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v-mos suppresses platelet-derived growth factor (PDGF) type-beta receptor autophosphorylation and inhibits
D V Faller1, L J Mundschau, L W Forman
1Cancer Research Center, Boston University School of Medicine, Massachusetts 02118.
Abstract:
The function of mos protein in somatic cells, the mechanisms underlying its ability to transform cells, and its relationship to growth factor autonomy and growth factor-mediated signal transduction are not well defined. This report demonstrates that the expression of transforming mos (v-mos) can block the stimulation of growth-related gene expression mediated by the platelet-derived growth factor (PDGF-BB). This blockade by v-mos of PDGF-BB signal transduction occurs very early in the signalling pathway, at the level of PDGF type-beta receptor autophosphorylation. Although the expression of PDGF type-beta receptor, as detected by Western blot with anti-PDGF type-beta receptor antibody,was not diminished in v-mos transformed BALB/c-3T3 murine fibroblasts, the autophosphorylation of PDGF-beta receptor in response to ligand (recombinant PDGF-BB homodimer) stimulation was profoundly suppressed. This same phenomenon of v-mos-mediated PDGF type-beta receptor autophosphorylation inhibition was also demonstrated in NIH-3T3 fibroblasts. A v-mos mutant gene, which was incapable of binding ATP and was kinase-defective, did not block ligand-mediated receptor autophosphorylation. Factor(s) present in v-mos expressing fibroblasts, and found in the membrane fractions of these cells, dominantly inhibit the autophosphorylation of the PDGF type-beta receptor obtained from normal fibroblasts. This trans-acting factor does not appear to be a protein-tyrosine phosphatase. These findings suggest a role for mos, or a similar serine/threonine kinase, as a control mechanism in one of the earliest steps of the PDGF signal transduction pathway, and may provide a model for the functional interaction of mos with growth factor receptors.
Insights
Transforming mos (v-mos) protein blocks platelet-derived growth factor (PDGF) signaling early in the pathway by inhibiting PDGF receptor autophosphorylation. This suggests mos acts as a control mechanism in growth factor signaling.
Area of Science:
- Cell Biology
- Molecular Biology
- Oncology
Background:
- The precise function of mos protein in somatic cells and its role in cell transformation and growth factor signaling remain unclear.
- Understanding mos protein's interaction with growth factor-mediated signal transduction is crucial for deciphering cellular growth control.
Purpose of the Study:
- To investigate the mechanisms by which transforming mos (v-mos) protein affects platelet-derived growth factor (PDGF) signaling.
- To determine the specific stage in the PDGF signal transduction pathway where v-mos exerts its inhibitory effect.
Main Methods:
- Expression of transforming mos (v-mos) in BALB/c-3T3 and NIH-3T3 fibroblasts.
- Analysis of PDGF type-beta receptor autophosphorylation in response to PDGF-BB stimulation using Western blotting.
- Utilizing a kinase-defective v-mos mutant to assess the role of mos kinase activity.
Main Results:
- v-mos expression profoundly suppressed PDGF type-beta receptor autophosphorylation in response to PDGF-BB, without reducing receptor expression.
- A kinase-defective v-mos mutant failed to inhibit receptor autophosphorylation, indicating the necessity of mos kinase activity.
- Membrane fractions from v-mos expressing cells contained a trans-acting factor that inhibited PDGF type-beta receptor autophosphorylation.
Conclusions:
- Mos protein, or a similar serine/threonine kinase, plays a role in regulating early steps of PDGF signal transduction.
- v-mos acts as an inhibitor of PDGF type-beta receptor autophosphorylation, suggesting a novel control mechanism in growth factor signaling pathways.