University of California, Riverside

School of Medicine



Faculty Biographies


Kathryn DeFea

Associate Professor of Biomedical Sciences

Kathryn DeFea

University of California, Riverside
Riverside, CA 92521

Tel: (951) 827-2871
Fax: (951) 827-5504
E-mail: katie.defea@ucr.edu
Office: 1116A Webber Hall

Education and Training

  • B.A., University of California, Berkeley, 1986
  • Ph.D., Endocrinology, University of California, San Francisco, 1994
  • Postdoctoral Fellow, Stanford University, 1994-97
  • Postdoctoral Fellow, University of California, San Francisco 1997-2000.

Research Summary

Research in my laboratory focuses on G-protein-coupled receptor signaling through β-arrestins, with particular emphasis on protease-activated-receptor-2 (PAR2). We have done pioneering work in the elucidation of the molecular mechanisms underlying β-arrestin-dependent regulation of the cytoskeleton and cell migration, and identified several novel β-arrestin scaffolds. Recent studies have extended beyond biochemical characterization of these scaffolds and we are investigating the contribution of β-arrestin-dependent signaling in inflammation, insulin resistance and cancer.

GPCR signaling: G-protein coupled receptors (GPCRs) are 7 transmembrane receptors responsible for regulation of numerous cellular pathways. Over the past decade, it has become increasingly clear that these receptors can signal not just through the classic G-protein pathway after which they were named, but through various other effector proteins as well. The most common of these alternate pathways involves the adaptor proteins β-arrestins-1 and 2. β-arrestins can interact with multiple signaling cascades, in some cases potentiating and other times directly inhibiting enzymatic activities to elicit specific responses. Our lab studies various signaling pathways regulated by β-arrestins from the molecular to physiological level. Most of these studies focus on a specific GPCR, PAR2, that is activated by proteases released from inflammatory cells, infectious pathogens (e.g fungi and bacteria) and found in insect feces. PAR2 signals through multiple G-proteins as well as β-arrestin-dependent pathways and we have identified a number of downstream signaling proteins regulated by β-arrestins specifically upon activation of PAR2.

Regulation of Cell motility by β-arrestins. During directed cell motility, or chemotaxis, a cell senses a chemical signal from one direction and must polarize itself in order to move towards the chemotactic agent. This means, 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. Signals from outside the cell induce changes in cellular proteins that regulate structural elements of the cell, such as actin. PAR2-stimulated cell motility involves β-arrestin-dependent regulation of proteins involved in regulation of actin assembly. For example, β-arrestins can bind to and inhibit LIMK, scaffold the actin filament severing protein, cofilin, with its upstream activator and activate and scaffold ERK1/2 with its upstream kinases leading to phosphorylation of proteins within the leading edge of the cell. Using a combination of FRET, labeling of dynamic actin filaments and biochemical separation cell body and leading edge, we are investigated the spatial control of the cytoskeleton by β-arrestins and how it pertains to PAR2-stimulated cell motility. Other studies focus on biochemical dissection of these signaling scaffolds, and examination of the protein/protein interactions that determine their specificity.

PAR2/β-arrestin signaling in Inflammation: We are also investigating the physiological consequences of formation of β-arrestin scaffolding complexes, and the possibility that PAR2-induced cell migration play a role in cellular airway inflammation induced by pathogens such as the German cockroach and Alternaria Alternata. We are currently employing several mouse models of airway inflammation to examine the role of β-arrestin-dependent PAR2 signaling in asthma. In other studies we are examining the role of the PAR2/β-arrestin signaling axis in osteoarthritis and tumor cell metastasis.

