic development. Mutations in PTPN11 in human patients cause aberrant signaling of SHP2, resulting in multiple rare hereditary diseases, including Noonan Syndrome (NS), Noonan Syndrome with Multiple Lentigines (NSML), Juvenile Myelomonocytic Leukemia (JMML) and Metachondromatosis (MC). Somatic mutations in PTPN11 have been found to cause cancer. Here, we focus on the role of SHP2 variants in rare diseases and advances in the understanding of its pathogenesis using model systems.

Published
2022

7. Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome

Author

Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Motta, Marialetizia; Solman, Maja; Bonnard, Adeline; Kuechler, Alma; Pantaleoni, Francesca; Priolo, Manuela; Chandramouli, Balasubramanian; Coppola, Simona; Pizzi, Simone; Zara, Erika; Ferilli, Marco; Onesimo, Roberta; Leoni, Chiara; Brinkmann, Julia; Vial, Yoann; Kamphausen, Susanne B.; Thomas-Teinturier, Cecile; Guimier, Anne; Cordeddu, Viviana; Mazzanti, Laura; Zampino, Giuseppe; Chillemi, Giovanni; Zenker, Martin; Cave, Helene; Hertog, Jeroen; Tartaglia, Marco, Koç University Hospital, School of Medicine, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Motta, Marialetizia; Solman, Maja; Bonnard, Adeline; Kuechler, Alma; Pantaleoni, Francesca; Priolo, Manuela; Chandramouli, Balasubramanian; Coppola, Simona; Pizzi, Simone; Zara, Erika; Ferilli, Marco; Onesimo, Roberta; Leoni, Chiara; Brinkmann, Julia; Vial, Yoann; Kamphausen, Susanne B.; Thomas-Teinturier, Cecile; Guimier, Anne; Cordeddu, Viviana; Mazzanti, Laura; Zampino, Giuseppe; Chillemi, Giovanni; Zenker, Martin; Cave, Helene; Hertog, Jeroen; Tartaglia, Marco, Koç University Hospital, and School of Medicine

Abstract

We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A?>?G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A?>?G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here, we provide new data on the clinical spectrum and molecular diversity of this disorder and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge toward an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene and definitively establish a gain-of-function behavior as the mechanism of disease., European Union (EU); Horizon 2020; European Joint Program on Rare Diseases (EJP-RD); Associazione Italiana per la Ricerca sul Cancro (AIRC); Italian Ministry of Health (Ricerca Corrente 2022); Italian Ministry of Research (FOE 2019); German Federal Ministry of Education and Research; BMBF (German Network for RASopathy Research ""GeNeRARe""); European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA)

Published
2022

8. Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome

Author

Hubrecht Institute with UMC, Motta, Marialetizia, Solman, Maja, Bonnard, Adeline A., Kuechler, Alma, Pantaleoni, Francesca, Priolo, Manuela, Chandramouli, Balasubramanian, Coppola, Simona, Pizzi, Simone, Zara, Erika, Ferilli, Marco, Kayserili, Hülya, Onesimo, Roberta, Leoni, Chiara, Brinkmann, Julia, Vial, Yoann, Kamphausen, Susanne B., Thomas-Teinturier, Cécile, Guimier, Anne, Cordeddu, Viviana, Mazzanti, Laura, Zampino, Giuseppe, Chillemi, Giovanni, Zenker, Martin, Cavé, Hélène, den Hertog, Jeroen, Tartaglia, Marco, Hubrecht Institute with UMC, Motta, Marialetizia, Solman, Maja, Bonnard, Adeline A., Kuechler, Alma, Pantaleoni, Francesca, Priolo, Manuela, Chandramouli, Balasubramanian, Coppola, Simona, Pizzi, Simone, Zara, Erika, Ferilli, Marco, Kayserili, Hülya, Onesimo, Roberta, Leoni, Chiara, Brinkmann, Julia, Vial, Yoann, Kamphausen, Susanne B., Thomas-Teinturier, Cécile, Guimier, Anne, Cordeddu, Viviana, Mazzanti, Laura, Zampino, Giuseppe, Chillemi, Giovanni, Zenker, Martin, Cavé, Hélène, den Hertog, Jeroen, and Tartaglia, Marco

