Oncology Intelligence


PKCs, serine/threonine protein kinases, are involved in receptor desensitization, regulating transcription, mediating immune responses, and regulating cell growth.(1) PKCs are activated by increases in the concentration of diacylglycerol (DAG) or Ca2+, phorbol ester.(1, 2). The PKC family consists of fifteen isozymes, divided into three subfamilies, based on their second messenger requirements: conventional, novel, and atypical.(3) Conventional PKCs contain the isoforms PKC-α, PKC-βI, PKC-βII, and PKC-γ. These require Ca2+, DAG, and a phospholipid such as phosphatidylserine for activation. Novel PKCs include the PKC-δ, PKC-ε, PKC-η, and PKC-θ isoforms, and require DAG, but do not require Ca2+ for activation. Conventional and novel PKCs are activated through the same signal transduction pathway as phospholipase C, whereas atypical PKCs require neither Ca2+ nor diacylglycerol for activation, and include PKC-λ, PKC-ζ, PK-N1, PK-N2, and PK-N3.(1)
The structure of all PKCs consists of a regulatory domain and a catalytic domain tethered together by a hinge region. The catalytic region is highly conserved among the different isoforms. The second messenger requirement differences in the isoforms are a result of the regulatory region, which are similar within the classes, but differ among them. Most of the crystal structure of the catalytic region of PKC has not been determined, except for PKC theta and iota. Due to its homology to other kinases whose crystal structure have been determined, the structure can be predicted. The regulatory domain or the amino-terminus of the PKCs contains several shared subregions. The C1 domain has a binding site for DAG as well as non-hydrolysable, non-physiological analogues called phorbol esters. The C2 domain acts as a Ca2+ sensor and is present in both conventional and novel isoforms, but functional as a Ca2+ sensor only in the conventional. The pseudo-substrate 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 phosphor-acceptor residues, keeping the enzyme inactive. When Ca2+ and DAG are present in sufficient concentrations, they bind to the C2 and C1 domain, respectively, and recruit PKC to the membrane. 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. This is contingent upon phosphorylation of the catalytic region, discussed below. The catalytic region or kinase core of the PKC allows for different functions to be processed; PKB (also known as Akt) and PKC kinases contain approximately 40% amino acid sequence similarity. This similarity increases to ~ 70% across PKCs and even higher when comparing within classes. Of the over-30 protein kinase structures whose crystal structure has been revealed, all have the same basic organization. They are a bilobal structure with a β sheet comprising the N-terminal lobe and an α helix constituting the C-terminal lobe. The conventional and novel PKCs have three phosphorylation sites, termed: the activation loop, the turn motif, and the hydrophobic motif. The atypical PKCs are phosphorylated only on the activation loop and the turn motif. Phosphorylation of the hydrophobic motif is rendered unnecessary by the presence of a glutamic acid in place of a serine, which, as a negative charge, acts similar in manner to a phosphorylated residue. The consensus sequence of PKC enzymes is similar to that of PKA, since it contains basic amino acids close to the Ser/Thr to be phosphorylated. Their substrates are, e.g., MARCKS proteins, MAPk, transcription factor inhibitor IκB, the vitamin D3 receptor VDR, Raf kinase, calpain, and the EGFR. Upon activation, PKC enzymes are translocated to the plasma membrane by RACK proteins (membrane-bound receptor for activated PKC proteins). The PKC enzymes remain activated after the original activation signal or the Ca2+-wave is gone. 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.(1)
PKC inhibitors, such as ruboxistaurin, may potentially be beneficial in peripheral diabetic retinopathy. The PKC activator ingenol mebutate, derived from the plant Euphorbia peplus, is FDA-approved for the treatment of actinic keratosis.(1)

Marketed Drugs/Indications
Generic Code Old Code Brand Company Indication trials
ingenol mebutate PEP005  Picato  LEO Pharma  Mkt: actinic keratoses; P2: Basal Cell Carcinoma, squamous trials
Trial Drugs/Indications
Generic Code Old Code Brand Company Indication trials
tetradecanoylphorbol PD-616 Pfizer P3; actinic keratoses; P2: basal cell, squamous cell; P1/2: AML, MDS trials
enzastaurin LY317615  Eli Lilly P3: GBM (2014), NHL (2013), DLBCL (failed); P2: ovarian, fallopian, peritoneal, SCLC, BC, CRC, NSCLC (2014), PC, pancreatic, WM, RCC, lymphoma; P1: solid, CNS, brain, leukemia trials
sotrastaurin AEB071 Novartis P2: lrolymphocytic leukemia, mantle cell lymphoma; P1/2: DLBCL, melanoma trials
PKC412 Novartis P1/2: leukemia; P1: AML trials
Generic Code Old Code Brand Company Indication trials
aprinocarsen LY900003 ISIS 3521 Affinitac Eli Lilly Last new trial started in 2002; failed to meet endpoint; P3: NSCLC; P2: melanoma, BC trials
bryostatin Noncorporate Last new trial started in 2005; P2: Fallopian, Peritoneal, Ovarian, pancreatic, GIST, RCC, esophageal, lung, PC, BC, CRC, cervical, HNN, MM, AML, MDS, lymphoma, leukemia: P1: melanoma, small intestine, solid, Burkitt, CML trials
PKC-Alpha LY900003 ISIS 3521 Eli Lilly Last trial started 2002; P2: NSCLC, solid trials

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1. Protein_kinase_C. [cited]; Available from:

2. Yamasaki T, Takahashi A, Pan J, Yamaguchi N, Yokoyama KK. Phosphorylation of activation transcription factor-2 at serine 121 by protein kinase C controls c-Jun-mediated activation of transcription. Journal of Biological Chemistry. 2009;284(13):8567-81.

3. Nishizuka Y. Protein kinase C and lipid signaling for sustained cellular responses. The FASEB Journal. 1995;9(7):484-96.

4. Griner EM, Kazanietz MG. Protein kinase C and other diacylglycerol effectors in cancer. Nature Reviews Cancer. 2007;7(4):281-94.