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Vol. 61, Issue 4, 759-767, April 2002
Center for Experimental Therapeutics and Department of
Pharmacology, University of Pennsylvania School of Medicine,
Philadelphia, Pennsylvania
In recent years, there have been great advances in our understanding of
the pharmacology and biology of the receptors for the phorbol ester
tumor promoters and the second messenger diacylglycerol (DAG). The
traditional view of protein kinase C (PKC) as the sole receptor for the
phorbol esters has been challenged with the discovery of proteins
unrelated to PKC that bind phorbol esters with high affinity,
suggesting a high degree of complexity in the signaling pathways
activated by DAG. These novel "nonkinase" phorbol ester receptors
include chimaerins (a family of Rac GTPase activating proteins),
RasGRPs (exchange factors for Ras/Rap1), and Munc13 isoforms
(scaffolding proteins involved in exocytosis). In all cases, phorbol
ester binding occurs at the single C1 domain present in these proteins
and, as in PKC isozymes, ligand binding is a phospholipid-dependent
event. Moreover, the novel phorbol ester receptors are also subject to
subcellular redistribution or "translocation" by phorbol esters,
leading to their association to different effector and/or regulatory
molecules. Clearly, the use of phorbol esters as specific activators of
PKC in cellular models is questionable. Alternative pharmacological and
molecular approaches are therefore needed to dissect the involvement of
each receptor class as a mediator of phorbol ester/DAG responses.
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