Published
2022

10. Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects

Author

Medische Fysiologie, Solman, Maja, Blokzijl-Franke, Sasja, Piques, Florian, Yan, Chuan, Yang, Qiqi, Strullu, Marion, Kamel, Sarah M., Ak, Pakize, Bakkers, Jeroen, Langenau, David M., Cavé, Hélène, Den Hertog, Jeroen, Medische Fysiologie, Solman, Maja, Blokzijl-Franke, Sasja, Piques, Florian, Yan, Chuan, Yang, Qiqi, Strullu, Marion, Kamel, Sarah M., Ak, Pakize, Bakkers, Jeroen, Langenau, David M., Cavé, Hélène, and Den Hertog, Jeroen

Published
2022

11. Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects

Author

Solman, Maja, primary, Blokzijl-Franke, Sasja, additional, Piques, Florian, additional, Yan, Chuan, additional, Yang, Qiqi, additional, Strullu, Marion, additional, Kamel, Sarah M, additional, Ak, Pakize, additional, Bakkers, Jeroen, additional, Langenau, David M, additional, Cavé, Hélène, additional, and den Hertog, Jeroen, additional

Published
2022
Full Text
View/download PDF

12. Expanding the molecular spectrum of pathogenicSHOC2variants underlying Mazzanti syndrome

Author

Motta, Marialetizia, primary, Solman, Maja, additional, Bonnard, Adeline A, additional, Kuechler, Alma, additional, Pantaleoni, Francesca, additional, Priolo, Manuela, additional, Chandramouli, Balasubramanian, additional, Coppola, Simona, additional, Pizzi, Simone, additional, Zara, Erika, additional, Ferilli, Marco, additional, Kayserili, Hülya, additional, Onesimo, Roberta, additional, Leoni, Chiara, additional, Brinkmann, Julia, additional, Vial, Yoann, additional, Kamphausen, Susanne B, additional, Thomas-Teinturier, Cécile, additional, Guimier, Anne, additional, Cordeddu, Viviana, additional, Mazzanti, Laura, additional, Zampino, Giuseppe, additional, Chillemi, Giovanni, additional, Zenker, Martin, additional, Cavé, Hélène, additional, den Hertog, Jeroen, additional, and Tartaglia, Marco, additional

Published
2022
Full Text
View/download PDF

13. Author response: Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects

Author

Solman, Maja, primary, Blokzijl-Franke, Sasja, additional, Piques, Florian, additional, Yan, Chuan, additional, Yang, Qiqi, additional, Strullu, Marion, additional, Kamel, Sarah M, additional, Ak, Pakize, additional, Bakkers, Jeroen, additional, Langenau, David M, additional, Cavé, Hélène, additional, and den Hertog, Jeroen, additional

Published
2022
Full Text
View/download PDF

14. Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein–Protein Interactions

Author

Bobone, Sara, primary, Pannone, Luca, additional, Biondi, Barbara, additional, Solman, Maja, additional, Flex, Elisabetta, additional, Canale, Viviana Claudia, additional, Calligari, Paolo, additional, De Faveri, Chiara, additional, Gandini, Tommaso, additional, Quercioli, Andrea, additional, Torini, Giuseppe, additional, Venditti, Martina, additional, Lauri, Antonella, additional, Fasano, Giulia, additional, Hoeksma, Jelmer, additional, Santucci, Valerio, additional, Cattani, Giada, additional, Bocedi, Alessio, additional, Carpentieri, Giovanna, additional, Tirelli, Valentina, additional, Sanchez, Massimo, additional, Peggion, Cristina, additional, Formaggio, Fernando, additional, den Hertog, Jeroen, additional, Martinelli, Simone, additional, Bocchinfuso, Gianfranco, additional, Tartaglia, Marco, additional, and Stella, Lorenzo, additional

