Megakaryocyte proliferation and ploidy regulated by the cytoplasmic tail of glycoprotein Ibalpha.
We have investigated the ability of glycoprotein (GP) Ibalpha, a megakaryocytic gene product, to sequester the signal transduction protein 14-3-3xi and to influence megakaryocytopoiesis. Using a Gp1ba(-/-) mouse colony, we compared the rescued phenotypes produced by a wild-type human GP Ibalpha allele or a similar allele containing a 6-residue cytoplasmic tail truncation that abrogates binding to 14-3-3xi. The observed phenotypes illustrate an involvement for GP Ibalpha 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 Ibalpha/14-3-3xi/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 Ibalpha 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.
Department of Molecular and Experimental Medicine, Division of Experimental Hemostasis and Thrombosis, Roon Research Center for Arteriosclerosis and Thrombosis, MEM175, 10550 N Torrey Pines Rd, La Jolla, CA 92037, USA.
Taisuke
T
Kanaji
Susan
S
Russell
Janet
J
Cunningham
Kenji
K
Izuhara
Joan E B
JE
Fox
Jerry
J
Ware
D048948:14-3-3 Proteins / Q000378:metabolism; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001792:Blood Platelets / Q000502:physiology; D002455:Cell Division / Q000502:physiology; D006801:Humans; D008533:Megakaryocytes / Q000166:cytology* / Q000502:physiology*; D051379:Mice; D008822:Mice, Transgenic; D010766:Phosphorylation; D019038:Platelet Glycoprotein GPIb-IX Complex / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism*; D011003:Ploidies; D017346:Protein Serine-Threonine Kinases / Q000378:metabolism; D017434:Protein Structure, Tertiary; D011518:Proto-Oncogene Proteins / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt; D012720:Severity of Illness Index; D013921:Thrombocytopenia / Q000503:physiopathology
D048948:14-3-3 Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D011518:Proto-Oncogene Proteins; C494918:AKT1 protein, human; D017346:Protein Serine-Threonine Kinases; D051057:Proto-Oncogene Proteins c-akt