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Cell Growth & Differentiation Vol. 10, 231-241, April 1999
© 1999 American Association for Cancer Research

Src Promotes PKC{delta} Degradation

Robert A. Blake, Pilar Garcia-Paramio, Peter J. Parker and Sara A. Courtneidge1

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{delta}, and its subsequent degradation. Enforced expression of PKC{delta} inhibited PDGF-stimulated DNA synthesis, whereas expression of PKC{alpha} and PKC{epsilon} did not, a finding consistent with a model in which PKC{delta} negatively regulates G1-to-S-phase progression. We used mutagenesis to map a critical Src phosphorylation site on PKC{delta} to tyrosine 311. A mutant form of PKC{delta} 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{delta} tyrosine phosphorylation. We conclude that PKC{delta} 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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Copyright © 1999 by the American Association of Cancer Research.