Published
2021
Full Text
View/download PDF

15. Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions

Author

Bobone, Sara, Pannone, Luca, Biondi, Barbara, Solman, Maja, Flex, Elisabetta, Canale, Viviana Claudia, Calligari, Paolo, De Faveri, Chiara, Gandini, Tommaso, Quercioli, Andrea, Torini, Giuseppe, Venditti, Martina, Lauri, Antonella, Fasano, Giulia, Hoeksma, Jelmer, Santucci, Valerio, Cattani, Giada, Bocedi, Alessio, Carpentieri, Giovanna, Tirelli, Valentina, Sanchez, Massimo, Peggion, Cristina, Formaggio, Fernando, den Hertog, Jeroen, Martinelli, Simone, Bocchinfuso, Gianfranco, Tartaglia, Marco, Stella, Lorenzo, Bobone, Sara, Pannone, Luca, Biondi, Barbara, Solman, Maja, Flex, Elisabetta, Canale, Viviana Claudia, Calligari, Paolo, De Faveri, Chiara, Gandini, Tommaso, Quercioli, Andrea, Torini, Giuseppe, Venditti, Martina, Lauri, Antonella, Fasano, Giulia, Hoeksma, Jelmer, Santucci, Valerio, Cattani, Giada, Bocedi, Alessio, Carpentieri, Giovanna, Tirelli, Valentina, Sanchez, Massimo, Peggion, Cristina, Formaggio, Fernando, den Hertog, Jeroen, Martinelli, Simone, Bocchinfuso, Gianfranco, Tartaglia, Marco, and Stella, Lorenzo

Abstract

We developed a new class of inhibitors of protein-protein interactions of the SHP2 phosphatase, which is pivotal in cell signaling and represents a central target in the therapy of cancer and rare diseases. Currently available SHP2 inhibitors target the catalytic site or an allosteric pocket but lack specificity or are ineffective for disease-associated SHP2 mutants. Considering that pathogenic lesions cause signaling hyperactivation due to increased levels of SHP2 association with cognate proteins, we developed peptide-based molecules with nanomolar affinity for the N-terminal Src homology domain of SHP2, good selectivity, stability to degradation, and an affinity for pathogenic variants of SHP2 that is 2-20 times higher than for the wild-type protein. The best peptide reverted the effects of a pathogenic variant (D61G) in zebrafish embryos. Our results provide a novel route for SHP2-targeted therapies and a tool for investigating the role of protein-protein interactions in the function of SHP2.

Published
2021

16. Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting Its Protein-Protein Interactions

Author

Hubrecht Institute with UMC, Bobone, Sara, Pannone, Luca, Biondi, Barbara, Solman, Maja, Flex, Elisabetta, Canale, Viviana Claudia, Calligari, Paolo, De Faveri, Chiara, Gandini, Tommaso, Quercioli, Andrea, Torini, Giuseppe, Venditti, Martina, Lauri, Antonella, Fasano, Giulia, Hoeksma, Jelmer, Santucci, Valerio, Cattani, Giada, Bocedi, Alessio, Carpentieri, Giovanna, Tirelli, Valentina, Sanchez, Massimo, Peggion, Cristina, Formaggio, Fernando, Den Hertog, Jeroen, Martinelli, Simone, Bocchinfuso, Gianfranco, Tartaglia, Marco, Stella, Lorenzo, Hubrecht Institute with UMC, Bobone, Sara, Pannone, Luca, Biondi, Barbara, Solman, Maja, Flex, Elisabetta, Canale, Viviana Claudia, Calligari, Paolo, De Faveri, Chiara, Gandini, Tommaso, Quercioli, Andrea, Torini, Giuseppe, Venditti, Martina, Lauri, Antonella, Fasano, Giulia, Hoeksma, Jelmer, Santucci, Valerio, Cattani, Giada, Bocedi, Alessio, Carpentieri, Giovanna, Tirelli, Valentina, Sanchez, Massimo, Peggion, Cristina, Formaggio, Fernando, Den Hertog, Jeroen, Martinelli, Simone, Bocchinfuso, Gianfranco, Tartaglia, Marco, and Stella, Lorenzo

Published
2021

17. Inflammatory response in hematopoietic stem and progenitor cells triggered by activating SHP2 mutations evokes blood defects

