TY - JOUR
T1 - Pak2 restrains endomitosis during megakaryopoiesis and alters cytoskeleton organization
AU - Kosoff, R.
AU - Aslan, Joseph E.
AU - Kostyak, John C.
AU - Dulaimi, Essel
AU - Chow, Hoi Yee
AU - Prudnikova, T. Y.
AU - Radu, Maria
AU - Kunapuli, Satya P.
AU - McCarty, Owen J.T.
AU - Chernoff, Jonathan
N1 - Publisher Copyright:
© 2015 by The American Society of Hematology.
PY - 2015
Y1 - 2015
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84983454132&partnerID=8YFLogxK
U2 - 10.1182/blood-2014-10-604504
DO - 10.1182/blood-2014-10-604504
M3 - Article
C2 - 25824689
SN - 0006-4971
VL - 125
SP - 2995
EP - 3005
JO - Blood
JF - Blood
IS - 19
ER -