Abstract
Insulin activates the ras signaling pathway and promotes hematopoietic cell proliferation. One possible mediator in such signaling is the vav proto-oncogene product (p95vav), which is specifically expressed in cells of hematopoietic origin and contains domains typical of guanine nucleotide exchange factors as well as Src homology 2 and Src homology 3 domains. We studied the tyrosine phosphorylation of p95vav in hematopoietic cells expressing insulin receptors. Immunoblotting experiments with an antiphosphotyrosine monoclonal antibody disclosed that insulin induces rapid and transient tyrosine phosphorylation of p95vav in the human U-266 myeloma cell line. These findings were confirmed by immunoprecipitation experiments performed with 32P-labeled cells and phosphoamino acid analysis of the bands corresponding to p95vav. Similarly, insulin-dependent tyrosine phosphorylation of p95vav was observed in the human IM-9 and mouse J558L hematopoietic cell lines. Furthermore, insulin treatment of cells led to the association of the Src homology 2 domain of p95vav with the activated beta-subunit of the insulin receptor in vitro. Altogether, these data suggest that p95vav is a substrate for the insulin receptor tyrosine kinase and may be involved in an insulin signaling pathway linking receptor-generated signals to Ras or other GTP-binding proteins in cells of hematopoietic origin.
Highlights
From the Wi vision of Hematology-Oncology, Loyola University of Chicago, Maywood, Illinois 60153, the §Hines Veterans Administration Medical Center, Hines, Illinois 60141, the ~Terry Fox Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, Montreal H3T 1E2, Canada, the lrDepartments of Oncology and Medicine, McGill University, Montreal H3G 1Y6, Canada, and the **Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215
Vav was predicted to function as a guanine nucleotide exchange factor for Rho-like proteins, it was recently demonstrated that it exhibits guanine nucleotide exchange activity toward ras during T-cell activation [13], in NIH-3T3 cells transfected with the vav gene [14], and in antigen receptor-triggered B-cells [15]
We examined the effect of insulin on the phosphorylation status of p95va v We report that p95va v is tyrosine-phosphorylated in response to insulin in several hematopoietic cell lines expressing the insulin receptor
Summary
Vol 270, No 13, Issue of March 31, pp. 7712-7716, 1995 Printed in U.S.A. Insulin-dependent Tyrosine Phosphorylation of the vav Protooncogene Product in Cells of Hematopoietic Origin*. Platanias:j:§:j::j: From the Wi vision of Hematology-Oncology, Loyola University of Chicago, Maywood, Illinois 60153, the §Hines Veterans Administration Medical Center, Hines, Illinois 60141, the ~Terry Fox Molecular Oncology Group, Lady Davis Institute, Jewish General Hospital, Montreal H3T 1E2, Canada, the lrDepartments of Oncology and Medicine, McGill University, Montreal H3G 1Y6, Canada, and the **Research Division, Joslin Diabetes Center, Harvard Medical School, Boston, Massachusetts 02215. Insulin treatment of cells led to the association of the Src homology 2 domain of p95va v with the activated f3-subunit of the insulin receptor in vitro These data suggest that p95va v is a substrate for the insulin receptor tyrosine kinase and may be involved in an insulin signaling pathway linking receptorgenerated signals to Ras or other GTP-binding proteins in cells of hematopoietic origin.
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