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Ann Marie Pendergast

Professor and Vice Chair, Pharmacology & Cancer Biology
Pharmacology and Cancer Biology
Research Interest: 
Developmental biology
Signal transduction
Research Summary: 
Regulation of cellular signaling networks by tyrosine kinases in development and cancer.
Research Description: 

Research Interests
The overall goal of our research is to define the role of tyrosine kinase signaling networks in the regulation of “intercellular conversations” between cells during normal development, tissue homeostasis, and pathological conditions including cancer and inflammation. Specifically, we focus on the role of the Abl family of tyrosine kinases, Abl and Arg (Abl2), and associated actin regulatory proteins in diverse cellular processes leading to changes in cell morphology, motility, invasion, adhesion, as well as cell growth and survival. Among the research areas currently being pursued in our laboratory are defining the mechanisms that regulate the cross-talk between tumor cells and immune cells in the tumor microenvironment; and dissecting the signaling networks that regulate cell polarity, motility and invasion of T cells and other immune cell types during inflammation and cancer. Representative areas of research in recent publications are:
Regulation of epithelial cell polarity. Establishment and maintenance of epithelial cell polarity is regulated in part by signaling from adhesion receptors. Loss of cell polarity is associated with multiple pathologies including the initiation and progression of various cancers. The beta1-integrin plays a role in the regulation of cell polarity. We identified a role for Arg in the regulation of beta1-integrin signals and epithelial cell polarity. In a three-dimensional (3D) cell culture model, activation of Arg resulted in a striking inversion of apical-basal polarity. In contrast, loss of Arg function impaired the establishment of a polarized epithelial cyst structure. Active Arg kinase disrupted beta1-integrin signaling and localization, and inhibited Rac1-mediated laminin assembly. Disruption of beta1-integrin function by active Arg altered the distribution of selected polarity proteins though Rap1 GTPase signaling. We showed that Rap1 and Rac1 signal independently in the regulation of epithelial polarity downstream of the Arg kinase. Thus, Arg activation may promote pathologies associated with loss of cell polarity (Li and Pendergast, 2011).
Abl kinases are required for invadopodia formation and chemokine-induced invasion. Abl kinases are highly active in a number of invasive cancers. We showed that Abl kinases are essential regulators of invadopodia assembly and function. Abl kinases are activated downstream of the CXCR4 chemokine receptor in response to SDF1-alpha and are required for cancer cell invasion and matrix degradation induced by SDF1-alpha, serum growth factors or activated Src kinase. Arg localizes to invadopodia and Abl/Arg inhibition prevents the assembly of actin and cortactin at invadopodia structures. We found that active Abl kinases form complexes with membrane type1 matrix metalloproteinase (MT1-MMP), a critical invadopodia component required for matrix degradation. Further, loss of Abl kinase signaling induces internalization of MT1-MMP from the cell surface promoting its accumulation in the perinuclear compartment and inhibits MT1-MMP tyrosine phosphorylation (Smith-Pearson et al., 2010).
