Activation of phosphatidylinositol-3-kinase by platelet-derived growth factor and insulin-like growth factor-1 is inhibited by a transmembrane phosphotyrosine phosphatase.
Expression of the transmembrane phosphotyrosine phosphatase (PTPase) CD45 has been shown to inhibit hormone-dependent tyrosine phosphorylation and mitogenesis (Mooney, R. A., Freund, G. G., Way, B. A., and Bordwell, K. L. (1992) J. Biol. Chem. 267, 23443-23446). Here the impact of PTPase expression on insulin-like growth factor-1 (IGF-1) and platelet-derived growth factor- (PDGF) dependent activation of PI-3-K was investigated. In PTPase+ cells, IGF-1 and PDGF-dependent PI-3-K activity in antiphosphotyrosine immunoprecipitates was decreased by 62 +/- 13 and 46 +/- 17%, respectively, compared to control cells. Similar decreases in PI-3-K activity associated with anti-PDGF receptor and anti-insulin receptor substrate-1 (IRS-1) immunoprecipitates were also observed. Association of PI-3-K with the hormone-activated PDGF receptor decreased approximately 55%, paralleling its loss of activation in PTPase+ cells. Tyrosine phosphorylation of the 85-kDa subunit of PI-3-K was also inhibited. Similarly, IGF-1 dependent tyrosine phosphorylation of IRS-1 was decreased by 45%, and its association with PI-3-K was decreased by 65% in PTPase+ cells. Finally, PDGF-dependent tyrosine phosphorylation of phospholipase C-gamma 1 and GTPase-activating protein was reduced by 60-70% in the PTPase+ cells as was tyrosine phosphorylation of the PDGF receptor associated with these proteins. In summary, expression of a transmembrane PTPase decreased hormone-dependent PI-3-K activation, tyrosine phosphorylation of receptor substrates, and their association with signaling complexes. These data support a role for transmembrane PTPases in the regulation of receptor signal transduction pathways.
Way
B A
BA
Department of Pathology and Laboratory Medicine, University of Rochester School of Medicine and Dentistry, New York 14642.
Mooney
R A
RA
D000818:Animals; D002462:Cell Membrane / Q000201:enzymology; D004789:Enzyme Activation; D007334:Insulin-Like Growth Factor I / Q000037:antagonists & inhibitors / Q000378:metabolism*; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D010766:Phosphorylation; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000037:antagonists & inhibitors / Q000378:metabolism*; D010982:Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000378:metabolism*; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism*; D014407:Tumor Cells, Cultured; D014443:Tyrosine / Q000378:metabolism
D010982:Platelet-Derived Growth Factor; D014443:Tyrosine; D007334:Insulin-Like Growth Factor I; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D017027:Protein Tyrosine Phosphatases