Author

Solman, Maja, primary, Blokzijl-Franke, Sasja, additional, Piques, Florian, additional, Yan, Chuan, additional, Yang, Qiqi, additional, Strullu, Marion, additional, Kamel, Sarah M., additional, Ak, Pakize, additional, Bakkers, Jeroen, additional, Langenau, David M., additional, Cavé, Hélène, additional, and den Hertog, Jeroen, additional

Published
2020
Full Text
View/download PDF

18. Targeting Oncogenic Src Homology 2 Domain-Containing Phosphatase 2 (SHP2) by Inhibiting its Protein-Protein Interactions

Author

Bobone, Sara, primary, Pannone, Luca, additional, Biondi, Barbara, additional, Solman, Maja, additional, Flex, Elisabetta, additional, Canale, Viviana, additional, Calligari, Paolo, additional, Faveri, Chiara De, additional, Gandini, Tommaso, additional, Quercioli, Andrea, additional, Torini, Giuseppe, additional, Venditti, Martina, additional, Lauri, Antonella, additional, Fasano, Giulia, additional, Hoeksma, Jelmer, additional, Santucci, Valerio, additional, Cattani, Giada, additional, Bocedi, Alessio, additional, Carpentieri, Giovanna, additional, Tirelli, Valentina, additional, Sanchez, Massimo, additional, Peggion, Cristina, additional, Formaggio, Fernando, additional, Hertog, Jeroen den, additional, Martinelli, Simone, additional, Bocchinfuso, Gianfranco, additional, Tartaglia, Marco, additional, and Stella, Lorenzo, additional

Published
2020
Full Text
View/download PDF

19. The sixth international RASopathies symposium : Precision medicine—From promise to practice

Author

Gripp, Karen W., Schill, Lisa, Schoyer, Lisa, Stronach, Beth, Bennett, Anton M., Blaser, Susan, Brown, Amanda, Burdine, Rebecca, Burkitt-Wright, Emma, Castel, Pau, Darilek, Sandra, Dias, Alwyn, Dyer, Tuesdi, Ellis, Michelle, Erickson, Gregg, Gelb, Bruce D., Green, Tamar, Gross, Andrea, Ho, Alan, Holder, James Lloyd, Inoue, Shin Ichi, Jelin, Angie C., Kennedy, Annie, Klein, Richard, Kontaridis, Maria I., Magoulas, Pilar, McConnell, Darryl B., McCormick, Frank, Neel, Benjamin G., Prada, Carlos E., Rauen, Katherine A., Roberts, Amy, Rodriguez-Viciana, Pablo, Rosen, Neal, Rumbaugh, Gavin, Sablina, Anna, Solman, Maja, Tartaglia, Marco, Thomas, Angelica, Timmer, William C., Venkatachalam, Kartik, Walsh, Karin S., Wolters, Pamela L., Yi, Jae Sung, Zenker, Martin, Ratner, Nancy, Gripp, Karen W., Schill, Lisa, Schoyer, Lisa, Stronach, Beth, Bennett, Anton M., Blaser, Susan, Brown, Amanda, Burdine, Rebecca, Burkitt-Wright, Emma, Castel, Pau, Darilek, Sandra, Dias, Alwyn, Dyer, Tuesdi, Ellis, Michelle, Erickson, Gregg, Gelb, Bruce D., Green, Tamar, Gross, Andrea, Ho, Alan, Holder, James Lloyd, Inoue, Shin Ichi, Jelin, Angie C., Kennedy, Annie, Klein, Richard, Kontaridis, Maria I., Magoulas, Pilar, McConnell, Darryl B., McCormick, Frank, Neel, Benjamin G., Prada, Carlos E., Rauen, Katherine A., Roberts, Amy, Rodriguez-Viciana, Pablo, Rosen, Neal, Rumbaugh, Gavin, Sablina, Anna, Solman, Maja, Tartaglia, Marco, Thomas, Angelica, Timmer, William C., Venkatachalam, Kartik, Walsh, Karin S., Wolters, Pamela L., Yi, Jae Sung, Zenker, Martin, and Ratner, Nancy

