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Src Promotes PKC Degradation

SUGEN Inc., South San Francisco, California 94080-4811 [R. A. B., S. A. C.], and Imperial Cancer Research Fund, London WC2A 3PX, United Kingdom [P. G-P., P. J. P.]

Platelet-derived growth factor BB (PDGF) stimulates DNA synthesis through a mechanism that is at least partially dependent upon Src family tyrosine kinases, although the signal transduction pathway downstream of Src is poorly understood. We have studied the signaling between Src and different protein kinase C (PKC) isoforms and its possible role in the regulation of PDGF-stimulated DNA synthesis. We found that Src promoted the tyrosine phosphorylation of PKC, and its subsequent degradation. Enforced expression of PKC inhibited PDGF-stimulated DNA synthesis, whereas expression of PKC and PKC did not, a finding consistent with a model in which PKC negatively regulates G₁-to-S-phase progression. We used mutagenesis to map a critical Src phosphorylation site on PKC to tyrosine 311. A mutant form of PKC in which tyrosine 311 was replaced with phenylalanine (Y311F) was more stable in the presence of Src, suggesting that Src-induced degradation was a direct result of PKC tyrosine phosphorylation. We conclude that PKC is downstream of Src but is unlikely to play a positive role in the signaling pathway by which Src promotes DNA synthesis.

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