Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization

Rachelle E. Kosoff, Joseph E. Aslan, John C. Kostyak, Essel Dulaimi, Hoi Y ee Chow, Tatiana Y. Prudnikova, Maria Radu, Satya P. Kunapuli, Owen J T McCarty, Jonathan Chernoff

Research output: Contribution to journalArticlepeer-review


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 β1-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.

Original languageEnglish (US)
Pages (from-to)2995-3005
Number of pages11
Issue number19
StatePublished - May 7 2015

ASJC Scopus subject areas

  • Medicine(all)


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