Y. Hanazono et al., PROTOONCOGENE PRODUCTS VAV AND C-CBL ARE INVOLVED IN THE SIGNAL-TRANSDUCTION THROUGH GRB2 ASH IN HEMATOPOIETIC-CELLS/, Acta haematologica, 95(3-4), 1996, pp. 236-242
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
.