Eyes wide shut: protein kinase C isozymes are not the only receptors for the phorbol ester tumor promoters

Mol Carcinog. 2000 May;28(1):5-11. doi: 10.1002/(sici)1098-2744(200005)28:1<5::aid-mc2>3.0.co;2-g.


In addition to the well-characterized interaction with classical and novel protein kinase C (PKC) isozymes, the phorbol ester tumor promoters bind to other receptors lacking kinase activity. Among these novel phorbol ester receptors, two families of proteins may play a role in the regulation of cell growth and malignant transformation: chimaerins and ras guanyl-releasing protein (ras-GRP). These proteins possess a single copy of the C1 domain that is involved in binding of phorbol esters and the lipid second messenger diacylglycerol. Four isoforms of chimaerins (alpha1-, alpha2-, beta1-, and beta2-chimaerins) have been isolated to-date, all of them possessing GTPase-activating protein activity for Rac, a small GTP-binding protein that controls actin cytoskeleton organization, cell-cycle progression, adhesion, and migration. Ras-GRP is a guanine nucleotide exchange factor for ras and promotes malignant transformation in fibroblasts in a phorbol ester-dependent manner. The C1 domain in Ras-GRP may, therefore, have a dominant role in Ras-GRP activation and is essential for phorbol ester-dependent activation of downstream effectors of ras, i.e., the mitogen-activated protein kinase cascade. Thus, a novel concept emerges in which phorbol esters may exert cellular responses through pathways not involving phorbol ester-responsive PKC isozymes. The discovery of "nonPKC" phorbol ester receptors adds an additional level of complexity to the understanding of phorbol ester effects and the molecular mechanisms of carcinogenesis.

Publication types

  • Research Support, Non-U.S. Gov't
  • Research Support, U.S. Gov't, Non-P.H.S.
  • Research Support, U.S. Gov't, P.H.S.
  • Review

MeSH terms

  • Animals
  • Carcinogens* / toxicity
  • Cell Transformation, Neoplastic* / drug effects
  • DNA-Binding Proteins / physiology
  • Guanine Nucleotide Exchange Factors*
  • Humans
  • Isoenzymes / physiology
  • Phorbol Esters* / toxicity
  • Protein Kinase C / physiology*
  • Receptors, Cell Surface / physiology*
  • Signal Transduction


  • Carcinogens
  • DNA-Binding Proteins
  • Guanine Nucleotide Exchange Factors
  • Isoenzymes
  • Phorbol Esters
  • RASGRP1 protein, human
  • Receptors, Cell Surface
  • Protein Kinase C