Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeleton dynamics in platelets
| العنوان: | Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeleton dynamics in platelets |
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| المؤلفون: | Lola Martínez, David Partida, Javier Muñoz, Aicha El Bakkali, Marianna Trakala, Begoña Hurtado, Pilar Ximénez-Embún, Belén Sanz-Castillo, Ruth Sánchez-Martínez, Pablo García de Frutos, Marcos Malumbres, María Maroto, Mónica Álvarez-Fernández |
| المساهمون: | Ministerio de Ciencia e Innovación (España), Fundacion La Caixa, Comunidad de Madrid, Fundación La Mataró TV3 |
| المصدر: | Repisalud Instituto de Salud Carlos III (ISCIII) |
| بيانات النشر: | American Society for Clinical Investigation (ASCI), 2018. |
| سنة النشر: | 2018 |
| مصطلحات موضوعية: | 0301 basic medicine, Blood Platelets, Phosphoprotein phosphatases, Mutation, Missense, Hyperphosphorylation, Chromosome Disorders, Mice, Transgenic, macromolecular substances, Protein Serine-Threonine Kinases, Cell cycle, 03 medical and health sciences, Mice, 0302 clinical medicine, Animals, Phosphorylation, Cytoskeleton, Mitosis, Actin, Protein kinase C, Chemistry, Kinase, Chromosome Breakage, Thrombosis, General Medicine, Cell Biology, Hematology, Actin cytoskeleton, Thrombocytopenia, Cell biology, Actin Cytoskeleton, 030104 developmental biology, Amino Acid Substitution, 030220 oncology & carcinogenesis, Pseudopodia, Microtubule-Associated Proteins, Signal Transduction, Research Article |
| الوصف: | MASTL, a Ser/Thr kinase that inhibits PP2A-B55 complexes during mitosis, is mutated in autosomal dominant thrombocytopenia. However, the connections between the cell cycle machinery and this human disease remain unexplored. We report here that, whereas Mastl ablation in megakaryocytes prevented proper maturation of these cells, mice carrying the thrombocytopenia-associated mutation developed thrombocytopenia as a consequence of aberrant activation and survival of platelets. Activation of mutant platelets was characterized by hyper-stabilized pseudopods mimicking the effect of PP2A inhibition and actin polymerization defects. These aberrations were accompanied by abnormal hyper-phosphorylation of multiple components of the actin cytoskeleton and were rescued both in vitro and in vivo by inhibiting upstream kinases such as PKA, PKC, or AMPK. These data reveal an unexpected role of Mastl in actin cytoskeleton dynamics in postmitotic cells, and suggest that the thrombocytopenia-associated mutation in MASTL is a pathogenic dominant mutation that mimics decreased PP2A activity resulting in altered phosphorylation of cytoskeletal regulatory pathways. We thank Peter Storz (Mayo Clinic; Jacksonville, FL) for sharin g reagents and Sheila Rueda for her support with the management of the mouse colony. B.H. and R.S.-M. were supported by the Juan de la Cierva Programme from the Spanish M inistry of Economy and Competitiveness (MINECO). M.T. was supported by Foundation La Caixa. A.E.B. was supported by the Programa de Empleo Juvenil, Comunidad de M adrid. M.A.-F. received a young investigator g rant from MINECO (SAF2014-60442- JIN; co-financed by FEDER funds). P.G.dF. was supported by Fundació la Marató de TV3 (project 080121 and project 20153031). J.M. was supported by the Ramon y Cajal programme (MINECO; RYC-2012-10651). M.M. lab. is supported by grants from the MINE CO (SAF2015- 69920-R), Programa iLUNG from the Comunidad de Madrid (B2017/BM D-3884), and Worldwide Cancer Research (15-0278). CNIO is a Severo Ochoa Cen ter of Excellence (MINECO awards SEV-2015-0510) Sí |
| اللغة: | English |
| الوصول الحر: | https://explore.openaire.eu/search/publication?articleId=doi_dedup___::b1b8ddb51da52a95cc4540479224274bTest https://hdl.handle.net/20.500.12105/6505Test |
| حقوق: | OPEN |
| رقم الانضمام: | edsair.doi.dedup.....b1b8ddb51da52a95cc4540479224274b |
| قاعدة البيانات: | OpenAIRE |
| الوصف غير متاح. |