The GTPase-activating protein of Ras suppresses platelet-derived growth factor beta receptor signaling by silencing phospholipase C-gamma 1.
The beta receptor for platelet-derived growth factor (beta PDGFR) is activated by binding of PDGF and undergoes phosphorylation at multiple tyrosine residues. The tyrosine-phosphorylated receptor associates with numerous SH2-domain-containing proteins which include phospholipase C-gamma 1 (PLC gamma), the GTPase-activating protein of Ras (GAP), the p85 subunit of phosphatidylinositol 3 kinase (PI3K), the phosphotyrosine phosphatase Syp, and several other proteins. Our previous studies indicated that PI3K and PLC gamma were required for relay of the mitogenic signal of beta PDGFR, whereas GAP and Syp did not appear to be required for this response. In this study, we further investigated the role of GAP and Syp in mitogenic signaling by beta PDGFR. Focusing on the PLC gamma-dependent branch of beta PDGFR signaling, we constructed a series of mutant beta PDGFRs that contained the binding sites for pairs of the receptor-associated proteins: PLC gamma and PI3K, PLC gamma and GAP, or PLC gamma and Syp. Characterization of these mutants showed that while all receptors were catalytically active and bound similar amounts of PLC gamma, they differed dramatically in their ability to initiate DNA synthesis. This signaling deficiency related to an inability to efficiently tyrosine phosphorylate and activate PLC gamma. Surprisingly, the crippled receptor was the one that recruited PLC gamma and GAP. Thus, GAP functions to suppress signal relay by the beta PDGFR, and it does so by silencing PLC gamma. These findings demonstrate that the biological response to PDGF depends not only on the ability of the beta PDGFR to recruit signal relay enzymes but also on the blend of these receptor-associated proteins.
Valius
M
M
Department of Pediatrics, National Jewish Center for Immunology and Respiratory Medicine, Denver, Colorado 80206, USA.
Secrist
J P
JP
Kazlauskas
A
A
D001665:Binding Sites / Q000235:genetics; D002460:Cell Line; D020690:GTPase-Activating Proteins; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism*; D009154:Mutation; D051966:Phospholipase C gamma; D010766:Phosphorylation; D011506:Proteins / Q000378:metabolism* / Q000494:pharmacology; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000235:genetics / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction; D010738:Type C Phospholipases / Q000378:metabolism*; D020703:ras GTPase-Activating Proteins
D020690:GTPase-Activating Proteins; D007527:Isoenzymes; D011506:Proteins; D020703:ras GTPase-Activating Proteins; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; D010738:Type C Phospholipases; D051966:Phospholipase C gamma