Experimental and clinical studies highlight the potential for T cells in enhancing anti-tumor response and their pathological role in inflammation. Thus, efforts aimed at understanding the signal transduction mechanisms utilized during T cell activation provide a foundation for developing strategies to pharmacologically or genetically enhance or suppress T cell functions when needed. The actin cytoskeleton and its regulators play a key role in T-cell receptor (TCR)-, costimulatory-, and integrin-mediated signaling. Our preliminary data suggest that the dynamic interaction of three actin-regulatory proteins, Dynamin 2, Vav1 and WAVE2 influence cytoskeletal changes and the activation of kinase cascades following TCR engagement. The mechanistic experiments outlined in this proposal will functionally characterize the role of Dyn2 and its effector molecules in actin-mediated processes following TCR crosslinking by testing the central hypothesis that: Dyn2 contributes to T cell activation by functioning as a molecular scaffold for the assembly of actin regulatory proteins at the T cell - ARC contact site. In addition, we propose that the novel Dyn2-Vav1 interaction is required for the localization of Vav1 to the immunological synapse where it will activate its target molecule Rac1. Moreover, we provide evidence that identifies a role for the Rac1-regulated WAVE2 complex as a target of Dyn2 that plays a key role in T cell activation. In order to test our central hypothesis, we will (1) Determine the role of Dynamin 2 in T cell activation; (2) Determine the mechanism by which Vav1 regulates Dynamin 2-mediated regulatory events; and (3) Determine the role of the Abi-WAVE2 complex in T cells. Together, these studies will provide an experimental basis for understanding the molecular events that are involved in the regulation of T cell activation, and will in a broader context, advance our understanding of fundamental processes involved in actin cytoskeletal dynamics during lymphocyte activation.
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| McNally, Kerrie E; Faulkner, Rebecca; Steinberg, Florian et al. (2017) Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat Cell Biol 19:1214-1225 |
| Jia, Da; Zhang, Jin-San; Li, Fang et al. (2016) Structural and mechanistic insights into regulation of the retromer coat by TBC1d5. Nat Commun 7:13305 |
| Bartuzi, Paulina; Billadeau, Daniel D; Favier, Robert et al. (2016) CCC- and WASH-mediated endosomal sorting of LDLR is required for normal clearance of circulating LDL. Nat Commun 7:10961 |
| Osborne, Douglas G; Piotrowski, Joshua T; Dick, Christopher J et al. (2015) SNX17 affects T cell activation by regulating TCR and integrin recycling. J Immunol 194:4555-66 |
| Li, Haiying; Koo, Yeon; Mao, Xicheng et al. (2015) Endosomal sorting of Notch receptors through COMMD9-dependent pathways modulates Notch signaling. J Cell Biol 211:605-17 |
| Deng, Zhi-Hui; Gomez, Timothy S; Osborne, Douglas G et al. (2015) Nuclear FAM21 participates in NF-?B-dependent gene regulation in pancreatic cancer cells. J Cell Sci 128:373-84 |
| Phillips-Krawczak, Christine A; Singla, Amika; Starokadomskyy, Petro et al. (2015) COMMD1 is linked to the WASH complex and regulates endosomal trafficking of the copper transporter ATP7A. Mol Biol Cell 26:91-103 |
| Osborne, Douglas G; Phillips-Krawczak, Christine A; Billadeau, Daniel D (2015) Monitoring receptor trafficking following retromer and WASH deregulation. Methods Cell Biol 130:199-213 |
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