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Kosoff RE , Aslan JE , Kostyak JC , Dulaimi E , Chow HY , Prudnikova TY , Radu M , Kunapuli SP , McCarty OJT , Chernoff J
Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization
Blood. 2015 May;125(19) :2995-3005
PMID: 25824689    PMCID: PMC4424419    URL: https://www.ncbi.nlm.nih.gov/pubmed/25824689
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Megakaryocyte maturation and polyploidization are critical for platelet production; abnormalities in these processes are associated with myeloproliferative disorders, including thrombocytopenia. Megakaryocyte maturation signals through cascades that involve p21-activated kinase (Pak) function; however, the specific role for Pak kinases in megakaryocyte biology remains elusive. Here, we identify Pak2 as an essential effector of megakaryocyte maturation, polyploidization, and proplatelet formation. Genetic deletion of Pak2 in murine bone marrow is associated with macrothrombocytopenia, altered megakaryocyte ultrastructure, increased bone marrow megakaryocyte precursors, and an elevation of mature CD41(+) megakaryocytes, as well as an increased number of polyploid cells. In Pak2(-/-) mice, platelet clearance rate was increased, as was production of newly synthesized, reticulated platelets. In vitro, Pak2(-/-) megakaryocytes demonstrate increased polyploidization associated with alterations in beta1-tubulin expression and organization, decreased proplatelet extensions, and reduced phosphorylation of the endomitosis regulators LIM domain kinase 1, cofilin, and Aurora A/B/C. Together, these data establish a novel role for Pak2 as an important regulator of megakaryopoiesis, polyploidization, and cytoskeletal dynamics in developing megakaryocytes.
Kosoff, Rachelle E. Aslan, Joseph E. Kostyak, John C. Dulaimi, Essel Chow, Hoi Yee Prudnikova, Tatiana Y. Radu, Maria Kunapuli, Satya P. McCarty, Owen J. T. Chernoff, Jonathan