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Protein Kinase C



Protein kinase C is a family of protein kinase enzymes that are involved in controlling the function of other proteins through the phosphorylation of hydroxyl groups of serine and threonine amino acid residues on these proteins, or a member of this family. Each member of this enzyme family displays distinct biochemical characteristics and is enriched in different cellular and subcellular locations. 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, as well as, to a lesser degree, among the catalytic region of other serine/threonine kinases.

PKC enzymes in turn are activated by signals such as increases in the concentration of diacylglycerol (DAG) or calcium ions (Ca2+). Hence PKC enzymes play important roles in several signal transduction cascades. The basic protein structure includes an N-terminal regulatory region connected to a C-terminal kinase domain by a hinge region. PKC enzymes contain an auto-inhibitory pseudosubstrate domain that binds a catalytic domain sequence to inhibit kinase activity.

PKC isozymes comprise three classes: conventional (cPKC: α, β, γ), novel (nPKC: δ, ε, η, θ), and atypical (aPKC: ζ, ι). Conventional PKCs (PKCα, βI, βII and γ) require both calcium and diacylglycerol (DAG) for their activation, which involves formation of several important second messengers.

*Formation of phosphatidylinositol (4, 5) bisphosphate (PIP2) and phosphatidylinositol (3, 4, 5) trisphosphate (PIP3)
Phosphatidylinositol or PI is a phospholipid which is anchored in the cytoplasmic layer of the cell membrane. PI 4-kinase generates phosphatidylinositol for phosphate, abbreviated PIP, by phosphorylating the inositol ring of PI. PI 5-kinase may phosphorylate this compound to PIP2. Finally PI 3-kinase generates PIP3. At first PI is phosphorylated by PI kinase in position 4. Subsequently, a PIP kinase phosphorylates the 5-position. PIP2 is generated. PI 3-kinase generates PIP3 from PIP2. As an antagonist of PI 3-kinase, the phosphatase PTEN can hydrolyze the phosphate group in 3-position to generate PIP2.

*Formation of diacylglycerol (DAG) and inositoltrisphosphate (IP3)
PIP 2 is an anchor for phospholipase C, abbreviated PLC. PLC hydrolyzes PIP2 into diacylglycerol or DAG and inositoltrisphosphate or IP 3. IP 3 opens intracellular calcium channels and releases calcium from intracellular stores. As a consequence the intracellular calcium concentration increases. The second messenger calcium exerts many functions. As an example, calcium binds to protein kinase C or PKC. In a positive feedback loop, calcium bound PKC is able to bind to membrane anchor DAG, which leads to the activation of the enzyme.

Downstream effects of protein kinase C
After its activation by calcium and DAG, protein kinase C activates many proteins which stimulate proliferation and growth. As a prominent example, PKC activates the kinase RAF by binding to the complex of RAF and the RAF kinase inhibitor protein RKIP. PKC transfers a phosphate group to RKIP which then dissociates from RAF. Free RAF which is no longer associated with RKIP is active and may exert the same effects as RAF activated by the raz GTP complex in the MAP-kinase pathway. DAG kinase is an additional substrate of protein kinase C. After its activation, DAG kinase phosphorylates DAG to phosphatidic acid which is no longer able to activate PKC. Thus DAG kinase forms a negative feedback loop within the protein kinase C pathway. The next example of an important PKC substrate is insulin receptor substrate 1 or IRS-1. Phosphorylated IRS-1 activates PI 3-kinase and many other proteins.

Protein Kinase C

PKC is frequently mutated in human cancers. PKC isozymes generally function as tumor suppressors, indicating that therapies should focus on restoring, not inhibiting, PKC activity. Corina E. Antal has found that the majority of cancer-associated PKC mutations are loss-of-function, and can act in a dominant-negative manner. They proposed that therapies should target mechanisms to restore the PKC signaling output rather than reduce it, for their comprehensive analysis revealed that 61% (even higher proportion in fact) of the PKC mutations characterized were LOF and none were activating. Clinical data reveal lower PKC protein levels and activity in tumor tissue compared with cognate normal tissue, also supporting a tumor-suppressive role for PKC. How could decreased PKC activity enhance tumorigenesis? One possibility is that PKC isozymes suppress oncogenic signaling by repressing signaling from oncogenes or stabilizing tumor suppressors. Supporting this, unbiased bioinformatics analysis of tumor samples harboring PKC LOF mutations revealed thatTP53(p53) is one of most frequently mutated genes in tumors harboring LOF mutations for each PKC isozyme. PKC might promote the tumor-suppressive function of p53 by stabilizing the WT protein. Considerable evidence suggests that phosphorylation by PKCdstabilizes p53, thus promoting apoptosis, but the role of other PKC isozymes is less clear.


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Reference

[1] Wilson CH, Ali ES, Scrimgeour N, Martin AM, Hua J, Tallis GA, Rychkov GY, Barritt GJ (2015). Steatosis inhibits liver cell store-operated Ca²⁺ entry and reduces ER Ca²⁺ through a protein kinase C-dependent mechanism. The Biochemical Journal. 466 (2): 379–90.

[2] Ali ES, Hua J, Wilson CH, Tallis GA, Zhou FH, Rychkov GY, Barritt GJ (2016). The glucagon-like peptide-1 analogue exendin-4 reverses impaired intracellular Ca2+ signalling in steatotic hepatocytes. BBA-Molecular Cell Research. 1863: 2135–46.

[3] Corina E. Antal, Andrew M. Hudson,John Brognard, etc. (2015). Cancer-Associated Protein Kinase C Mutations Reveal Kinase’s Role as Tumor Suppressor. Cell. 160: 489–502.

[4] Abbas, T., White, D., Hui, L., Yoshida, K., Foster, D.A., and Bargonetti, J. (2004). Inhibition of human p53 basal transcription by down-regulation of protein kinase Cdelta. J. Biol. Chem.279, 9970–9977.


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