Data are representative of three experiments. Relative activation was determined by measuring band intensities from GST-PAK1-CRIB coprecipitation assay. These parameters were selected as optimal for all subsequent assays. Right: The cells were treated with sema3E (3 μg/ml) for the indicated times. Left: The cells were treated with the indicated concentrations of Sema3E for 10 min. (A) Sema3E induces activated Cdc42 Rho GTPase in the DP-257-20-109 model DP thymocyte cell line. GAP activity is not intrinsic to thymocyte plexinD1. Our results suggest that TAGAP variation modulates the risk of autoimmunity by altering thymocyte migration during thymic selection. This suppression led to the impaired translocation of thymocytes from the cortex to the medulla and resulted in the formation of ectopic medullary structures within the thymic cortex. Knockdown of Tagap in mice suppressed the sema3E- and plexin-D1–mediated release of thymocytes that adhered within the cortex through β1-containing integrins. Both RhoA and Cdc42 are key mediators of cytoskeletal and integrin dynamics in thymocytes. In addition, Tagap indirectly mediated the activation of Cdc42 in response to the binding of sema3E to plexin-D1. Tagap physically interacted with the cytoplasmic domain of plexin-D1 and directly stimulated the activity and signaling of the GTPase RhoA. By promoting thymocyte detachment within the cortex of the thymus, Tagap-mediated signaling enabled their translocation to the medulla, which is required for continued thymic selection. We showed in mice that Tagap-mediated signaling by the sema3E/plexin-D1 ligand-receptor complex attenuates thymocytes’ adhesion to the cortex through their β1-containing integrins. Multiple autoimmune pathologies are associated with single-nucleotide polymorphisms of the human gene TAGAP, which encodes TAGAP, a guanosine triphosphatase (GTPase)–activating protein.
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