Phosphorylation of protein kinase C delta on distinct tyrosine residues regulates specific cellular functions

Protein kinase C delta (PKC delta) inhibits proliferation and decreases exp ression of the differentiation marker glutamine synthetase (GS) in C6 gliom a cells. Here, we report that distinct, specific tyrosine residues on PKC d elta are involved in these two responses. Transfection of cells with PKC de lta mutated at tyrosine 155 to phenylalanine caused enhanced proliferation in response to 12-phorbol la-myristate 13-acetate, whereas GS expression re sembled that for the PKC delta wild-type transfectant. Conversely, transfec tion with PKC delta mutated at tyrosine 187 to phenylalanine resulted in in creased expression of GS, whereas the rate of proliferation resembled that of the PKC delta wild-type transfectant. The tyrosine phosphorylation of PK C delta and the decrease in GS expression induced by platelet-derived growt h factor (PDGF) were abolished by the Src kinase inhibitors PP1 and PP2. In response to PDGF, Fyn associated with PKC delta via tyrosine 187. Finally, overexpression of dominant negative Fyn abrogated the decrease in GS expre ssion and reduced the tyrosine phosphorylation of PKC delta induced by PDGF . We conclude that the tyrosine phosphorylation of PKC delta and its associ ation with tyrosine kinases may be an important point of divergence in PKC signaling.