PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+).
The different classes of PKCs found in jawed vertebrates originate from 5 ancestral PKC family members (PKN, aPKC, cPKC, nPKCE, nPKCD) that expanded due to genome duplication.
The C1 domain, present in all of the isoforms of PKC has a binding site for DAG as well as non-hydrolysable, non-physiological analogues called phorbol esters.
The pseudosubstrate region, which is present in all three classes of PKC, is a small sequence of amino acids that mimic a substrate and bind the substrate-binding cavity in the catalytic domain, lack critical serine, threonine phosphoacceptor residues, keeping the enzyme inactive.
This interaction with the membrane results in release of the pseudosubstrate from the catalytic site and activation of the enzyme.
In order for these allosteric interactions to occur, however, PKC must first be properly folded and in the correct conformation permissive for catalytic action.
Both the ATP-binding protein (ATP)- and the substrate-binding sites are located in the cleft formed by these two terminal lobes.
It is presumed that this is achieved by the production of diacylglycerol from phosphatidylinositol by a phospholipase; fatty acids may also play a role in long-term activation.
PKC plays an important role in the immune system through phosphorylation of CARD-CC family proteins and subsequent NF-κB activation.
Thus, effects of PKC are cell-type-specific: Protein kinase C, activated by tumor promoter phorbol ester, may phosphorylate potent activators of transcription, and thus lead to increased expression of oncogenes, promoting cancer progression,[22] or interfere with other phenomena.
Low-level PKC activation is sufficient to reverse cell chirality through phosphatidylinositol 3-kinase/AKT signaling and alters junctional protein organization between cells with opposite chirality, leading to an unexpected substantial change in endothelial permeability, which often leads to inflammation and disease.
[25] Protein kinase C inhibitors, such as ruboxistaurin, may potentially be beneficial in peripheral diabetic nephropathy.
[29] The Protein kinase C activator ingenol mebutate, derived from the plant Euphorbia peplus, is FDA-approved for the treatment of actinic keratosis.