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Anthony R. Means Cancer Biology Professor of Pharmacology and Cancer Biology
Vice Chair, Pharmacology and Cancer Biology
Duke University School of Medicine
Durham, NC 27710
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 β1-integrin plays a role in the regulation of cell polarity. We identified a role for Arg in the regulation of β1-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 β1-integrin signaling and localization, and inhibited Rac1-mediated laminin assembly. Disruption of β1-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 SDF1α and are required for cancer cell invasion and matrix degradation induced by SDF1α, 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 α4β1 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 α4 integrin receptor is associated with enhanced protrusive activity and regulation of directional cell migration. Among integrin subunits, α4 predominantly accumulates at the leading edge of migrating cells. We identified Abi1 as a crucial linker between α4 and the actin nucleation machinery at the leading edge. We generated Abi1 knockout mice and found that loss of Abi1 phenocopies knockout of α4. Mice lacking Abi1 or α4 exhibit mid-gestational lethality with abnormalities in placental and cardiovascular development. Notably, purified Abi1 protein binds directly to the α4 cytoplasmic tail and endogenous Abi1 co-localizes with phosphorylated α4 at the leading edge of spreading cells. Abi1-deficient cells expressing α4 have impaired cell spreading, which is rescued by wild type Abi1 but not an Abi1 mutant lacking the α4-binding site. These data reveal the first direct link between the α4 integrin and actin polymerization and uncover a novel role for Abi1 in the regulation
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-gamma 1. 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. (PMCID: Journal-In Process).
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; PMC Journal-In process).
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 a4 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 beta 1-Integrin and Small GTPase Pathways. Current Biology 21: 1534-1542. (PMCID: PMC3189484).
Gu, J.J., Lavau, C.P., Pugacheva, E., Soderblom, E.J., Moseley, M.A., and Pendergast, A.M. (2012). Abl Family Kinases Modulate T Cell-Mediated Inflammation and Chemokine-Induced Migration through the Adaptor HEF1 and the GTPase Rap1. Science Signaling 5, ra51. [DOI: 10.1126/scisignal.2002632]
Carole Sourbier, Christopher J. Ricketts, Shingo Matsumoto, Daniel R. Crooks, Pei-Jyun Liao, Philip Z. Mannes, Youfeng Yang, Ming-Hui Wei, Gaurav Srivastava, Sanchari Ghosh, Viola Chen, Cathy D. Vocke, Maria Merino, Ramaprasad Srinivasan, Murali C. Krishna, James B. Mitchell, Ann Marie Pendergast, Tracey A. Rouault, Len Neckers, W. Marston Linehan (2014). Targeting ABL1-mediated Oxidative Stress Adaptation in Fumarate Hydratase-Deficient Cancer. Cancer Cell 26: 840-850.
Wang, J. and Pendergast, A.M. (2015). The emerging role of ABL kinases in solid tumors. Trends in Cancer (Cell Press) 1: 110-123 (PMCID: PMC4669955).
Wang, J., Rousse, C., Jasper, J.S., and Pendergast, A.M. (2016). ABL kinases promote breast cancer osteolytic metastasis by modulating tumor-bone interactions through TAZ and STAT5 signaling. Science Signaling 9 (issue 413): ra12. (Cover article of February 2, 2016 issue).