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Blood, 15 November 2004, Vol. 104, No. 10, pp. 3161-3168.
Prepublished online as a Blood First Edition Paper on July 22, 2004; DOI 10.1182/blood-2004-03-0893.


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HEMATOPOIESIS

Megakaryocyte proliferation and ploidy regulated by the cytoplasmic tail of glycoprotein Ib{alpha}

Taisuke Kanaji, Susan Russell, Janet Cunningham, Kenji Izuhara, Joan E. B. Fox, and Jerry Ware

From the Department of Molecular and Experimental Medicine, Division of Experimental Hemostasis and Thrombosis, Roon Research Center for Arteriosclerosis and Thrombosis, La Jolla, CA; the Department of Molecular Cardiology, Joseph J. Jacobs Center for Thrombosis and Vascular Biology, The Lerner Research Institute, The Cleveland Clinic Foundation, OH; and the Department of Biomolecular Sciences, Saga Medical School, Japan.

We have investigated the ability of glycoprotein (GP) Ib{alpha}, a megakaryocytic gene product, to sequester the signal transduction protein 14-3-3{xi} and to influence megakaryocytopoiesis. Using a Gp1ba–/– mouse colony, we compared the rescued phenotypes produced by a wild-type human GP Ib{alpha} allele or a similar allele containing a 6-residue cytoplasmic tail truncation that abrogates binding to 14-3-3{xi}. The observed phenotypes illustrate an involvement for GP Ib{alpha} in thrombopoietin-mediated events of megakaryocyte proliferation, polyploidization, and the expression of apoptotic markers in maturing megakaryocytes. We developed a hypothesis for the involvement of a GP Ib{alpha}/14-3-3{xi}/PI-3 kinase complex in regulating thrombopoietin-mediated responses. An observed increase in thrombopoietin-mediated Akt phosphorylation in the truncated variant supported the hypothesis and led to the development of a model in which the GP Ib{alpha} cytoplasmic tail sequestered signaling proteins during megakaryocytopoiesis and, as such, became a critical regulator in the temporal sequence of events that led to normal megakaryocyte maturation.


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