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© The Rockefeller University Press, 0021-9525/2000//1151 $5.00
The Journal of Cell Biology, Volume 148, Number 6, , 2000 1151-1158

Brief Report

The Small Gtpase, Rap1, Mediates Cd31-Induced Integrin Adhesion



Kris A. Reedquista, Ewan Rossb, Elianne A. Koopa, Rob M.F. Wolthuisa, Fried J.T. Zwartkruisa, Yvette van Kooykc, Mike Salmonb, Christopher D. Buckleyb, and Johannes L. Bosa

a Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Utrecht University Medical Center, Universiteitsweg 100, 3584 CG, Utrecht, The Netherlands
b Division of Immunity and Infection, MRC Center for Immune Regulation, University of Birmingham, Birmingham B15 2TT, United Kingdom
c Department of Tumor Immunology, University Hospital Nijmegen, Nijmegen, The Netherlands
Laboratory for Physiological Chemistry and Centre for Biomedical Genetics, Universiteitsweg 100, 3584 CG Utrecht, The Netherlands.31 30 253903531 30 2538989

j.l.bos{at}med.uu.nl

Integrin-mediated leukocyte adhesion is a critical aspect of leukocyte function that is tightly regulated by diverse stimuli, including chemokines, antigen receptors, and adhesion receptors. How cellular signals from CD31 and other adhesion amplifiers are integrated with those from classical mitogenic stimuli to regulate leukocyte function remains poorly understood. Here, we show that the cytoplasmic tail of CD31, an important integrin adhesion amplifier, propagates signals that induce T cell adhesion via β1 (VLA-4) and β2 (LFA-1) integrins. We identify the small GTPase, Rap1, as a critical mediator of this effect. Importantly, CD31 selectively activated the small Ras-related GTPase, Rap1, but not Ras, R-Ras, or Rap2. An activated Rap1 mutant stimulated T lymphocyte adhesion to intercellular adhesion molecule (ICAM) and vascular cell adhesion molecule (VCAM), as did the Rap1 guanine nucleotide exchange factor C3G and a catalytically inactive mutant of RapGAP. Conversely, negative regulators of Rap1 signaling blocked CD31-dependent adhesion. These findings identify a novel important role for Rap1 in regulating ligand-induced cell adhesion and suggest that Rap1 may play a more general role in coordinating adhesion-dependent signals during leukocyte migration and extravasation. Our findings also suggest an alternative mechanism, distinct from interference with Ras-proximal signaling, by which Rap1 might mediate transformation reversion.

Key Words: guanine nucleotide exchange factor • extravasation • leukocyte function-associated antigen 1 • integrin-mediated adhesion • lymphocyte

© 2000 The Rockefeller University Press

Abbreviations used in this paper: GAP, GTPase activating protein; GEF, guanine nucleotide exchange factor; GPI, glycosylphosphatidylinositol; GST, glutathione-S-transferase; HA, hemagglutinin; ICAM, intercellular cell adhesion molecule; PECAM, platelet endothelial cell adhesion molecule; RBD, Ras-binding domain; VCAM, vascular cell adhesion molecule; WT, wild-type.


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J. Cell Biol. 2000 148: 1-2. [Full Text] [PDF]





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