A working model for the role of β-arrestins in CXCR2-driven responses. Our findings support the hypothesis that β-arrestins act sequentially to Gα_i-driven signaling in regulating CXCR2-driven responses. Rapid onset (subsecond) adhesion requires Rap1 activity, cooperatively induced by Gα_i-triggered PLC, via the CalDAG GEF (gray lines and symbols) and by CXCR2-associated β-arrestins 1 and 2. A plausible (dashed lines) intermediate in the β-arr–dependent component of KC-driven rapid onset adhesion is RhoA, as it is involved in inside-out activation of integrins⁴³  and has been previously shown to be induced by β-arr signaling in several model systems.^17,44  Later events (seconds to minutes after agonist binding) in KC-induced leukocyte extravasation are differentially affected by the 2 β-arr isoforms, which become independently associated to phosphorylated CXCR2; both β-arr isoforms are involved in triggering a PI3K-ERK1/2 cascade that may control leukocyte motility during the crawling, diapedesis, and interstitial migration steps (black lines and symbols). Conversely, β-arr 2 specifically controls a postintegrin binding Rap1 activation step, which is involved in the stabilization of integrin-dependent adhesion, (red lines and symbols). Intermediates in this pathway, including potential Rap1 GEFs, have yet to be identified.