Suggested model for the relative contributions of the cooperating 4β1 and 4β7 integrins and their cognate binding sites in the process of cell adhesion and migration on fibronectin. Both receptors interchangeably recognize at least 4 different binding sites residing within the central cell-binding and IIICS alternative spliced domains and acting in concert. Within the former, three 3Fn modules are the ones primarily implicated, ie, 3Fn8-10. Each of these modules embodies at least one binding site, which is differentially recognized by the integrins during the process of leukocyte adhesion and chemotactic migration. The RGD site is the active one of 3Fn10, whereas the synergistic sites residing within 3Fn8/3Fn9 remain unidentified. The CS-1 site seems to be the only active one of the IIICS domain. Both the relative contributions of the two domains and of the integrin receptors recognizing the corresponding sites within these domains differ in the processes of adhesion and migration. In the case of cell adhesion, 4β7 shows a bias towards the putative novel synergistic site within 3Fn8, whereas 4β1 preferentially binds to the RGD site of 3Fn10.