The study investigates the direct activation of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C) by tumor-promoting phorbol esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA). In vitro experiments show that TPA can substitute for unsaturated diacylglycerol, increasing the enzyme's affinity for Ca2+ and phospholipid. Kinetic analysis indicates that TPA significantly reduces the required Ca2+ concentration and enhances the enzyme's activation. In human platelets, TPA activates protein kinase C without provoking phosphatidylinositol breakdown, leading to the phosphorylation of a 40-kilodalton protein and serotonin release. Various phorbol derivatives with tumor-promoting activity also activate protein kinase C. These findings suggest that TPA may act directly on cell surface membranes, potentially influencing cellular functions or proliferation through protein kinase C activation.The study investigates the direct activation of Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C) by tumor-promoting phorbol esters, such as 12-O-tetradecanoylphorbol-13-acetate (TPA). In vitro experiments show that TPA can substitute for unsaturated diacylglycerol, increasing the enzyme's affinity for Ca2+ and phospholipid. Kinetic analysis indicates that TPA significantly reduces the required Ca2+ concentration and enhances the enzyme's activation. In human platelets, TPA activates protein kinase C without provoking phosphatidylinositol breakdown, leading to the phosphorylation of a 40-kilodalton protein and serotonin release. Various phorbol derivatives with tumor-promoting activity also activate protein kinase C. These findings suggest that TPA may act directly on cell surface membranes, potentially influencing cellular functions or proliferation through protein kinase C activation.