Published
2020

20. The sixth international RASopathies symposium: Precision medicine—From promise to practice

Author

Hubrecht Institute with UMC, Gripp, Karen W., Schill, Lisa, Schoyer, Lisa, Stronach, Beth, Bennett, Anton M., Blaser, Susan, Brown, Amanda, Burdine, Rebecca, Burkitt-Wright, Emma, Castel, Pau, Darilek, Sandra, Dias, Alwyn, Dyer, Tuesdi, Ellis, Michelle, Erickson, Gregg, Gelb, Bruce D., Green, Tamar, Gross, Andrea, Ho, Alan, Holder, James Lloyd, Inoue, Shin Ichi, Jelin, Angie C., Kennedy, Annie, Klein, Richard, Kontaridis, Maria I., Magoulas, Pilar, McConnell, Darryl B., McCormick, Frank, Neel, Benjamin G., Prada, Carlos E., Rauen, Katherine A., Roberts, Amy, Rodriguez-Viciana, Pablo, Rosen, Neal, Rumbaugh, Gavin, Sablina, Anna, Solman, Maja, Tartaglia, Marco, Thomas, Angelica, Timmer, William C., Venkatachalam, Kartik, Walsh, Karin S., Wolters, Pamela L., Yi, Jae Sung, Zenker, Martin, Ratner, Nancy, Hubrecht Institute with UMC, Gripp, Karen W., Schill, Lisa, Schoyer, Lisa, Stronach, Beth, Bennett, Anton M., Blaser, Susan, Brown, Amanda, Burdine, Rebecca, Burkitt-Wright, Emma, Castel, Pau, Darilek, Sandra, Dias, Alwyn, Dyer, Tuesdi, Ellis, Michelle, Erickson, Gregg, Gelb, Bruce D., Green, Tamar, Gross, Andrea, Ho, Alan, Holder, James Lloyd, Inoue, Shin Ichi, Jelin, Angie C., Kennedy, Annie, Klein, Richard, Kontaridis, Maria I., Magoulas, Pilar, McConnell, Darryl B., McCormick, Frank, Neel, Benjamin G., Prada, Carlos E., Rauen, Katherine A., Roberts, Amy, Rodriguez-Viciana, Pablo, Rosen, Neal, Rumbaugh, Gavin, Sablina, Anna, Solman, Maja, Tartaglia, Marco, Thomas, Angelica, Timmer, William C., Venkatachalam, Kartik, Walsh, Karin S., Wolters, Pamela L., Yi, Jae Sung, Zenker, Martin, and Ratner, Nancy

Published
2020

21. The sixth international RASopathies symposium: Precision medicine—From promise to practice

Author

Gripp, Karen W., primary, Schill, Lisa, additional, Schoyer, Lisa, additional, Stronach, Beth, additional, Bennett, Anton M., additional, Blaser, Susan, additional, Brown, Amanda, additional, Burdine, Rebecca, additional, Burkitt‐Wright, Emma, additional, Castel, Pau, additional, Darilek, Sandra, additional, Dias, Alwyn, additional, Dyer, Tuesdi, additional, Ellis, Michelle, additional, Erickson, Gregg, additional, Gelb, Bruce D., additional, Green, Tamar, additional, Gross, Andrea, additional, Ho, Alan, additional, Holder, James Lloyd, additional, Inoue, Shin‐Ichi, additional, Jelin, Angie C., additional, Kennedy, Annie, additional, Klein, Richard, additional, Kontaridis, Maria I., additional, Magoulas, Pilar, additional, McConnell, Darryl B., additional, McCormick, Frank, additional, Neel, Benjamin G., additional, Prada, Carlos E., additional, Rauen, Katherine A., additional, Roberts, Amy, additional, Rodriguez‐Viciana, Pablo, additional, Rosen, Neal, additional, Rumbaugh, Gavin, additional, Sablina, Anna, additional, Solman, Maja, additional, Tartaglia, Marco, additional, Thomas, Angelica, additional, Timmer, William C., additional, Venkatachalam, Kartik, additional, Walsh, Karin S., additional, Wolters, Pamela L., additional, Yi, Jae‐Sung, additional, Zenker, Martin, additional, and Ratner, Nancy, additional

