Src promotes PKC delta degradation

Platelet-derived growth factor BB (PDGF) stimulates DNA synthesis through a mechanism that is at least partially dependent upon Src family tyrosine ki nases, although the signal transduction pathway downstream of Src is poorly understood. We have studied the signaling between Src and different protei n kinase C (PKC) isoforms and its possible role in the regulation of PDGF-s timulated DNA synthesis. We found that Src promoted the tyrosine phosphoryl ation of PKC delta, and its subsequent degradation. Enforced expression of PKC delta inhibited PDGF-stimulated DNA synthesis, whereas expression of PK C alpha and PKC epsilon did not, a finding consistent with a model in which PKC delta negatively regulates G(1)-to-S-phase progression. We used mutage nesis to map a critical Src phosphorylation site on PKC delta to tyrosine 3 11. A mutant form of PKC delta in which tyrosine 311 was replaced with phen ylalanine (Y311F) was more stable in the presence of Src, suggesting that S rc-induced degradation was a direct result of PKC delta tyrosine phosphoryl ation. We conclude that PKC delta is downstream of Src but is unlikely to p lay a positive role in the signaling pathway by which Src promotes DNA synt hesis.