LAUSR

Rap1 is a major convergence point of the platelet and lymphocyte signaling pathways that result in talin1 binding to the integrin β-cytoplasmic domain and consequent integrin activation, effective hemostasis and immune functions. The nature of the connection between Rap1 and talin1 in integrin activation is an important remaining gap in our understanding of this process. Deletion of RIAM in T cells partially suppressed αLβ2 and α4β7 integrin activation but did not block activation of α4β1. In sharp contrast, deletion of both Rap1a and Rap1b isoforms or deletion of talin1 profoundly suppressed activation of α4β1 in addition to the other two integrins. The loss of homing of T cells to peripheral lymphoid organs was correlated with the loss of integrin activation in these mutant T cells. We recently identified two Rap1 binding sites in talin1 F0 and F1 domains and generated mice bearing point mutations, which block Rap1 binding to both talin1 F0 and F1 domains (R35E,R118E). In platelets, which lack endogenous RIAM, a talin1 (R35E,R118E) mutation suppresses activation of integrin αIIbβ3 and platelet aggregation to a similar extent to that observed in Rap1a,b null platelets. In contrast, talin1 (R35E,R118E)-expressing T cells manifest only partial loss of integrin activation, whereas RIAM null T cells expressing talin1 (R35E,R118E) exhibit a much more profound defect. Importantly, overexpression of RIAM can completely rescue the integrin activation defect in talin1 (R35E,R118E)-expressing T cells indicating that Rap1 binding to RIAM and talin1 are partially redundant in T cells. These findings reveal that although both Rap1 and talin1 are essential for integrin action in blood cells, the connections between them vary in different blood cells and that the final steps in integrin activation and blood cell function can be manipulated in a cell-type specific manner. No relevant conflicts of interest to declare.