Publications

  • Scott Boitano, Justin Hoffman, Andrea N Flynn, Marina N Asiedu, Dipti V Tillu, Zhenyu Zhang, Cara L Sherwood, Candy M Rivas, Kathryn A DeFea, Josef Vagner and Theodore J Price, 2015, The novel PAR2 ligand C391 blocks multiple PAR2 signalling pathways in vitro and in vivo, British Journal of Pharmacology, 172(18) 4535–4545.
  • Muhammad Asaduzzaman, Ahmed Nadeem, Narcy Arizmendi, Courtney Davidson, Heddie L Nichols, Melanie Abel, Lavinia Iuliana Ionescu, Lakshmi Puttagunta, Bernard Thebaud, John Gordon, Katie DeFea, Morley D Hollenberg, Harissios Vliagoftis. Functional inhibition of PAR2 alleviates allergen-induced airway hyperresponsiveness and inflammation. 2015, Clin. Exp. Allergy Aug 27. Epub 2015 Aug 27.
  • Nitish Mittal, Kristofer Roberts, Katsuri Pal, Laurent A. Bentolila, Elissa Fultz, Ani Minasyan, Catherine Cahill, Amynah Pradhan, David Conner, Kathryn DeFea, Christopher Evans, Wendy Walwyn. Select G-protein coupled receptors modulate agonist-induced signaling via a ROCK, LIMK and beta-arrestin 1 pathway. 2013, Cell Reports, 5, 1010–1021.
  • Kasturi Pal, Maneesh Mathur, Puneet Kumar and Kathryn DeFea, Divergent β-arrestin-dependent signaling events are dependent upon sequences within G-protein-coupled-receptor C-termini, 2013, J. Biol. Chem, 288, 3265-3274.
  • Nichols HL, Saffeddine M, Theriot BS, Hegde A, Polley D, El-Mays T, Vliagoftis H, Hollenberg MD, Wilson EH, Walker JK, DeFea KA. β-Arrestin-2 mediates the proinflammatory effects of proteinase-activated receptor-2 in the airway, 2012, Proc Natl Acad Sci U S A. Oct 9;109(41):16660-5.
  • Crystal G Pontrello, Min-Yu Sun, Alice Lin, Todd A Fiacco, Kathryn A. DeFea and Iryna M Ethell. Cofilin under control of β-arrestin-2 in NMDA-dependent dendritic spine plasticity, LTD and learning. 2012, Proc Natl Acad Sci U S A Feb 14;109(7):E442-51.
  • Ramachandran R, Noorbakhsh F, DeFea K, Hollenberg MD, Targeting proteinase-activated receptors: therapeutic potential and challenges. 2012, Nat Rev Drug Discov Jan 3;11(1):69-86.
  • Jungah Min and Kathryn A. DeFea, Beta-arrestin-dependent actin reorganization? Bringing the right players together at the leading edge, 2011, Molecular Pharmacology, Nov;80(5):760-8.
  • Kathryn A. DeFea,Beta-arrestins as regulators of signal termination and transduction: How do they determine what to scaffold?, 2011, Cellular Signaling,23(4): 621-9.
  • Ramachandran R, Mihara K, Chung H, Renaux B, Lau CS, DeFea KA, Bouvier M, Hollenberg MD, Neutrophil elastase acts as a biased agonist for proteinase activated receptor-2 (PAR2), 2011, J Biol Chem. 286(28) 24638-48.
  • Chang S. Lau, Christian Lytle, Daniel S. Straus and Kathryn DeFea. Apical and basolateral pools of proteinase-activated receptor-2 direct distinct signaling events in the intestinal epithelium, 2011, Amer. J. Physiology Cell Physiology, vol. 300 no. 1 C113-C123.
  • Ping Wang, Yong Jiang, Yinsheng Wang, John Shyy and Kathryn DeFea, Inhibition of CAMKKb-dependent AMPK activation downstream of protease-activated-receptor-2, 2010, BMC Biochemistry, 11:36.
  • Maria Zoudilova, Jungah Min, Heddie L. Richards, Timothy Huang, David Carter and Kathryn DeFea,β-Arrestins direct cofilin association with chronophin and localized cofilin activity in response to Protease-activated-receptor-2 stimulation, 2010, J. Biol. Chem, 285: 14318-14329.
  • Ramachandran, R., Mihara, K., Mathur, M., Rochdi, M.D., Bouvier, M., DeFea, K., Hollenberg, M.D. Agonist-biased signaling via Proteinase Activated Receptor-2: differential activation of calcium and MAPkinase pathways. 2009. Molecular Pharmacology., vol. 76 no. 4 791-801.
  • Shi, Y., Pontrello, C.G., DeFea, K., Reichardt, L.F., Ethell, I.M. Focal adhesion kinase acts downstream of EphB receptors to maintain mature dendritic spines by regulating cofilin activity, 2009, Journal of Neuroscice. Vol. 25: p.8129-42.
  • Kathryn DeFea, β-arrestins and heterotrimeric G-proteins: collaborators and competitors in signal transduction, 2008, British J. Pharmacology, Volume 153, Issue S1, pages S298–S309.
  • Lee, J.W., P. Wang, M.G. Kattah, S. Youssef, L. Steiman, K. DeFea*, and D.S. Straus. Differential regulation of chemokines by Interleukin 17 in colonic epithelial cells, 2008, J. Immunol; 181(9):6536-45.
  • Melissa L. Petreaca, Min Yao, Qijing Li, Kathryn DeFea, and Manuela Martins-Green. Transactivation of Vascular endothelial growth factor receptor-2 (VEGFr2) by Interleukin-8 (IL-8/CXCL8) is required for IL-8/CXCL8-Induced Endothelial Permeability, Molecular Biology of the Cell, 2007, 18(12), 5014-23.
  • Ping Wang, Puneet Kumar, Chang Wang and Kathryn DeFea, Differential regulation of Class IA Phosphatidylinositol 3-Kinase catalytic subunits p110alpha and beta by protease-activated-receptor-2 and beta-arrestins, 2007, Biochem J, 408, 221-20.
  • M. Zoudilova, Puneet Kumar, L. Ge, P. Wang, Gary Bokoch and K. DeFea, β-arrestin-dependent regulation of the cofilin pathway downstream of Protease-activated receptor-2. 2007, J. Biol. Chem, 282(28):20634-46.
  • P. Kumar, C. Lau, M. Mathur, P. Wang and K. DeFea, Differential regulation of PAR2 desensitization, internalization and signaling by b-arrestins, 2007, Amer. J. Physiology Cell Physiology, 293(1):C346-57.
  • 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).
  • 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.
  • 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.
  • 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.

More Information 

General Campus Information

University of California, Riverside
900 University Ave.
Riverside, CA 92521
Tel: (951) 827-1012

School Information

School of Medicine
2608 School of Medicine Education Building

Admissions Inquiries: (951) 827-7353
E-mail: medadmissions@ucr.edu

General Inquiries: (951) 827-4568
E-mail: medschool@ucr.edu

Related Links

Footer