Published
2019
Full Text
View/download PDF

22. Targeting prohibitins at the cell surface prevents Th17-mediated autoimmunity.

Author

Buehler, Ulrike, Schulenburg, Katharina, Yurugi, Hajime, Solman, Maja, Abankwa, Daniel, Ulges, Alexander, Tenzer, Stefan, Bopp, Tobias, Thiede, Bernd, Zipp, Frauke, Rajalingam, Krishnaraj, Buehler, Ulrike, Schulenburg, Katharina, Yurugi, Hajime, Solman, Maja, Abankwa, Daniel, Ulges, Alexander, Tenzer, Stefan, Bopp, Tobias, Thiede, Bernd, Zipp, Frauke, and Rajalingam, Krishnaraj

Abstract

T helper (Th)17 cells represent a unique subset of CD4(+) T cells and are vital for clearance of extracellular pathogens including bacteria and fungi. However, Th17 cells are also involved in orchestrating autoimmunity. By employing quantitative surface proteomics, we found that the evolutionarily conserved prohibitins (PHB1/2) are highly expressed on the surface of both murine and human Th17 cells. Increased expression of PHBs at the cell surface contributed to enhanced CRAF/MAPK activation in Th17 cells. Targeting surface-expressed PHBs on Th17 cells with ligands such as Vi polysaccharide (Typhim vaccine) inhibited CRAF-MAPK pathway, reduced interleukin (IL)-17 expression and ameliorated disease pathology with an increase in FOXP3(+)-expressing Tregs in an animal model for multiple sclerosis (MS). Interestingly, we detected a CD4(+) T cell population with high PHB1 surface expression in blood samples from MS patients in comparison with age- and sex-matched healthy subjects. Our observations suggest a pivotal role for the PHB-CRAF-MAPK signalling axis in regulating the polarization and pathogenicity of Th17 cells and unveil druggable targets in autoimmune disorders such as MS.

Published
2018
Full Text
View/download PDF

23. Specific cancer-associated mutations in the switch III region of Ras increase tumorigenicity by nanocluster augmentation

Author

University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Solman, Maja, Ligabue, Alessio, Blazevits, Olga, Jaiswal, Alok, Zhou, Yong, Liang, Hong, Lectez, Benoit, Kopra, Kari, Guzman, Camilo, Harma, Harri, Hancock, John F., Aittokallio, Tero, Abankwa, Daniel, University of Helsinki, Institute for Molecular Medicine Finland (FIMM), Solman, Maja, Ligabue, Alessio, Blazevits, Olga, Jaiswal, Alok, Zhou, Yong, Liang, Hong, Lectez, Benoit, Kopra, Kari, Guzman, Camilo, Harma, Harri, Hancock, John F., Aittokallio, Tero, and Abankwa, Daniel

Abstract

Hotspot mutations of Ras drive cell transformation and tumorigenesis. Less frequent mutations in Ras are poorly characterized for their oncogenic potential. Yet insight into their mechanism of action may point to novel opportunities to target Ras. Here, we show that several cancer-associated mutations in the switch III region moderately increase Ras activity in all isoforms. Mutants are biochemically inconspicuous, while their clustering into nanoscale signaling complexes on the plasma membrane, termed nanocluster, is augmented. Nanoclustering dictates downstream effector recruitment, MAPK-activity, and tumorigenic cell proliferation. Our results describe an unprecedented mechanism of signaling protein activation in cancer.

Published
2015

24. Specific cancer associated mutations in the switch III-region of Ras increase tumorigenicity by nanocluster augmentation.

Author

Solman, Maja, Ligabue, Alessio, Blazevits, Olga, Jaiswal, Alok, Yong Zhou, Hong Liang, Lectez, Benoit, Kopra, Kari, Guzman, Camilo, Härmä, Harri, Hancock, John F., Aittokallio, Tero, and Abankwa, Daniel

Subjects
*NEOPLASTIC cell transformation, *RAS oncogenes, *GENETIC mutation
Abstract

The article discusses a study which shows the increase of tumorigenicity following the cancer-associated mutations in the switch III region of Ras.

