Studies on heterogeneity of protein kinase C, their structures, regulations and functions.

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Protein kinase C (PKC) is a multifunctional protein Ser/Thr kinase and generally accepted to be involved in a wide variety of cellular signal transduction. In this study, we have found the existence of multiple subspecies of PKC through molecular cloning and enzymological analysis. Their relative activity and individual pattern of expression and intracellular locarization in several tissues and cell types are distinctly different one another. The PKC subspecies thus far obtained from various tissues exhibit subtle differences in their mode of activation, enzymological properties, and phorbol ester-induced down-regulation.In addition, the expressions of PKC subspecies are differently regulated during the differentiation of HL-60 cell toward granulocyte. Thus, it is strongly suggested that the members of PKC family each show distinctly different preference for substrate proteins that are located in specific intracellular comportments of the cell types in which they are expressed. Analysis of the activation of T-lymphocyte through PKC activation using phorbol esters or membrane-permeable diacylglycerols indicates a dual action of PKC, modulation of membrane receptor and regulation of gene expression. Short term PKC activation, which may be induced by the breakdown of inositol phospholipid, provides the down-regulation of TCR-CD3 complex on the surface of lymphocyte. On the other hand, sustained PKC activation is necessary to enhance the expression of IL-2 receptor eventually leading to cell proliferation.There appear to be several additional routes, other than the hydrolysis of inositol phospholipid, to provide the diacylglycerol that is needed for prolonged enzyme activation. This novel mechanisms leading to PKC activation as well as functional specificities of PKC subspecies remain to be explored to elucidate roles of PKC in the regulation of gene expression and growth control.