Integrin activation in leukocytes and platelets. (A) Chemokines presented on the endothelial surface activate leukocyte integrins via G protein–coupled receptors, which trigger Rap1 activation, RIAM-dependent talin-1 mobilization, and kindlin-3 recruitment to the integrin β-cytoplasmic tail, leading to the allosteric change toward the high-affinity conformation (inside-out signaling). Subsequent ligand binding, integrin clustering, and connection to the cytoskeleton ensure cell adhesion and amplify downstream signaling (outside-in signaling). (B) In platelets, soluble agonist or matrix receptors can trigger inside-out activation, which depends critically on CalDAG-GEFI. In contrast, RIAM is not required, and Rap1 can bind directly to talin-1. ADP, adenosine diphosphate; ER, endoplasmic reticulum; GDP, guanosine diphosphate; GP, glycoprotein, IP3, inositol trisphosphate; PKC, protein kinase C; TxA2, thromboxane A2.