Abi1 is a novel target of alpha4-beta1 integrin signaling. Dynamic signals linking the actin cytoskeleton and cell adhesion receptors are essential for morphogenesis during development and normal tissue homeostasis. Abi1 is a central regulator of actin polymerization and a binding partner of the Abl kinases. The alpha4 integrin receptor is associated with enhanced protrusive activity and regulation of directional cell migration. Among integrin subunits, alpha4 predominantly accumulates at the leading edge of migrating cells. We identified Abi1 as a crucial linker between alpha4 and the actin nucleation machinery at the leading edge. We generated Abi1 knockout mice and found that loss of Abi1 phenocopies knockout of alpha4. Mice lacking Abi1 or alpha4 exhibit mid-gestational lethality with abnormalities in placental and cardiovascular development. Notably, purified Abi1 protein binds directly to the alpha4 cytoplasmic tail and endogenous Abi1 co-localizes with phosphorylated alpha4 at the leading edge of spreading cells. Abi1-deficient cells expressing alpha4 have impaired cell spreading, which is rescued by wild type Abi1 but not an Abi1 mutant lacking the alpha4-binding site. These data reveal the first direct link between the alpha4 integrin and actin polymerization and uncover a novel role for Abi1 in the regulation of morphogenesis in vivo. (Ring et al., 2011).
Selected Publications
• Pendergast, A.M., Quilliam. L.A., Cripe, L.D., Bassing, C.H., Dai, Z., Li, N., Batzer, A., Rabun, K.M. Der, C.J. Schlessinger, J. and Gishizky, M.L. (1993). BCR-ABL-induced oncogenesis is mediated by direct interaction with the SH2 domain of the GRB-2 adaptor protein. Cell 75, 175-185.
• 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.
• 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.
• 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.
• Tanos, B., and Pendergast, A.M. (2006). ABL tyrosine kinase regulates endocytosis of the Epidermal Growth Factor Receptor. J. Biol. Chem. 281, 32714-32723.
• Zandy, N.L., Playford, M., and Pendergast, A.M. (2007). Abl Tyrosine Kinases regulate cell-cell adhesion via Rho GTPases. PNAS 104: 17686-17691. (PMCID: PMC2077043).
• 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. J. Immunol.179: 7334-7343.
• Augustine, C.K., Yoshimoto, Y., Gupta, M., Zipfel, P.A., Selim, M.A., Febbo, P., Pendergast, A.M., Peters, W.P., and Tyler, D.S. (2008). Targeting N-Cadherin enhances antitumor activity of cytotoxic therapies in melanoma treatment. Cancer Research 68: 3777-3784. (PMID: 18483261).
• Yogalingam, G., and Pendergast, A.M. (2008). ABL kinases regulate autophagy by promoting the trafficking and function of lysosomal components. J. Biol. Chem. 283: 35941-35953. (PMCID: PMC2602914).
• Ryun Ryu, J., Echarri. A., Li, R., and Pendergast, A.M. (2009). Regulation of cell-cell adhesion by Abi/Diaphanous complexes. Mol. Cell. Biol. 29: 1735-1748. (PMCID: PMC2655615).
• Smith-Pearson, P.S., Greuber, Greuber, E. K., Yogalingam, G., and Pendergast, A.M. (2010). Abl Kinases are required for invadopodia formation and chemokine-induced invasion. J. Biol. Chem. 285, 40201-40211. Epub Oct 11, 2010. (PMCID: PMC3001002).
• Ring, C., Ginsberg, M.H., Haling, J., and Pendergast, A.M. (2011). Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the alpha4 integrin. PNAS 108, 149-154. Cover Article for the January 4, 2011 issue. Epub Dec 20, 2010. (PMCID: PMC3017183).
• Li, R. and Pendergast, A.M. (2011). Arg Kinase Regulates Epithelial Cell Polarity by Targeting beta1-Integrin and Small GTPase Pathways. Current Biology 21: 1534-1542. (PMCID: PMC3189484).

Arg kinase regulates epithelial cell polarity by targeting β1-integrin and small GTPase pathways.
Li R, Pendergast AM.
Curr Biol. 2011. 21:1534-42.

Abl-interactor-1 (Abi1) has a role in cardiovascular and placental development and is a binding partner of the alpha4 integrin.
Ring C, Ginsberg MH, Haling J, Pendergast AM.
Proc Natl Acad Sci U S A. 2011. 108:149-54.

Abl kinases are required for invadopodia formation and chemokine-induced invasion.
Smith-Pearson PS, Greuber EK, Yogalingam G, Pendergast AM.
J Biol Chem. 2010. 285:40201-11.

Regulation of cell-cell adhesion by Abi/Diaphanous complexes.
Ryu JR, Echarri A, Li R, Pendergast AM.
Mol Cell Biol. 2009. 29:1735-48.

Regulation of cell-cell adhesion by Abi/Diaphanous complexes.
Ryu JR, Echarri A, Li R, Pendergast AM.
Mol Cell Biol. 2009. 29:1735-48.