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

Abstract

Protein kinase Cδ (PKCδ) 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 PKCδ are involved in these two responses. Transfection of cells with PKCδ mutated at tyrosine 155 to phenylalanine caused enhanced proliferation in response to 12-phorbol 12-myristate 13-acetate, whereas GS expression resembled that for the PKCδ wild-type transfectant. Conversely, transfection with PKCδ mutated at tyrosine 187 to phenylalanine resulted in increased expression of GS, whereas the rate of proliferation resembled that of the PKCδ wild-type transfectant. The tyrosine phosphorylation of PKCδ 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 PKCδ via tyrosine 187. Finally, overexpression of dominant negative Fyn abrogated the decrease in GS expression and reduced the tyrosine phosphorylation of PKCδ induced by PDGF. We conclude that the tyrosine phosphorylation of PKCδ and its association with tyrosine kinases may be an important point of divergence in PKC signaling.