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oai:repisalud.isciii.es:20.500.12105/65052024-11-29T16:45:27Zcom_20.500.12105_2173com_20.500.12105_2051col_20.500.12105_19597

00925njm 22002777a 4500 dc Hurtado Villarejo, Begoña author Trakala, Marianna author Ximenez-Embun, Pilar author El Bakkali, Aicha author Partida, David author Sanz-Castillo, Belén author Alvarez Fernandez, Monica author Maroto, María author Sánchez-Martínez, Ruth author Martinez Garcia, Maria Dolores author Muoz Peralta, Javier author García de Frutos, Pablo author Malumbres Martinez, Marcos author 2018-09-25 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. J Clin Invest.2018 ; pii: 121876 10.1172/JCI121876 1558-8238 1558-8238 The Journal of clinical investigation 30252678 http://hdl.handle.net/20.500.12105/6505 Cell Biology Cell cycle Hematology Phosphoprotein phosphatases Thrombosis Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeleton dynamics in platelets