Proto-Oncogene 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 an 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 exclusively expressed in hematopoietic cells and has the guanine nucleotide exchange activity. Here we report that granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and erythropoietin (EPO) induce rapid and transient tyrosine phosphorylation of Vav and that Vav is constitutively associated with the SH3 domain of Grb2/Ash in a human leukemia cell line UT-7. These data suggest that Vav is implicated in a signaling pathway leading to activation of Ras or Ras-related proteins in hematopoietic cells.
Furthermore, we have shown that the proto-oncogene c-cblc product (c-Cbl) is also tyrosine-phosphorylated by stimulation with GM-CSF or EPO and is constitutively associated with the SH3 domain of Grb2/Ash in UT-7. However, we could not find the homologous regions with guanine nucleotide exchange factors or GTPase-activating proteins in the c-cbl gene. Therefore, Grb2/Ash might also transduce a signal that is different from the signal leading to the small-G protein regulation.
KeywordsLymphoma Tyrosine Fluoride Leucine Tate
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- 5.. Rozakis-Adcock M, McGlade J, Mbamalu G, Pelicci G, Daly R, Li W, Batzer A, Thomas S, Brugge J, Pelicci PG, Schlessinger J, Pawson T: Association of the Shc and Grb2/Sem5 SH2-containing proteins is implicated in activation of the Ras pathway by tyrosine kinases. Nature 360: 689, 1992PubMedCrossRefGoogle Scholar
- 6.. Skolnik EY, Lee CH, Batzer A, Vicentini LM, Zhou M, Daly R, Myers Jr MJ, Backer JM, Ullrich A, White MF, Schlessinger J: The SH2/SH3 domain-containing protein GRB2 interacts with tyrosine-phosphorylated IRS1 and Shc: implications for insulin control of rassignalling. EMBO J 12: 1929, 1993PubMedGoogle Scholar
- 11.. Tanaka S, Morishita T, Hashimoto Y, Hattori S, Nakamura S, Shibuya M, Matsuoka K, Takenawa T, Kurata T, Nagashima K, Matsuda M: C3G, a guanine nucleotide-releasing protein expressed ubiquitously, binds to the Src homology 3 domains of CRK and GRB2/ASH proteins. Proc Natl Acad Sci USA 91: 3443, 1994PubMedCrossRefGoogle Scholar
- 18.. Komatsu N, Nakauchi H, Miwa A, Ishihara T, Eguchi M, Moroi M, Okada M, Sato Y, Wada H, Yawata Y, Suda T, Miura Y: Establishment and characterization of a human leukemic cell line with megakaryocyte features: dependency on granulocyte-macrophage colony-stimulating factor, interleukin 3, or erythropoietin for growth and survival. Cancer Res 51: 341, 1991PubMedGoogle Scholar