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Dissociation of platelet-derived growth factor (PDGF) receptor autophosphorylation from other PDGF-mediated second
M A Quiñones1, L J Mundschau, J B Rake
1Brigham and Women's Hospital, Boston, Massachusetts.
Abstract:
Activated p21ras alters the platelet-derived growth factor (PDGF) signal transduction pathway in fibroblasts by inhibiting autophosphorylation of the receptor as well as by inhibiting the induction of the growth-related genes c-myc, c-fos, and JE. To elucidate the cause and effect relationships between receptor autophosphorylation and other second messenger events in the PDGF signaling pathway we created revertants of v-ras transformed cells by two methods: 1) the use of cAMP analogues, and 2) the introduction of a gene, Krev-1, which has been reported previously to revert ras transformed cells to normal morphology. Analysis of the revertants shows that the PDGF-mediated tyrosine phosphorylation of the 180-kDa PDGF receptor remains inhibited; however, the PDGF-mediated activation of phospholipase C and the induction of the growth-related genes c-myc, c-fos, and JE have been restored. These data suggest the presence of parallel pathways for PDGF signal transduction which are not dependent on autophosphorylation of the PDGF receptor.
Insights
Activated p21ras disrupts platelet-derived growth factor (PDGF) signaling by inhibiting receptor autophosphorylation. Revertant cells restored PDGF-mediated gene induction, suggesting parallel signaling pathways independent of receptor autophosphorylation.
Area of Science:
- Cellular Biology
- Molecular Biology
- Signal Transduction
Background:
- Activated p21ras oncogene perturbs platelet-derived growth factor (PDGF) signaling in fibroblasts.
- This perturbation involves inhibition of PDGF receptor autophosphorylation and induction of growth-related genes (c-myc, c-fos, JE).
Purpose of the Study:
- To investigate the relationship between PDGF receptor autophosphorylation and downstream signaling events.
- To determine if restored PDGF signaling in revertant cells depends on receptor autophosphorylation.
Main Methods:
- Creation of v-ras transformed cell revertants using cAMP analogues or Krev-1 gene introduction.
- Analysis of PDGF-mediated signaling events, including receptor tyrosine phosphorylation, phospholipase C activation, and gene induction in revertant cells.
Main Results:
- PDGF receptor autophosphorylation remained inhibited in revertant cells.
- PDGF-mediated activation of phospholipase C and induction of c-myc, c-fos, and JE genes were restored in revertant cells.
- These findings indicate that restored PDGF signaling is independent of receptor autophosphorylation.
Conclusions:
- The PDGF signaling pathway involves parallel routes.
- These parallel pathways for PDGF signal transduction are not reliant on PDGF receptor autophosphorylation.