- Protein kinase C (PKC) encodes a family of enzymes implicated in cellular differentiation, growth control, and tumor promotion. However, very little is known with respect to the molecular mechanisms that link protein kinase C to cell cycle control. Here we report that PKCη associates with the cyclin E/Cdk2 complex. This is shown for the ectopically overexpressed PKCη in NIH-3T3 cells, the inducibly expressed PKCη in MCF-7 cells (under control of the tetracycline-responsive promoter), and the endogenously expressed PKCη in mouse mammary epithelial HC11 cells. Subcellular cell fractionation experiments revealed that the complex with cyclin E is formed mostly in the nuclear fractions, although in these cells PKCη is predominantly expressed in the cytosolic fractions. The complex of PKCη and cyclin E was studied at various phases of the cell cycle, in serum-starved quiescent cells and in cells stimulated with serum to reenter the cell cycle. Interestingly, the interaction between PKCη and cyclin E was most prominent in serum-starved cells and was disintegrated when cells entered the cells cycle. Immunofluorescence staining demonstrated that in serum-starved cells PKCη is concentrated at the perinuclear zone, which is also the site of its colocalization with cyclin E. Colocalization of PKCη and cyclin E in the perinuclear region was observed in serum-starved cells, and less in proliferating cells. These experiments suggest that the interaction between PKCη and cyclin E is carefully regulated, and is correlated with the inactivated form of the cyclin E/Cdk2 complex. Thus, our studies support an important link between PKC and cell cycle control.