Regulation of platelet-derived growth factor signaling by activated p21Ras.
Elucidating the molecular mechanisms regulating transduction of growth control signals and the discovery of the subversion of these pathways by oncogenes has proven critical in unraveling the biochemical factors leading to cellular transformation. One such line of investigation has been study of the effects of transforming p21Ras on platelet-derived growth factor type-beta receptor (PDGF-betaR) signaling. Platelet-derived growth factor is an important extracellular factor regulating the G0-S phase transition of mesenchymal cells. Expression of activated, oncogenic Kirsten- or Harvey-p21Ras in cells influences PDGF-betaR signaling at multiple levels. At least two separate mechanisms account for defective PDGF-betaR signaling in activated p21Ras-expressing cells: (i) transcriptional down-regulation of PDGF-betaR expression, and (ii) inhibition of ligand-induced PDGF-betaR phosphorylation by a factor which is present in the cellular membrane fraction of fibroblasts expressing activated p21Ras. The state of growth arrest in G0 is associated with increased expression of the PDGF-betaR, and oncogene-transformed cell lines, which fail to undergo growth-arrest following prolonged serum-deprivation, express constitutively low levels of the PDGF-betaR mRNA, and possess greatly reduced numbers of PDGF-BB-binding sites. This repression of PDGF-betaR expression by p21Ras is, at least in large part, transcriptional. The membrane-associated factor induced by oncogenic p21Ras provides a connection between cell morphology and cytoskeletal elements and control of ligand-dependent PDGF-betaR autophosphorylation. Reversion of the transformed phenotype results in the recovery of PDGF-betaR kinase activity. Conversely, disruption of the actin cytoskeleton of untransformed fibroblasts leads to the loss of PDGF-betaR function. These studies define two potential mechanisms for feedback control of PDGF-betaR function by downstream elements in the PDGF signaling pathway. In addition, the connection between cell morphology and the function of the PDGF-betaR established by these studies provides a new mechanistic link between the organization of the cytoskeleton, the Ras-related small G proteins, and the activity of membrane-bound receptor tyrosine kinases.
Stice
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Cancer Research Center, Boston University School of Medicine, Boston, MA, USA.
Vaziri
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Faller
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D000818:Animals; D002453:Cell Cycle; D002454:Cell Differentiation; D002455:Cell Division; D002461:Cell Line, Transformed; D048429:Cell Size; D003598:Cytoskeletal Proteins / Q000378:metabolism; D019204:GTP-Binding Proteins / Q000378:metabolism; D005786:Gene Expression Regulation; D006801:Humans; D016023:Integrins / Q000502:physiology; D010744:Phosphoric Monoester Hydrolases / Q000378:metabolism; D010766:Phosphorylation; D010982:Platelet-Derived Growth Factor / Q000378:metabolism / Q000494:pharmacology / Q000502:physiology*; D016283:Proto-Oncogene Proteins p21(ras) / Q000378:metabolism / Q000502:physiology*; D017479:Receptors, Platelet-Derived Growth Factor / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000502:physiology*; D015398:Signal Transduction / Q000187:drug effects; D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins
D003598:Cytoskeletal Proteins; D016023:Integrins; D010982:Platelet-Derived Growth Factor; D017479:Receptors, Platelet-Derived Growth Factor; D010744:Phosphoric Monoester Hydrolases; D019204:GTP-Binding Proteins; C501009:HRAS protein, human; D016283:Proto-Oncogene Proteins p21(ras); D020744:rac GTP-Binding Proteins; D020741:rho GTP-Binding Proteins