Protein kinase C: perfectly balanced

Abstract

Protein kinase C (PKC) isozymes belong to a family of Ser/Thr kinases whose activity is governed by reversible release of an autoinhibitory pseudosubstrate. For conventional and novel isozymes, this is effected by binding the lipid second messenger, diacylglycerol, but for atypical PKC isozymes, this is effected by binding protein scaffolds. PKC shot into the limelight following the discovery in the 1980s that the diacylglycerol-sensitive isozymes are “receptors” for the potent tumor-promoting phorbol esters. This set in place a concept that PKC isozymes are oncoproteins. Yet three decades of cancer clinical trials targeting PKC with inhibitors failed and, in some cases, worsened patient outcome. Emerging evidence from cancer-associated mutations and protein expression levels provide a reason: PKC isozymes generally function as tumor suppressors and their activity should be restored, not inhibited, in cancer therapies. And whereas not enough activity is associated with cancer, variants with enhanced activity are associated with degenerative diseases such as Alzheimer’s disease. This review describes the tightly controlled mechanisms that ensure PKC activity is perfectly balanced and what happens when these controls are deregulated. PKC isozymes serve as a paradigm for the wisdom of Confucius: “to go beyond is as wrong as to fall short.”

Keywords:

• Protein kinase C
• pseudosubstrate
• phorbol esters
• diacylglycerol
• phosphorylation
• tumor suppressor
• cancer
• Alzheimer’s disease

Acknowledgements

The author thanks Gerard Manning for providing a figure of the AGC branch of kinome, Gema Lorden for assistance in drafting, and members of the Newton lab for helpful comments.

Disclosure statement

No potential conflict of interest was reported by the author.

Additional information

Funding

This work was supported by NIH [R35 GM122523] and the Cure Alzheimer’s Fund.