Published
2015
Full Text
View/download PDF

26. Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome

Author

Marialetizia Motta, Maja Solman, Adeline A Bonnard, Alma Kuechler, Francesca Pantaleoni, Manuela Priolo, Balasubramanian Chandramouli, Simona Coppola, Simone Pizzi, Erika Zara, Marco Ferilli, Hülya Kayserili, Roberta Onesimo, Chiara Leoni, Julia Brinkmann, Yoann Vial, Susanne B Kamphausen, Cécile Thomas-Teinturier, Anne Guimier, Viviana Cordeddu, Laura Mazzanti, Giuseppe Zampino, Giovanni Chillemi, Martin Zenker, Hélène Cavé, Jeroen den Hertog, Marco Tartaglia, Hubrecht Institute for Developmental Biology and Stem Cell Research, Karabey, Hülya Kayserili (ORCID 0000-0003-0376-499X & YÖK ID 7945), Motta, Marialetizia, Solman, Maja, Bonnard, Adeline, Kuechler, Alma, Pantaleoni, Francesca, Priolo, Manuela, Chandramouli, Balasubramanian, Coppola, Simona, Pizzi, Simone, Zara, Erika, Ferilli, Marco, Onesimo, Roberta, Leoni, Chiara, Brinkmann, Julia, Vial, Yoann, Kamphausen, Susanne B., Thomas-Teinturier, Cecile, Guimier, Anne, Cordeddu, Viviana, Mazzanti, Laura, Zampino, Giuseppe, Chillemi, Giovanni, Zenker, Martin, Cave, Helene, Hertog, Jeroen, Tartaglia, Marco, Koç University Hospital, and School of Medicine

Subjects
ras Proteins/genetics, Medizin, Loose Anagen Hair Syndrome/genetics, functional validation, Biochemistry and molecular biology, Genetics and heredity, RAS signalling, Abnormalities, Multiple/genetics, Loose Anagen Hair Syndrome, Genetics, Humans, Noonan syndrome, Abnormalities, Multiple, Molecular Biology, Genetics (clinical), SHOC2, Intracellular Signaling Peptides and Proteins, General Medicine, MAPK, SHOC2, Noonan syndrome, RASopathy, MAPK, RAS signalling, functional validation, Phenotype, RASopathy, Multiple/genetics, ras Proteins, Abnormalities, Phenotypecongenital abnormality, Signal transduction, Cell membrane, Embryo, Growth factor, Leucine, Mitogen-activated protein kinases, Protein kinase, Up-regulation (physiology) zebrafish genetics, Homogeneity, Fluid flow, Functional behavior, Psychology, Intracellular Signaling Peptides and Proteins/genetics
Abstract

We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A?>?G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A?>?G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here, we provide new data on the clinical spectrum and molecular diversity of this disorder and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge toward an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene and definitively establish a gain-of-function behavior as the mechanism of disease., European Union (EU); Horizon 2020; European Joint Program on Rare Diseases (EJP-RD); Associazione Italiana per la Ricerca sul Cancro (AIRC); Italian Ministry of Health (Ricerca Corrente 2022); Italian Ministry of Research (FOE 2019); German Federal Ministry of Education and Research; BMBF (German Network for RASopathy Research ""GeNeRARe""); European Reference Network on Rare Congenital Malformations and Rare Intellectual Disability (ERN-ITHACA)

Published
2022

27. Expanding the molecular spectrum of pathogenic SHOC2 variants underlying Mazzanti syndrome.

Author

Motta M, Solman M, Bonnard AA, Kuechler A, Pantaleoni F, Priolo M, Chandramouli B, Coppola S, Pizzi S, Zara E, Ferilli M, Kayserili H, Onesimo R, Leoni C, Brinkmann J, Vial Y, Kamphausen SB, Thomas-Teinturier C, Guimier A, Cordeddu V, Mazzanti L, Zampino G, Chillemi G, Zenker M, Cavé H, den Hertog J, and Tartaglia M

Subjects
Humans, Phenotype, ras Proteins genetics, ras Proteins metabolism, Abnormalities, Multiple genetics, Intracellular Signaling Peptides and Proteins genetics, Loose Anagen Hair Syndrome genetics
Abstract

We previously molecularly and clinically characterized Mazzanti syndrome, a RASopathy related to Noonan syndrome that is mostly caused by a single recurrent missense variant (c.4A > G, p.Ser2Gly) in SHOC2, which encodes a leucine-rich repeat-containing protein facilitating signal flow through the RAS-mitogen-associated protein kinase (MAPK) pathway. We also documented that the pathogenic p.Ser2Gly substitution causes upregulation of MAPK signaling and constitutive targeting of SHOC2 to the plasma membrane due to the introduction of an N-myristoylation recognition motif. The almost invariant occurrence of the pathogenic c.4A > G missense change in SHOC2 is mirrored by a relatively homogeneous clinical phenotype of Mazzanti syndrome. Here, we provide new data on the clinical spectrum and molecular diversity of this disorder and functionally characterize new pathogenic variants. The clinical phenotype of six unrelated individuals carrying novel disease-causing SHOC2 variants is delineated, and public and newly collected clinical data are utilized to profile the disorder. In silico, in vitro and in vivo characterization of the newly identified variants provides evidence that the consequences of these missense changes on SHOC2 functional behavior differ from what had been observed for the canonical p.Ser2Gly change but converge toward an enhanced activation of the RAS-MAPK pathway. Our findings expand the molecular spectrum of pathogenic SHOC2 variants, provide a more accurate picture of the phenotypic expression associated with variants in this gene and definitively establish a gain-of-function behavior as the mechanism of disease., (© The Author(s) 2022. Published by Oxford University Press. All rights reserved. For Permissions, please email: journals.permissions@oup.com.)

Published
2022
Full Text
View/download PDF

28. Nanoclustering and heterogeneous membrane diffusion of Ras studied by FRAP and RICS analysis.

Author

Guzmán C, Solman M, and Abankwa D

Subjects
Animals, Cell Line, Cricetinae, Diffusion, Microscopy, Confocal, Statistics as Topic, Cell Membrane metabolism, Fluorescence Recovery After Photobleaching methods, Nanostructures, Spectrometry, Fluorescence methods, ras Proteins chemistry, ras Proteins metabolism
Abstract

Fluorescence Recovery After Photobleaching (FRAP) and Raster Image Correlation Spectroscopy (RICS) are two powerful techniques to study the diffusion dynamics of fluorescently labeled proteins. FRAP and RICS can be easily applied on any commercial confocal microscope. In this chapter, we describe the principles of these methods and provide the reader with a detailed guide on how to apply these methods in the study of Ras nanoclustering and diffusion in the plasma membrane of live cells.

Published
2014
Full Text
View/download PDF

29. Cellular FRET-Biosensors to Detect Membrane Targeting Inhibitors of N-Myristoylated Proteins.

Author

Najumudeen AK, Köhnke M, Solman M, Alexandrov K, and Abankwa D

Subjects
Animals, Cell Line, Cluster Analysis, Cricetinae, Fluorescence Resonance Energy Transfer, Humans, Biosensing Techniques, Cell Membrane metabolism, Membrane Proteins metabolism, Myristic Acid metabolism
Abstract

Hundreds of eukaryotic signaling proteins require myristoylation to functionally associate with intracellular membranes. N-myristoyl transferases (NMT) responsible for this modification are established drug targets in cancer and infectious diseases. Here we describe NANOMS (NANOclustering and Myristoylation Sensors), biosensors that exploit the FRET resulting from plasma membrane nanoclustering of myristoylated membrane targeting sequences of Gαi2, Yes- or Src-kinases fused to fluorescent proteins. When expressed in mammalian cells, NANOMS report on loss of membrane anchorage due to chemical or genetic inhibition of myristoylation e.g. by blocking NMT and methionine-aminopeptidase (Met-AP). We used Yes-NANOMS to assess inhibitors of NMT and a cherry-picked compound library of putative Met-AP inhibitors. Thus we successfully confirmed the activity of DDD85646 and fumagillin in our cellular assay. The developed assay is unique in its ability to identify modulators of signaling protein nanoclustering, and is amenable to high throughput screening for chemical or genetic inhibitors of functional membrane anchorage of myristoylated proteins in mammalian cells.

Published
2013
Full Text
View/download PDF

Catalog

Books, media, physical & digital resources
See catalog results