Modularity of the oncoprotein-like properties of platelet glycoprotein Ibalpha.
Glycoprotein Ib alpha (GpIbalpha), a trans-membrane glycoprotein, is expressed on the surface of megakaryocytes and platelets, where, in association with glycoprotein Ib beta, glycoprotein V, and glycoprotein IX, it normally forms the von Willebrand factor receptor (vWFR). A fully functional vWFR is necessary for platelet attachment, aggregation, and activation and has also been shown to regulate megakaryocyte ploidy. We have recently shown that the gene encoding GpIbalpha is a transcriptional target for the c-Myc oncoprotein and is more widely expressed than previously thought, with particularly high levels occurring in transformed cells. Indeed, GpIbalpha can substitute for c-Myc in promoting growth, transformation, and genomic instability. In the current work, we have demonstrated that, despite the promiscuous expression of GpIbalpha, other vWFR subunits remain largely restricted to megakaryocytes. We have characterized a panel of GpIbalpha mutants and shown that some regions of the protein essential for vWFR activity are not necessary for c-Myc-like functions. Specifically, the six C-terminal amino acids of the cytoplasmic domain, which mediate vWFR signaling, are entirely dispensible for the c-Myc-like functions of GpIbalpha. Instead, these require a more membrane-proximal filamin-binding domain. Also important is the GpIbalpha signal peptide, which, in the absence of other vWFR subunits, directs GpIbalpha to the endoplasmic reticulum rather than the membrane. Together, these results provide strong evidence that the domains of GpIbalpha mediating c-Myc-like functions are modular, genetically distinct, and independent of those involved in vWFR signaling.
Li
Youjun
Y
Section of Hematology/Oncology, Children's Hospital of Pittsburgh Pittsburgh, Pennsylvania 15213, USA.
Lu
Jie
J
Prochownik
Edward V
EV
D000818:Animals; D001792:Blood Platelets / Q000378:metabolism; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D015972:Gene Expression Regulation, Neoplastic / Q000235:genetics; D042822:Genomic Instability / Q000235:genetics; D006367:HeLa Cells; D006801:Humans; D008533:Megakaryocytes / Q000378:metabolism; D008562:Membrane Glycoproteins; D008565:Membrane Proteins / Q000096:biosynthesis* / Q000235:genetics / Q000378:metabolism; D051379:Mice; D009154:Mutation; D010973:Platelet Adhesiveness / Q000235:genetics; D019038:Platelet Glycoprotein GPIb-IX Complex; D011003:Ploidies; D021382:Protein Sorting Signals / Q000235:genetics; D017434:Protein Structure, Tertiary / Q000235:genetics; D016271:Proto-Oncogene Proteins c-myc / Q000235:genetics / Q000378:metabolism*; D051381:Rats; D015398:Signal Transduction / Q000235:genetics; D014841:von Willebrand Factor / Q000235:genetics / Q000378:metabolism
C489427:MYC protein, human; D008562:Membrane Glycoproteins; D008565:Membrane Proteins; D019038:Platelet Glycoprotein GPIb-IX Complex; D021382:Protein Sorting Signals; D016271:Proto-Oncogene Proteins c-myc; C094990:adhesion receptor; D014841:von Willebrand Factor