A role for activated p21 ras in inhibition/regulation of platelet-derived growth factor (PDGF) type-beta receptor activation.
Ligand-stimulated Platelet-Derived Growth Factor (PDGF) type-beta receptor autophosphorylation, and tyrosine phosphorylation of receptor-associated signalling proteins, is blocked in cells expressing activated Ras genes. A factor present in membrane fractions of v-ras-expressing fibroblasts (Kbalb cells) dominantly inhibits the autophosphorylation of the PDGF type-beta receptor. Purification of this factor, via ion exchange, reveals that the inhibitor can be physically separated from the PDGF type-beta receptor, with reconstitution of PDGF type-beta receptor kinase activity in response to ligand binding. The inhibitor exhibited specificity for the PDGF type-beta receptor, and consistently co-purified with activated p21 ras, with Syp/PTP-2, and with Grb2. Neutralization of the p21 ras protein from the Kbalb cell membranes by p21 ras-specific monoclonal antibodies, however, completely removed the inhibition of PDGF type-beta receptor, rendering the PDGF type-beta receptor molecule capable of autophosphorylation in response to ligand. These results indicate that activated p21 ras either interacts directly with the PDGF type-beta receptor to inhibit autokinase activity, or complexes with different molecules such as Syp and/or Grb2 at the cell membrane to act on another effector which then inhibits PDGF type-beta receptor function.
Zubiaur
M
M
Cancer Research Center, Boston University School of Medicine, MA 02118, USA.
Forman
L W
LW
Stice
L L
LL
Faller
D V
DV
D016475:3T3 Cells / Q000502:physiology; D000595:Amino Acid Sequence; D000818:Animals; D000911:Antibodies, Monoclonal / Q000494:pharmacology; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008969:Molecular Sequence Data; D010766:Phosphorylation; D016283:Proto-Oncogene Proteins p21(ras) / Q000502:physiology*; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors* / Q000378:metabolism / Q000502:physiology*; D012680:Sensitivity and Specificity
D000911:Antibodies, Monoclonal; D020797:Receptor, Platelet-Derived Growth Factor beta; D017479:Receptors, Platelet-Derived Growth Factor; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras)