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KATHRYN DEFEA, PH.D.

Associate Professor
Ph.D., 1994, University of California, San Francisco

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Research Summary

A number of receptors generate signals that converge at the activation of protein and lipid kinases, yet they are still able to elicit specific downstream effects, such as cell motility and proliferation. Furthermore, a number of receptor-mediated events require precise spatial and temporal control over these signaling molecules. A perfect example is directed cell motility or chemotaxis, in which a cell senses a chemical signal from one direction and must polarize itself in order to move towards the chemotactic agent. In this example, a receptor must generate conflicting signals in different parts of the cell-so that actin assembly in the front (aka leading edge) allows the cell to extend a lamellipodia in the direction of the signal, while this same process is silenced in the back of the cell. An increasingly common theme in cell biology is the concept that molecular scaffolds can serve not only to bring proteins in a signaling cascade together, but also to localize their activity to specific cellular microdomains. We have focused on the mechanisms by which different G-protein coupled receptors can utilize such protein scaffolding complexes to direct the subcellular localization of promiscuous kinase activities, in order to promote specific downstream events. We have purified two such complexes, which we have dubbed “endosomal scaffolds”, because of their common requirement for binding to clathrin adaptor proteins of the b-arrestin family. One such endosomal scaffold is induced upon activation of Protease Activated Receptor 2 (PAR2), leading to actin assembly and cell motility. Another such scaffold forms in response to activation of Neurokinin-1 receptor (NK1R), leading to proliferation and protection of cells from apoptosis. In both cases, b-arrestins 1 and 2 are required.
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Our studies focus on biochemical dissection of these endosomal scaffolds, with particular emphasis on PAR-2 signaling. Current projects include a molecular characterization of the role of b-arrestins in localized actin assembly through regulation of filament severing, capping and nucleation promoting proteins.  We are also investigating the physiological consequences of formation of PAR-2 and NK1R complexes, and the possibility that PAR2-induced cytoskeletal rearrangements play a role in tumor metastasis and regulation of epithelial barrier function during inflammatory diseases such as IBD and asthma.


Recent Publications

Ping Wang, Puneet Kumar, Chang Wang and Kathryn DeFea.  Differential regulation of Class IA phosphatidylinositol 3-kinase catalytic subunits p110alpha and beta by proteast-activated-receptor-2 and beta-arrestins.  Biochemical Journal, in press, 2007.

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., 2007, 293 (1): C346-57.

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., 2007, 282(28): 20634-46.

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

Lan Ge, Sudha Shenoy, Robert J. Lefkowitz and Kathryn A. DeFea, 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.

Lan Ge, Youly Ly, Morley D. Hollenberg and Kathryn A. DeFea, β-arrestin-dependent sequestration of MAPK to pseudopodia is involved in PAR-2 mediated chemotaxis, J. Biol. Chem, 2003, 278 (36): 34418-26.

Tong Lin; Lingfang Zeng; Yi Liu; Kathryn DeFea; Martin A Schwartz; Shu Chien; John Y.-J.Shyy, Rho-ROCK-LIMK-Cofilin Pathway Regulates Shear Stress Activation of Sterol Regulatory Element Binding Proteins. Circulation Research, 2003, 92(12), 1296-1304.

K.A. DeFea, Z. Vaughn, E.M. O’Bryan, D. Nishijima, O. Dery and N.W. Bunnett. The Proliferative and Anti-Apoptotic Effects of Substance P are facilitated by Formation of a β-Arrestin Dependent Scaffolding Complex. Proc. Natl. Acad. Sci., U S A, 2000 26;97(20):11086-91.

K.A. DeFea, J. Zalevsky, M.S. Thoma, O. Dery, R.D. Mullins and N.W. Bunnett, b-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 EF, Bunnett NW, 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.

Olivier Dery, Kathryn DeFea and Nigel W. Bunnett, 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 EF, Bunnett NW.  Dynamin and Rab5a-dependent trafficking and signaling of the neurokinin 1 receptor. J. Biol Chem. 2001 Jul 6;276(27):25427-37.
 

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