The Cytoskeletal Adaptor Protein IQGAP1 Regulates TCR-mediated Signaling and F-actin Dynamics1

The Ras GTPase-activating-like protein IQGAP1 is a multi-modular scaffold that controls signaling and cytoskeletal regulation in fibroblasts and epithelial cells. However, the functional role of IQGAP1 in T cell development, activation and cytoskeletal regulation has not been investigated. Herein, we show that IQGAP1 is dispensable for thymocyte development, as well as microtubule organizing center polarization and cytolytic function in CD8 + T cells. However, IQGAP1-deficient CD8 + T cells, as well as Jurkat T cells suppressed for IQGAP1 were hyper-responsive, displaying increased IL-2 and IFN-γ production, heightened LCK activation, and augmented global phosphorylation kinetics following TCR ligation. Additionally, IQGAP1-deficient T cells exhibited increased TCR-mediated F-actin assembly and amplified F-actin velocities during spreading. Moreover, we found that discrete regions of IQGAP1 regulated cellular activation and F-actin accumulation. Taken together, our data suggest that IQGAP1 acts as a dual negative regulator in T cells, limiting both TCR-mediated activation kinetics and F-actin dynamics via distinct mechanisms.