- Protein kinase C (PKC) represents a family of serin/threonine kinases, playing a central role in the regulation of cell growth, differentiation and transformation. These enzymes differ in their primary structure, biochemical properties, tissue distribution and subcellular localization. The specific cellular functions of PKC isoforms are largely controlled by their localization. PKCη, a member of the novel subfamily, is expressed predominantly in epithelial tissues. However, not much is known with respect to its mechanism of activation and regulation. Our recent studies suggest its role in cell cycle control. Here we show that PKCη is localized at the Golgi apparatus, ER and the nuclear envelope. Furthermore, using GFP-fusion proteins of the different functional domains of PKCη we deciphered the specific structural domains of the protein responsible for its apparent localization. We show that the cysteine-rich repeat C1b is responsible for its Golgi localization, while for its presence at the ER/nuclear envelope the pseudosubstrate containing fragment coupled to the C1 domain is required. In response to short-term activation by PMA we show translocation of PKCη to the plasma membrane and the nuclear envelope. We demonstrate that the C1b is sufficient for its translocation to the plasma membrane. Interestingly, accumulation of PKCη at the nuclear envelope also occurred in response to serum-starvation. It should be noted that interaction of PKCη with the cyclin E/Cdk2 complex at the perinuclear region was recently reported by us in response to serum-starvation. Thus, our studies demonstrate translocation of PKCη to the nuclear envelope, and suggest that the spatial regulation of PKCη could be important for its cellular functions including effects on cell cycle control and involvement in tumor promotion.