PROTOONCOGENE PRODUCTS VAV AND C-CBL ARE INVOLVED IN THE SIGNAL-TRANSDUCTION THROUGH GRB2 ASH IN HEMATOPOIETIC-CELLS/

Grb2/Ash is composed of one SH2 and two SH3 domains and functions as a n adapter linking tyrosine kinase receptors and Ras in fibroblasts. We have investigated the nature of proteins interacting with Grb2/Ash in hematopoietic cells. The product of the vav proto-oncogene (Vav) is e xpressed exclusively in hematopoietic cells and has guanine nucleotide exchange activity. Here we report that granulocyte/macrophage-colony- stimulating factor (GM-CSF), interleukin-3, and erythropoietin (Epo) i nduce rapid and transient tyrosine phosphorylation of Vav and that Vav is constitutively associated with the SH3 domain of Grb2/Ash in a hum an leukemia cell line UT-7. These data implicate Vav in a signaling pa thway leading to activation of Ras or Ras-related proteins in hematopo ietic cells. Furthermore, we have shown that the protooncogene c-cbl p roduct (c-Cbl) is also tyrosine-phosphorylated by stimulation with GM- CSF or Epo and is constitutively associated with the SH3 domain of Grb 2/Ash in UT-7. However, we could not find the homologous regions with guanine nucleotide exchange factors or GTPase-activating proteins in t he c-cbl gene. Therefore, Grb2/Ash might also transduce a signal that is different from the signal leading to the small-G protein regulation .