Protein kinase C: perfectly balanced

• Published in: Critical reviews in biochemistry and molecular biology Vol. 53; no. 2; pp. 208 - 230
• Main Author: Newton, Alexandra C.
• Format: Journal Article
• Language: English
• Published: England Taylor & Francis 01.04.2018
• Subjects: Alzheimer Disease - drug therapy; Alzheimer Disease - enzymology; Alzheimer Disease - genetics; Alzheimer Disease - pathology; Alzheimer's disease; Animals; cancer; diacylglycerol; Humans; Isoenzymes - antagonists & inhibitors; Isoenzymes - genetics; Isoenzymes - metabolism; Mutation; Neoplasms - drug therapy; Neoplasms - enzymology; Neoplasms - genetics; Neoplasms - pathology; Oncogene Proteins - antagonists & inhibitors; Oncogene Proteins - genetics; Oncogene Proteins - metabolism; phorbol esters; phosphorylation; Protein kinase C; Protein Kinase C - antagonists & inhibitors; Protein Kinase C - genetics; Protein Kinase C - metabolism; Protein Kinase Inhibitors - therapeutic use; pseudosubstrate; Second Messenger Systems; tumor suppressor; Tumor Suppressor Proteins - antagonists & inhibitors; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Protein kinase C; Alzheimer’s disease; phorbol esters; tumor suppressor; cancer; pseudosubstrate; phosphorylation; diacylglycerol
• ISSN: 1040-9238; 1549-7798; 1549-7798
• DOI: 10.1080/10409238.2018.1442408

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."