Thrombocytopenia-associated mutations in Ser/Thr kinase MASTL deregulate actin cytoskeletal dynamics in platelets

J Clin Invest. 2018 Dec 3;128(12):5351-5367. doi: 10.1172/JCI121876. Epub 2018 Oct 29.

Abstract

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 hyperstabilized pseudopods mimicking the effect of PP2A inhibition and actin polymerization defects. These aberrations were accompanied by abnormal hyperphosphorylation 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 cytoskeletal 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.

Keywords: Cell Biology; Cell cycle; Hematology; Phosphoprotein phosphatases; Thrombosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Actin Cytoskeleton* / enzymology
  • Actin Cytoskeleton* / genetics
  • Amino Acid Substitution
  • Animals
  • Blood Platelets / enzymology*
  • Blood Platelets / pathology
  • Chromosome Breakage*
  • Chromosome Disorders* / enzymology
  • Chromosome Disorders* / genetics
  • Chromosome Disorders* / pathology
  • Mice
  • Mice, Transgenic
  • Microtubule-Associated Proteins* / genetics
  • Microtubule-Associated Proteins* / metabolism
  • Mutation, Missense*
  • Phosphorylation
  • Protein-Serine-Threonine Kinases* / genetics
  • Protein-Serine-Threonine Kinases* / metabolism
  • Signal Transduction / genetics*
  • Thrombocytopenia / congenital*
  • Thrombocytopenia / enzymology
  • Thrombocytopenia / genetics
  • Thrombocytopenia / pathology

Substances

  • Microtubule-Associated Proteins
  • Protein-Serine-Threonine Kinases
  • greatwall protein, mouse

Supplementary concepts

  • Thrombocytopenia chromosome breakage