Pharmacology of the receptors for the phorbol ester tumor promoters: Multiple receptors with different biochemical properties

• Published in: Biochemical pharmacology Vol. 60; no. 10; pp. 1417 - 1424
• Main Authors: Kazanietz, Marcelo G, Caloca, Marı́a J, Eroles, Pilar, Fujii, Teruhiko, Garcı́a-Bermejo, Marı́a L, Reilly, Muredach, Wang, HongBin
• Format: Journal Article
• Language: English
• Published: New York, NY Elsevier Inc 15.11.2000; Elsevier Science
• Subjects: Animals; Biological and medical sciences; Biological Transport; Caenorhabditis elegans Proteins; Carcinogenesis, carcinogens and anticarcinogens; Carcinogens - pharmacology; Carcinogens - toxicity; Carrier Proteins; Cell receptors; Cell structures and functions; Chemical agents; chimaerins; Conserved Sequence; diacylglycerol; Diglycerides - chemistry; Diglycerides - metabolism; Enzyme Activation; Fundamental and applied biological sciences. Psychology; Humans; Isoenzymes - chemistry; Isoenzymes - metabolism; Medical sciences; Miscellaneous; Molecular and cellular biology; Molecular Mimicry; phorbol esters; Phorbol Esters - pharmacology; Phorbol Esters - toxicity; PKC; Protein Conformation; Protein Kinase C - chemistry; Protein Kinase C - drug effects; Protein Kinase C - metabolism; RasGRP; Receptors, Drug - chemistry; Receptors, Drug - drug effects; Receptors, Drug - metabolism; Second Messenger Systems; Tumors; chimaerins; RasGRP; phorbol esters; PKC; diacylglycerol; Translocation; Protein kinase C; Enzyme; Isozyme; Transferases; Tumor promotor; Diacylglycerol; Pharmacology; Binding site; Review; Carcinogen; Analog; Second messenger; Biological receptor
• ISSN: 0006-2952; 1873-2968
• DOI: 10.1016/S0006-2952(00)00470-6

The phorbol ester tumor promoters and related analogs are widely used as potent activators of protein kinase C (PKC). The phorbol esters mimic the action of the lipid second messenger diacylglycerol (DAG). The aim of this commentary is to highlight a series of important and controversial concepts in the pharmacology and regulation of phorbol ester receptors. First, phorbol ester analogs have marked differences in their biological properties. This may be related to a differential regulation of PKC isozymes by distinct analogs. Moreover, it seems that marked differences exist in the ligand recognition properties of the C1 domains, the phorbol ester/DAG binding sites in PKC isozymes. Second, an emerging theme that we discuss here is that phorbol esters also target receptors unrelated to PKC isozymes, a concept that has been largely ignored. These novel receptors lacking kinase activity include chimaerins (a family of Rac-GTPase-activating proteins), RasGRP (a Ras exchange factor), and Unc-13/Munc-13 (a family of proteins involved in exocytosis). Unlike the classical and novel PKCs, these “non-kinase” phorbol ester receptors possess a single copy of the C1 domain. Interestingly, each receptor class has unique pharmacological properties and biochemical regulation. Lastly, it is well established that phorbol esters and related analogs can translocate each receptor to different intracellular compartments. The differential pharmacological properties of the phorbol ester receptors can be exploited to generate specific agonists and antagonists that will be helpful tools to dissect their cellular function.