Role of Protein Kinase C in Cellular Proliferation

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It has been proposed that protein kinase C plays important roles in cell proliferation because this enzyme is activated by diacylglycerol transiently formed by phosphatidylinositol breakdown induced by various growth factors or by tumorpromoting phorbol esters. It has also been shown that protein kinase C is subjected to limited proteolysis and down regulation of this enzyme is induced during prolonged treatment of various cells with phorbol esters. In an attempt to understand the molecular mechanism of the down regulation of protein kinase C, we analyzed the proteolytic modification of this enzyme using the rat liver plasma membrane. Under higher ionic strength than physiological level (>140 mM NaCl) and slightly alkaline pH (7.5-8.0), proteaseーactivated form of protein kinase C with Mr. 50,000 was rapidly released from the membrane. The properties of this activated enzyme were essentially the same as those of protein kinase M (corresponding to the catalytic fragment of protein kinase C) reported earlir. Based on these results, we supposed that activation of Na^+/H^+ exchanger in plasma membrane may be a trigger for inducing the down regulation of protein kinase C, because Na^+ influx and cytoplasmic alkalinization are usually observed after activation of Na^+/H^+ exchanger by various extracellular stimuli. In contrast, higher molecular weight form of protein kinase C (Mr. 80,000) was generated from membrane under lower ionic strength condion. The activity of this enzyme was stimulated 2-fold by Ca2+ and phospholipid. This partially activated kinase was converted to a Ca2+-phospholipid-independent form by further digestion with trypsin without significant change in molecullar mass. However, the physiological significance of these proteolyzed enzymes with Mr. 80,000 is not clear at this time. Further detailed analyses of down regulation of protein kinase C seems to be important for understanding the role of protein kinase C in cell proliferation.