title: The PDGF receptor alpha subunit activates p21ras and triggers DNA synthesis without interacting with rasGAP.
abstract: There are two closely related, but distinct platelet-derived growth factor receptor (PDGFR) subunits: alpha and beta. Recent studies have indicated that relay of a biological signal from the activated PDGFR beta subunit is determined to a large degree by the intracellular signal transduction enzymes with which the beta subunit associates. Like the beta subunit, the PDGFR alpha subunit encodes a tyrosine kinase that is activated and tyrosine phosphorylated upon binding of PDGF. To investigate the mechanism by which the PDGFR alpha subunit mediates signal transduction, we examined the proteins that associate with the activated PDGFR alpha subunit. The human alpha subunit was expressed in PhB cells, fibroblasts derived from Ph/Ph mouse embryos, which express the beta subunit but do not express the PDGFR alpha subunit. In response to binding of PDGF, the alpha subunit stably associated with phospholipase C gamma 1 (PLC-gamma 1), phosphatidylinositol 3 kinase (PI3K), the phosphotyrosine phosphatase Syp, and a 120 kd protein. These same proteins were detected binding to the activated PDGFR beta subunit. Unlike the PDGFR beta subunit, the PDGF-activated alpha subunit did not stably associate with the GTPase activating protein of ras (rasGAP), nor did it mediate tyrosine phosphorylation of rasGAP. Despite its apparent inability to interact with rasGAP, the alpha subunit was fully able to trigger PDGF-dependent p21ras activation and DNA synthesis. We conclude that the PDGFR alpha subunit does not mediate tyrosine phosphorylation or associate with ras-GAP, and that these events are not required for PDGF-AA-mediated activation of p21ras or DNA synthesis.
authors.affiliation: National Jewish Center for Immunology and Respiratory Medicine, Department of Pediatrics, Denver, Colorado 80206.
authors.forename: C E
authors.initials: CE
authors.lastname: Bazenet
authors.forename: A
authors.initials: A
authors.lastname: Kazlauskas
mesh_terms: D016475:3T3 Cells; D000818:Animals; D015153:Blotting, Western; D004247:DNA / Q000096:biosynthesis* / Q000235:genetics; D005347:Fibroblasts / Q000737:chemistry / Q000166:cytology / Q000378:metabolism; D020690:GTPase-Activating Proteins; D005786:Gene Expression Regulation / Q000235:genetics; D011905:Genes, ras / Q000235:genetics; D051379:Mice; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor) / Q000378:metabolism; D011233:Precipitin Tests; D000091402:Prohibitins; D017027:Protein Tyrosine Phosphatases / Q000378:metabolism; D011505:Protein-Tyrosine Kinases / Q000235:genetics; D011506:Proteins / Q000235:genetics / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000032:analysis / Q000235:genetics* / Q000378:metabolism; D017479:Receptors, Platelet-Derived Growth Factor / Q000032:analysis / Q000378:metabolism* / Q000502:physiology*; D015398:Signal Transduction / Q000502:physiology; D013936:Thymidine / Q000378:metabolism; D014316:Tritium; D010738:Type C Phospholipases / Q000378:metabolism; D020703:ras GTPase-Activating Proteins
chemical_list: D004247:DNA; D020690:GTPase-Activating Proteins; D019869:Phosphatidylinositol 3-Kinases; D017853:Phosphotransferases (Alcohol Group Acceptor); D000091402:Prohibitins; D017027:Protein Tyrosine Phosphatases; D011505:Protein-Tyrosine Kinases; D011506:Proteins; D016283:Proto-Oncogene Proteins p21(ras); D017479:Receptors, Platelet-Derived Growth Factor; D013936:Thymidine; D014316:Tritium; D010738:Type C Phospholipases; D020703:ras GTPase-Activating Proteins; C000717328:PHB protein, human