Chimaerins: DAG/phorbol Esters with Rac-GAP Activity
Chimaerins belong to the family of "non-kinase" DAG/phorbol ester receptors. The cloning of different chimaerin isoforms (alpha1-, alpha2-, beta1-, and beta2-chimaerins) suggests that a high degree of complexity may exist in the downstream pathways regulated by DAG. Chimaerin isoforms are high affinity receptors for DAG and phorbol ester analogs, and phorbol esters regulate their localization and association to targets. Unlike PKC isozymes, chimaerins do not have kinase activity, but have a Rac-GAP domain that accelerates GTP hydrolysis from Rac leading to its inactivation. Rac is a small GTP-binding protein of the Ras superfamily that is involved in the control of cytoskeleton function, proliferation, adhesion, migration, gene expression, endocytosis, and metastasis. Our goal is to elucidate the regulation of the activity of the chimaerins by phorbol esters and by receptors linked to elevations in the second messenger DAG, to identify intracellular partners for individual chimaerin isofoms, and to establish their cellular function and roles in carcinogenesis.
- Chimaerins as high affinity phorbol ester receptors.
- Regulation of Rac by chimaerins.
- Subcellular relocalization of chimaerins by phorbol esters
- Isolation of chimaerin-interacting proteins.
- Chimaerins and inhibition of tumorigenesis in breast cancer cells.
- Control of the metastatic cascade by beta2-chimaerin.
- Control of cell cycle by chimaerins.
- Z-chimaerin: the zebrafish homologue of beta2-chimaerin.
Representative papers (PubMed)
- Caloca, M.J., Fernandez, M.N., Lewin, N.E., Ching, D., Modali, R., Blumberg, P.M., and Kazanietz, M.G. beta2-chimaerin is a high affinity receptor for the phorbol ester tumor promoters. J. Biol. Chem. 272: 26488-26496 (1997). [ html ] [ pdf ]
- Caloca, M.J., García-Bermejo, M.L., Blumberg, P.M., Lewin, N.L., Kremmer, E., Mischak, H., Wang, S., Nacro, K., Bienfait, B., Marquez, V.E., Kazanietz, M.G. beta2-chimaerin is a novel target for diacylglycerol: binding properties and changes in subcellular localization mediated by ligand binding to its C1 domain. Proc. Natl. Acad. Sci. USA 96: 11854-11859 (1999). [ html ] [ pdf ]
- Caloca, M.J., Wang, H.B., Delemos, A., Wang, S., and Kazanietz, M.G. Phorbol esters and related analogs regulate the subcellular localization of beta2-chimaerin, a "non-PKC" phorbol ester receptor. J. Biol. Chem. 276: 18303-18312 (2001). [ html ] [ pdf ]
- Wang, H., and Kazanietz, M.G. Chimaerins, novel "non-PKC" phorbol ester receptors, associate with Tmp21-I (p23). Evidence for a novel anchoring mechanism involving the chimaerin C1 domain. J. Biol. Chem. 277: 4541-4550 (2002). [ html ] [ pdf ]