We have previously shown that chymotrypsin-cleaved soluble uPAR (D2D3(88-274)) elicits migration of monocytic cells through interaction with FPRL-1, a G protein-coupled receptor that is homologous to the fMLP receptor. Here, we report that D2D3(88-274) also modulates the ability of monocytes to migrate in response to other chemokines. Pretreatment of monocytes with increasing amounts of D2D3(88-274) prevents cell migration in response to MCP-1, RANTES and fMLP. We demonstrate that D2D3(88-274) does not inhibit MCP-1 receptor binding, elicit CCR2 internalization and prevent MCP-1-induced intracellular Ca(2+) increase. Thus, CCR2 receptor desensitization cannot account for D2D3(88-274)-mediated inhibition of MCP-1-induced cell migration. Rather, we show that pretreatment of monocytes with D2D3(88-274) dramatically decreases chemokine-induced integrin-dependent rapid cell adhesion by interacting with FPRL-1. Together, our results indicate that chemokine-dependent cell migration can be regulated not only by homologous and heterologous receptor desensitization, but also by inhibition of integrin-dependent cell adhesion, an important step in cell transmigration.