UC San Diego

Integrins are essential transmembrane adhesion receptors that mediate cell-cell and cell-extracellular matrix adhesions and induce bidirectional signaling across the cell membrane to regulate cell functions in lymphocytes. Ras-related protein 1 (Rap1) is a small GTPase known to regulate the recruitment and tethering of Talin1 to the plasma membrane to initiate integrin activation. Previous studies have shown that Rap1 can bind to Talin1 F0 and F1 domains directly to regulate integrin activation in platelets. However, the function of such interaction remains unclear in integrin activation in T lymphocytes. In our study, we examined mice bearing point mutations in Talin1 F0 and F1 domains, which block Rap1 direct binding to Talin1 without disturbing Talin1 expression, and found that the direct interaction between Rap1 and Talin1 is pivotal in both CD4+ T cells and regulatory T (Treg) cells integrin activations. Furthermore, by cross-breeding mice bearing F0F1 double mutations with other transgenic mice strains, we also tested whether the binding of Rap1 and Talin1 could compensate for known integrin activation pathways such as the Rap1-RIAM-Talin1 axis in T lymphocytes. We found that the direct interaction between Rap1 and Talin1 is redundant with the Rap1-RIAM/Lamellipodin-Talin1 pathways on T lymphocytes and that the overexpression of Rap1-GTP-interacting adaptor molecule (RIAM) could compensate for the loss of Rap1 and Talin1 direct binding in CD4+ T cells.