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

Protein kinase C delta (PKC delta) inhibits proliferation and decreases expression of the differentiation marker glutamine synthetase (GS) in C6 glioma cells. Here, we report that distinct, specific tyrosine residues on PKC delta are involved in these two responses. Transfection of cells with PKC delta mutated at tyrosine 155 to phenylalanine caused enhanced proliferation in response to 12-phorbol la-myristate 13-acetate, whereas GS expression resembled that for the PKC delta wild-type transfectant. Conversely, transfection with PKC delta mutated at tyrosine 187 to phenylalanine resulted in increased expression of GS, whereas the rate of proliferation resembled that of the PKC delta wild-type transfectant. The tyrosine phosphorylation of PKC delta and the decrease in GS expression induced by platelet-derived growth 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 expression and reduced the tyrosine phosphorylation of PKC delta induced by PDGF. We conclude that the tyrosine phosphorylation of PKC delta and its association with tyrosine kinases may be an important point of divergence in PKC signaling.