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Signaling pathways involving PKC

​​Protein kinase C (PKC) refers to a large family of protein kinases. They regulate the activity of proteins by phosphorylating hydroxyl groups of their threonine and serine residues.

These kinases are involved in many cellular functions, including regulating cell proliferation and cell death, as well as controlling gene transcription and translation, cell shape and regulation of cell-cell contact. See the image below for an overview of PKCs involvement in these diverse biological functions.​


Figure 1: Multiple signaling pathways involving PKC regulation and signal transduction. Adapted from Jeong-Hun Kang (2014). 

PKC signaling

Like other protein kinasesPKC contains a catalytic domain as well as a regulatory region. The catalytic domain is located in the C-terminal region, which consists of a binding site for the phospho-acceptor sequence in substrate proteins and a conserved ATP/Mg2+-binding site. The regulatory region is N-terminal and consists of C1 and C2 domains. When inactive, this region binds to the catalytic domain and prevents its activity. Dissociation of this region from the catalytic domain is critical for the activation of the kinase.

Conventional PKCs (PKCα, βI, βII and γ) require both calcium and diacylglycerol (DAG) for their activation. Hydrolysis of phosphatidylinositol 4,5-bisphosphate (PIP2) by phospholipase C (PLC) generates both DAG and inositol 1,4,5 -triphosphate (IP3). IP3 diffuse through the cell to bind to IP3-sensitive Ca2+ channels on the endoplasmic reticulum (ER), releasing Ca2+ ions into the cytosol. PKC binds to these Ca2+ ions and this triggers its translocation to the cell membrane where it interacts with DAG, via its C1 domain. The conformational change in the structure of PKC allows it to phosphorylate its substrates.

In contrast, novel isozymes (PKC δ, ε, θ and η) can be activated by DAG alone, as the affinity of their C1 domains for DAG is much greater than in conventional PKCs, allowing them to be directly recruited to the membrane.

Finally, atypical PKCs (protein kinase Mζ and ι/λ isoforms) do not require DAG nor Ca2+  for their activation, however they are dependent on different lipid metabolite second messengers (Khalil, 2010; Wu-Zhang and Newton, 2013; Mochly-Rosen et al., 2012).

Visit guide on PKC isozyme specific tools


PKC and cancer

As PKC play important roles in vasculogenesis and cell proliferation, it is not surprising that PKC levels are greatly perturbed in many cancer cell lines. Usually, PKCs are not considered oncogenes activated by mutations, but promote tumor growth by enhancing cellular signaling pathways (Mochly-Rosen et al., 2012). For example, studies have shown that PKCδ can potentiate angiogenesis models of prostate cancer by binding to NADPH oxidase and whereby hypoxia-inducible factor ( HIF 1α) protein levels are increased (Kim et al., 2011). Targeting PKC for therapy in cancer will be archived by understanding the mechanisms of its regulation. Moreover, the development of small molecules with specificity for individual isozymes will aid the translation of this research from bench-side to bedside.

​​References

  • Jeong-Hun Kang (2014). Protein Kinase C (PKC) Isozymes and Cancer: New Journal of Science. 2014 May 1; Article ID 231418: 36 pages. 
  • Khalil RA (2010) Regulation of Vascular Smooth Muscle Function.San Rafael (CA): Morgan & Claypool Life Sciences.
  • Kim J, Koyanagi T, Mochly-Rosen D (2011) PKCδ activation mediates angiogenesis via NADPH oxidase activity in PC-3 prostate cancer cells. Prostate. 2011 Jun 15;71(9):946-54.
  • Mochly-Rosen D, Das K, Grimes KV (2012) Protein kinase C, an elusive therapeutic target? Nat Rev Drug Discov. 2012 Dec;11(12):937-57.
  • Wu-Zhang AX, Newton AC. (2013) Protein kinase C pharmacology: refining the toolbox. Biochem J. 2013 Jun 1;452(2):195-209.