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PKC
The protein kinase C (PKC) family is comprised of a group of serine/threonine kinases that are evolutionary conserved and expressed in a wide variety of species across phyla. The biological role of PKC has been intensely investigated in a wide range of normal physiological systems and in a variety of pathological conditions. The PKC-regulated signals are translated within cells into critical physiological processes regulating gene expression, cell-cycle progression, cell migration, proliferation and differentiation, cell survival and apoptosis. The distinct functions of individual PKC isoforms in cellular processes are regulated by the receptor-triggered translocation of individual isoforms to specific intracellular compartments. Absence of PKC and/or its dysregulation may therefore lead to different pathologies, including diabetes, heart failure, Alzheimer and Parkinson diseases, allergy, inflammatory diseases, and a range of autoimmune diseases. Activation of PKC under physiological conditions is made possible by extracellular agonists, such as growth factors, hormones, cytokines or antigens, following interaction with their cognate G protein-coupled receptors or receptor tyrosine kinases. Receptor engagement then initiates the activation of effector molecules, such as the membrane-associated phospholipase C (PLC), which hydrolyses the membrane phospholipid phosphatidylinositol 4,5-bisphosphatet (PIP2) to form two hydrolytic products: DAG and inositol 1,4,5-trisphosphate (IP3).
An increase in the membrane-associated DAG promotes low affinity DAG binding to the C1 domain in cPKC, followed by coordinated binding of the cPKC C2 domain to membrane phospholipids in a Ca2+ -dependent manner. This step causes cytosol-to-membrane translocation of cPKC, and involves changes in its conformation that release the catalytic domain from the pseudosubstrate, allowing for substrate binding and phosphorylation and activation of downstream signaling cascades. PKC mediated regulation of the protooncogene product rapidly accelerated fibrosarcoma (c-Raf; also termed Raf-1), may contribute to the c-Raf-induced cell transformation, since the c-Raf serine/threonine kinase is a gatekeeper of the mitogen-activated protein kinase (MAPK) pathway. Increased expression of selected PKC isoforms was observed in different types of cancer, including cancer of the breast, lung, brain, ovaries, bladder, kidney, and the gastrointestinal system.
An increase in the membrane-associated DAG promotes low affinity DAG binding to the C1 domain in cPKC, followed by coordinated binding of the cPKC C2 domain to membrane phospholipids in a Ca2+ -dependent manner. This step causes cytosol-to-membrane translocation of cPKC, and involves changes in its conformation that release the catalytic domain from the pseudosubstrate, allowing for substrate binding and phosphorylation and activation of downstream signaling cascades. PKC mediated regulation of the protooncogene product rapidly accelerated fibrosarcoma (c-Raf; also termed Raf-1), may contribute to the c-Raf-induced cell transformation, since the c-Raf serine/threonine kinase is a gatekeeper of the mitogen-activated protein kinase (MAPK) pathway. Increased expression of selected PKC isoforms was observed in different types of cancer, including cancer of the breast, lung, brain, ovaries, bladder, kidney, and the gastrointestinal system.
