Direct activation of calcium-activated, phospholipid-dependent protein kinase by tumor-promoting phorbol esters.

TLDR

Tumor‑promoting phorbol esters such as TPA directly activate Ca²⁺‑dependent, phospholipid‑dependent protein kinase C, a process normally triggered by diacylglycerol and linked to phosphatidylinositol breakdown that regulates cellular functions and proliferation. Kinetic studies show that TPA and other phorbol derivatives substitute for diacylglycerol, markedly increase PKC affinity for Ca²⁺ and phospholipid, and enhance PKC‑specific phosphorylation in human platelets even in the absence of phosphatidylinositol breakdown.

Abstract

Tumor-promoting phorbol esters such as 12-O-tetradecanoylphorbol-13-acetate (TPA) directly activate in vitro Ca2+-activated, phospholipid-dependent protein kinase (protein kinase C), which normally requires unsaturated diacylglycerol. Kinetic analysis indicates that TPA can substitute for diacylglycerol and greatly increases the affinity of the enzyme for Ca2+ as well as for phospholipid. Under physiological conditions, the activation of this enzyme appears to be linked to the receptor-mediated phosphatidylinositol breakdown which may be provoked by a wide variety of extracellular messengers, eventually leading to the activation of specific cellular functions or proliferation. Using human platelets as a model system, TPA is shown to enhance the protein kinase C-specific phosphorylation associated with the release reaction in the total absence of phosphatidylinositol breakdown. Various phorbol derivatives which have been shown to be active in tumor promotion are also capable of activating this protein kinase in in vitro systems.