Model for integrin activation by the chemokine SDF-1α in human T cells. SDF-1α binding to the G protein–coupled receptor CXCR4 activates Gq-coupled signaling to PLC-γ, generating DAG and releasing intracellular calcium via IP₃. These intracellular second messengers activate PKC and CalDAG-GEF1 to initiate inside-out signaling to the integrins VLA-4 (α4β1) and LFA-1 (αLβ2), respectively. The mechanism by which PKC triggers VLA-4 binding to VCAM is unknown. CalDAG-GEF1 is a Rap1-specific guanine nucleotide exchange factor whose catalytic (GEF) domain is activated by direct binding of calcium and DAG to adjacent EF hand domains and a DAG-binding motif. Rap1 activation by CalDAG-GEF1 selectively activates LFA-1 binding to ICAM. This may require the actions of the Rap1 effectors RIAM and RapL. RapL binds to LFA-1 and may help bring Rap1 to the plasma membrane. Adaptor molecules ADAP and SKAP-55 may also facilitate coupling of Rap1 to LFA-1.