Individual Listing

4481 BOYCE HALL
University of California
Riverside, CA 92521

DeFea, Kathryn

Associate Professor of Biomedical Sciences

Biomedical Sciences

Biomedical Sciences


Biography

Degrees

Ph>d. Endocrinology 1994

University of California, San Francisco

Research Area

A number of receptors generate signals that converge at the activation of MAP Kinase (MAPK), yet they are still able to elicit specific downstream effects. Research in my lab is concerned with how different G-protein coupled receptors can utilize protein scaffolding complexes to direct the subcellular localization, and thus the downstream effects, of MAPK activation. We have purified two such complexes: one that is induced upon activation of Protease Activated Receptor 2 (PAR2), leading to cytoskeletal rearrangements and cell motility and another that forms in response to activation of Neurokinin-1 receptor (NK1R), leading to mitogenesis and protection from apoptosis. Current studies focus on identification of substrates for these complexes. In the case of PAR2, one substrate is SCAR-1, a protein that mediates lamelipodia formation in motile cells. We are also investigating the role of PAR2-induced cytoskeletal changes in tumor metastasis, as both the receptor and its natural activator are highly expressed in metastatic tumor cells. A second project involves the biochemical dissection of these complexes and identification of the mechanisms by which they are able to direct such distinct physiological responses. A third project investigates the ability of NK1R to activate opposing MAPK cascades, in a cell cycle dependent fashion, and the role of specific scaffolding complexes in directing which pathway is activated under different conditions.

Publications

Defea, K.A. Stop That Cell! Beta-Arrestin-Dependent Chemotaxis: A Tale of Localized Actin Assembly and Receptor Desensitization, Annual Review of Physiology, Vol. 69: 535-560 (volume publication date March 2007).

Kumar, P., Lau, C., Wang, P., Mathur, M. and DeFea, K.A. Differential effects of beta-arrestins on internalization, desensitization and ERK1/2 activation downstream of Protease Activated Receptor-2. Am. J. Physiol./Cell Physiol., in press, 2007.

Zoudilova, M., Kumar, P., Ge, L., Wang, P., Bokoch, G.M. and DeFea, K.A. Beta-arrestin-dependent regulation of the cofilin pathway downstream of protease-activated receptor-2. J. Biol. Chem. in press, 2007.

Wang, P. and DeFea, K. Protease-activated-receptor-2 simultaneously directs beta-arrestin-dependent inhibition and Gaq-dependent activation of PI3K. Biochemistry, 2006, 45 (31): 9374-85.

Ge, L., Shenoy, S., Lefkowitz, R.J. and DeFea, K.A. Constitutive protease-activated-receptor-2 mediated migration of MDA MB-231 breast cancer cells requires both beta-arrestin-1 and 2. J. Biol. Chem. 2004 Dec 31;279(53):55419-24.

Ge, L., Ly, Y., Hollenberg, M.D. and DeFea, K.A. Beta-arrestin-dependent sequestration of MAPK to pseudopodia is involved in PAR-2 mediated chemotaxis. J. Biol. Chem. 2003, 278 (36): 34418-26.

Lin, T., Zeng, L., Liu, Y., DeFea, K., Schwartz, M.A., Chien, S. and Shyy, J.-Y. Rho-ROCK-LIMK-cofilin pathway regulates shear stress activation of sterol regulatory element binding proteins. Circulation Research 2003, 92(12), 1296-1304.

DeFea, K.A., Vaughn, Z., O’Bryan, E.M., Nishijima, D., Dery, O. and Bunnett, N.W. The proliferative and anti-apoptotic effects of substance P are facilitated by formation of a beta-arrestin dependent scaffolding complex. Proc. Natl. Acad. Sci. USA, 2000 26;97(20):11086-91.

DeFea, K.A., Zalevsky, J., Thoma, M.S., Dery, O., Mullins, R.D. and Bunnett, N.W. Beta-arrestin-dependent endocytosis of proteinase-activated receptor-2 is required for intracellular targeting of activated ERK1/2. J. Cell Biology, 2000, 297 (2); 685-8.

DeFea, K., Schmidlin, F., Dery, O., Grady, E.F. and Bunnett, N.W. Mechanisms of initiation and termination of signalling by neuropeptide receptors: a comparison with the proteinase-activated receptors. Biochem Soc Trans, 2000, Aug 1;28(4):419-426.

Dery, O., DeFea, K. and Bunnett, N.W. Protein kinase C-mediated desensitization of the neurokinin 1 receptor. Am. J. Physiol. Cell Physiol. 2001. 280: C1097-C1106.

Schmidlin, F., Dery, O., DeFea, K., Slice, L., Patierno, S., Sternini, C., Grady, E.F. and Bunnett, N.W. Dynamin and Rab5a-dependent trafficking and signaling of the neurokinin 1 receptor. J. Biol. Chem. 2001 Jul 6;276(27):25427-37.