title: Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization.
abstract: 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.
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA; Cell and Molecular Biology, University of Pennsylvania School of Medicine, Philadelphia, PA;
authors.forename: Rachelle E
authors.initials: RE
authors.lastname: Kosoff
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR;
authors.forename: Joseph E
authors.identifier: http://orcid.org/0000-0002-8873-0387
authors.initials: JE
authors.lastname: Aslan
authors.affiliation: Sol Sherry Thrombosis Research Center, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA; and.
authors.forename: John C
authors.initials: JC
authors.lastname: Kostyak
authors.affiliation: Department of Pathology, Fox Chase Cancer Center, Philadelphia, PA.
authors.forename: Essel
authors.initials: E
authors.lastname: Dulaimi
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA;
authors.forename: Hoi Yee
authors.initials: HY
authors.lastname: Chow
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA;
authors.forename: Tatiana Y
authors.initials: TY
authors.lastname: Prudnikova
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA;
authors.forename: Maria
authors.initials: M
authors.lastname: Radu
authors.affiliation: Sol Sherry Thrombosis Research Center, Department of Pharmacology, Temple University School of Medicine, Philadelphia, PA; and.
authors.forename: Satya P
authors.initials: SP
authors.lastname: Kunapuli
authors.affiliation: Department of Biomedical Engineering, Oregon Health and Science University, Portland, OR;
authors.forename: Owen J T
authors.identifier: http://orcid.org/0000-0001-9481-0124
authors.initials: OJ
authors.lastname: McCarty
authors.affiliation: Cancer Biology Program, Fox Chase Cancer Center, Philadelphia, PA;
authors.forename: Jonathan
authors.identifier: http://orcid.org/0000-0002-4803-7836
authors.initials: J
authors.lastname: Chernoff
mesh_terms: D000818:Animals; D001792:Blood Platelets / Q000378:metabolism* / Q000473:pathology; D001853:Bone Marrow / Q000378:metabolism / Q000473:pathology; D003599:Cytoskeleton / Q000378:metabolism / Q000473:pathology*; D008533:Megakaryocytes / Q000378:metabolism* / Q000473:pathology; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D016513:Mice, SCID; D008856:Microscopy, Fluorescence; D008938:Mitosis / Q000235:genetics*; D051762:PAX2 Transcription Factor / Q000502:physiology*; D011123:Polyploidy; D013234:Stem Cells / Q000378:metabolism / Q000473:pathology; D013921:Thrombocytopenia / Q000235:genetics* / Q000473:pathology; D034061:Thrombopoiesis / Q000502:physiology*
chemical_list: D051762:PAX2 Transcription Factor; C497319:Pax2 protein, mouse
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