Pharmacology & Cancer Biology | Duke University Medical Center

Dr. Ann Marie Pendergast

Ann Marie Pendergast, Ph.D.
James B. Duke Professor of Pharmacology and Cancer Biology

Duke University Medical Center
C233A LSRC
Box 3813
Durham, NC 27710

Phone: 919-681-8086
E-mail: pende014@mc.duke.edu

Research Interests

The overall goal of our research is to define the role of the Abl family of tyrosine kinases and their targets in normal development and pathological conditions including cancer, bacterial pathogenesis, muscular dystrophies, neurodegenerative disorders and immune deficiencies. We have shown that the Abl kinases, c-Abl and Arg, link activated growth factor receptors to reorganization of the actin cytoskeleton. Abl kinases are also activated by the Muscle Specific Tyrosine Kinase (MuSK) on the postsynaptic side of the neuromuscular junction (NMJ) in response to the nerve-derived organizing factor agrin. Activation of the endogenous Abl family kinases in muscle is required for the clustering of Acetylcholine receptors (AchRs), which is essential for muscle function. These findings reveal a novel role for Abl kinases in synapse formation. We are currently employing mouse models as well as cell biological and biochemical approaches, to define the roles of Abl family kinases and associated Abl-interacting proteins in synapse formation and maintenance. Additionally, we are dissecting the role of these proteins in cell morphogenesis, migration and adhesion downstream of several cell surface receptors in multiple cell types. Among the Abl-interactor proteins under study is the Abi protein family recently implicated in Wave-dependent actin polymerization. We showed that Abi proteins localize to the tips of lamellipodia and filopodia in living cells, and that they are critical regulators of cytoskeletal dynamics during mouse development.

More recently, we have begun to use bacterial pathogens as tools to dissect the mechanisms employed by Abl kinases to regulate cytoskeletal dynamics. We reported that endogenous Abl kinases are required for bacterial entry during Shigella flexneri infection. Shigella is a gram-negative bacterium that causes dysentery and affects over 160 million people per year around the world, killing one million, mostly children. Shigellosis is a severe health problem as the most affected populations exhibit antibiotic resistance. We discovered that pharmacological inhibition or genetic ablation of the Abl kinases impairs bacterial entry and the phosphorylation of Abl targets. We showed that Abl kinases are functionally linked to the Rac and Cdc42 GTPases in pathway initiated by Shigella entry into the host cell. Our findings reveal an unexpected role for Abl kinases in bacterial pathogenesis and suggest novel approaches to the treatment of Shigellosis through inhibition of host cell signaling pathways.

Publications

Pendergast. A.M. (2002) The Abl family kinases: mechanisms of regulation and signaling. Adv. Cancer Res. 85, 51-100.

Plattner, R., Irvin, B.J., Guo, S., Blackburn, K., Kazlauskas, A., Abraham, R.T., York, J.D., and Pendergast, A.M. (2003). A new link between the c-Abl tyrosine kinase and phosphoinositide signaling through PLC-gamma1. Nat. Cell Biol. 5, 309-319.

Finn, A.J., Feng, G., and Pendergast, A.M. (2003). Postsynaptic requirement for Abl kinases in assembly of the neuromuscular junction. Nat. Neurosci. 6, 717-723.

Burton, E.A., Plattner, R., and Pendergast, A.M. (2003). Abl tyrosine kinases are required for infection by Shigella flexneri. EMBO J. 22, 5471-5479.

Plattner, R., Koleske, A.J., Kazlauskas, A., and Pendergast, A.M. (2004). Bidirectional signaling links the Abelson Kinases to the Platelet-Derived Growth Factor Receptor. Mol. Cell. Biol. 24, 2573-2583.

Echarri, A., Lai, M.J., Robinson, M.R., and Pendergast, A.M. (2004). Abl Interactor 1 (Abi-1) Wave-binding and SNARE domains regulate its nucleocytoplasmic shuttling, lamellipodium localization, and Wave-1 levels. Mol. Cell. Biol. 24, 4979-4993.

Zipfel, P.A., Zhang, W., Quiroz, M., and Pendergast, A.M. (2004). Requirement for Abl kinases in T cell receptor signaling. Current Biology:14, 1222-1231.

Grove, M., Demyanenko, G., Echarri, A., Zipfel, P.A., Quiroz, M.E., Rodriguiz, R.M., Playford, M., Martensen, S.A., Robinson, M. R., Wetsel, W.C., Maness, P.F., and Pendergast, A.M. (2004). Abi2-deficient mice exhibit defective cell migration, aberrant dendritic spine morphogenesis and deficits in learning and memory. Mol. Cell. Biol. 24, 10905-10922.

Pendergast, A. M. (2005). Stress and death: breaking up the c-Abl/14-3-3 complex in apoptosis. Nat. Cell Biol. 7, 213-214.

Burton, E.A., Oliver, T.N., and Pendergast, A.M. (2005). Abl kinases regulate actin comet tail elongation via an N-WASP-dependent pathway. Mol. Cell. Biol. 25, 8834-8843.

Zipfel, P.A., Bunnell, S.C., Witherow, D.S., Gu, J.J., Chislock, E.M., Ring, C., and Pendergast, A.M. (2006). Role for the Abi/Wave protein complex in T cell receptor-mediated proliferation and cytoskeletal remodeling. Current Biology 16, 35-46.

Zandy, N.L., Playford, M., and Pendergast, A.M. (2007). Abl Tyrosine Kinases regulate cell-cell adhesion via Rho GTPases. PNAS 104: 17686-17691.

Gu, J.J., Zhang, N., He, Y.-H., Koleske, A.J., and Pendergast, A.M. (2007). Defective T cell development and function in the absence of Abl kinases. The Journal of Immunology 179: 7334-7343

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