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.
Kanaji
Taisuke
T
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.
Russell
Susan
S
Cunningham
Janet
J
Izuhara
Kenji
K
Fox
Joan E B
JE
Ware
Jerry
J
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