The small GTPase, Rap1, mediates CD31-induced integrin adhesion

Integrin-mediated leukocyte adhesion is a critical aspect of leukocyte func tion that is tightly regulated by diverse stimuli, including chemokines, an tigen receptors, and adhesion receptors, How cellular signals from CD31 and other adhesion amplifiers are integrated with those from classical mitogen ic stimuli to regulate leukocyte function remains poorly understood. Here, we show that the cytoplasmic tail of CD31, an important integrin adhesion a mplifier, propagates signals that induce T cell adhesion via beta 1 (VLA-4) and beta 2 (LFA-1) integrins. We identify the small GTPase, Rap1, as a cri tical mediator of this effect. Importantly, CD31 selectively activated the small Ras-related GTPase, Rap1,but not Ras, R-Ras, or Rap2. An activated Ra p1 mutant stimulated T lymphocyte adhesion to intercellular adhesion molecu le (ICAM) and vascular cell adhesion molecule (VCAM), as did the Rap1 guani ne nucleotide exchange factor C3G and a catalytically inactive mutant of Ra pGAP. Conversely, negative regulators of Rap1 signaling blocked CD31-depend ent adhesion. These findings identify a novel important role for Rap1 in re gulating ligand-induced cell adhesion and suggest that Rap1 may play a more general role in coordinating adhesion-dependent signals during leukocyte m igration and extravasation. Our findings also suggest an alternative mechan ism, distinct from interference with Ras-proximal signaling, by which Rap1 might mediate transformation reversion.