Nuclear localization of protein kinase C.

Abstract

Introduction A key issue in defining signal transduction pathways is understanding how signals generated at the plasma membrane are communicated to the nucleus. A number of studies have implicated a role for protein kinase C (PKC) in nuclear function. For example, the transcription of many genes, including c-fos and those coding for plasminogen activator, interferon and interleukin-2, is increased by the treatment of cells with phorbol esters, activators of PKC [ 1-41. Phosphorylation of a number of nuclear proteins, such as lamin €3, matrix proteins and DNA topoisomerase 11, is stimulated by phorbol 12myristate 13-acetate (PMA), suggesting that PKC may be phosphorylating these proteins directly, and thereby regulating their function [S-71. llsing immunological and biochemical analyses, we and others have demonstrated the presence of PKC in the nuclei in liver [HI, HIA0 cells [9] and 3T3 cells [lo-121. In some systems, such as the liver, PKC appears to be constitutively expressed in the nucleus [HI. In contrast, in other cell systems, PKC is present in nuclei prepared from stimulated, but not unstimulated cells. Stimulation of nuclear localization results not only from treatment with PMA, but also from incubation of cells with mitogens such as platelet-derived growth factor, insulin-like growth factor-I and a-thrombin [ 11-13]. The effect of PMA may result from a direct activation of PKC, but the mechanisms by which mitogens result in increased levels of nuclear PKC are not known. In this paper we will review our results demonstrating nuclear localization of PKC in two different cell lines, NIH 3T3 cells, and IIC9 cells [ lo , 131. Treatment of either cell type with PMA results in increased levels of PKC in the nucleus. In the IIC9 cells, we have also demonstrated that treatment with the physiological agonist a-thrombin stimulates nuclear localization. Furthermore, we have used the IIC9 system to begin to address the mechanisms for a-thrombin-induced PKC nuclear