Protein kinase C (PKC), a ubiquitous phospholipid dependent enzyme, is involved in signal transduction associated with cell proliferation, differentation, and apoptosis. At least eleven closely-related PKC isozymes have been reported that differ in their structure, biochemical properties, tissue distribution, subcellular localization, and substrate specificity. They are classified as conventional (α, β1, β2, γ), novel (δ, ε, η, θ , μ) and atypical (ζ, λ) PKC isozymes.
Conventional PKC isozymes are Ca2+-dependent, while novel and atypical isozymes do not require Ca2+ for their activation. All PKC isozymes, with the exception of ζ and λ, are activately by diacylglycerol (DAG), a product of receptor-mediated hydrolysis of inositol phospholipids.
PKC isozymes negatively or positively regulate critical cell cycle transitions, including cell cycle entry and exit at the G1 and G2 checkpoints.
The catalytic domain of PKC contains sequences, including an ATP-binding site, which resemble other protein kinases. The regulatory domain of PKC contains a Ca2+ binding site that is found only on α, β, and γ-isozymes. The regulatory domain of the α, β, and γ-isozymes contains two conserved regions, C1 and C2, that play a vital role in the regulation of enzyme activity. The catalytic domain is composed of highly conserved C3 and C4 regions. The C3 region contains the ATP-binding consensus sequence, whereas the C4 regions is responsible for protein substrate binding. The other PKC isozymes (δ, ε, η, θ, μ, ζ and λ) lack the C2 region and do not require Ca2+ for activation.
Binding of a hormone or other effector molecule to the membrane receptor results in activation of phospholipase C (PLC) or phospholipase A2 (PLA2) via a G-protein-dependent phenomenon. The activated PLC hydrolyzes phosphatidylinositol-4,5-bisphosphate (PIP2) to produce DAG and inositol-1,4,5-trisphosphate (IP3). The IP3 causes the release of endogenous Ca2+,which binds to the cytosolic PKC and exposes the phospholipid-binding site. The binding of Ca2+ translocates PKC to the membrane, where it interacts with DAG and is transformed into a fully active enzyme. Arachidonic acid released by PLA2 action also activates cytosolic PKC.
Altered PKC activity has been linked with various types of malignancies. Higher levels of PKC and differential activation of various PKC isozymes have been reported in breast tumors, adenomatous pituitaries, thyroid cancer tissue, leukemic cells, and lung cancer cells. Specifically, overexpression of PKC ε and β2 has been linked to uncontrolled cell growth and transformation. On the other hand, overexpression of PKC α, β1, and δ in certain carcinoma cell lines and in non-transformed intestinal epithelial cells, is reported to retard cell growth and inhibit tumorigenicity. Downregulation of PKCα is also reported in the majority of codon adenocarcinomas and in the early stages of intestinal carcinogenesis.
PKC inhibitors, such as tamoxifen and safingol, are currently being used in the treatment of breast cancer. The question as to whether PKC is a positive or a negative regulator of apoptosis is still controversial.