Targeting protein kinase C and "non-kinase" phorbol ester receptors: emerging concepts and therapeutic implications.
Phorbol esters, natural compounds that mimic the action of the lipid second messenger diacylglycerol (DAG), are known to exert their biological actions through the activation of classical and novel protein kinase C (PKC) isozymes. Phorbol esters, via binding to the PKC C1 domains, cause major effects on mitogenesis by controlling the activity of cyclin-cdk complexes and the expression of cdk inhibitors. In the last years it became clear that phorbol esters activate other molecules having a C1 domain in addition to PKCs. One of the most interesting families of "non-kinase" phorbol ester receptors is represented by the chimaerins, lipid-regulated Rac-GAPs that modulate actin cytoskeleton reorganization, migration, and proliferation. The discovery of the chimaerins and other "non-kinase" phorbol ester receptors has major implications in the design of agents for cancer therapy.
Kazanietz
Marcelo G
MG
Department of Pharmacology, University of Pennsylvania School of Medicine, 816 Biomedical Research Building II/III, 421 Curie Blvd., Philadelphia, PA 19104-6160, USA. marcelo@spirit.gcrc.upenn.edu
D000818:Animals; D016588:Anticarcinogenic Agents / Q000627:therapeutic use; D017209:Apoptosis; D002453:Cell Cycle / Q000187:drug effects / Q000502:physiology; D020740:Chimerin Proteins / Q000378:metabolism; D019852:Diacylglycerol Kinase / Q000378:metabolism; D004075:Diglycerides / Q000378:metabolism; D006801:Humans; D007527:Isoenzymes / Q000378:metabolism; D008954:Models, Biological; D010703:Phorbol Esters / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use; D011485:Protein Binding; D011493:Protein Kinase C / Q000037:antagonists & inhibitors / Q000378:metabolism* / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D011955:Receptors, Drug / Q000378:metabolism*; D015290:Second Messenger Systems; D015398:Signal Transduction / Q000187:drug effects
C011439:1,2-diacylglycerol; D016588:Anticarcinogenic Agents; D020740:Chimerin Proteins; D004075:Diglycerides; D007527:Isoenzymes; D010703:Phorbol Esters; D011955:Receptors, Drug; C027776:phorbol ester receptor; D019852:Diacylglycerol Kinase; D011493:Protein Kinase C