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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

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

^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

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• Ishida, D., Yang, H., Masuda, K., Uesugi, K., Kawamoto, H., Hattori, M., Minato, N. (2003). Antigen-driven T cell anergy and defective memory T cell response via deregulated Rap1 activation in SPA-1-deficient mice. Proc. Natl. Acad. Sci. USA 100: 10919-10924 [Abstract] [Full Text]  
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• Boettner, B., Harjes, P., Ishimaru, S., Heke, M., Fan, H. Q., Qin, Y., Van Aelst, L., Gaul, U. (2003). The AF-6 Homolog Canoe Acts as a Rap1 Effector During Dorsal Closure of the Drosophila Embryo. Genetics 165: 159-169 [Abstract] [Full Text]  
• Riggins, R. B., Quilliam, L. A., Bouton, A. H. (2003). Synergistic Promotion of c-Src Activation and Cell Migration by Cas and AND-34/BCAR3. J. Biol. Chem. 278: 28264-28273 [Abstract] [Full Text]  
• Murai, K. K., Pasquale, E. B. (2003). `Eph'ective signaling: forward, reverse and crosstalk. J. Cell Sci. 116: 2823-2832 [Abstract] [Full Text]  
• Rehmann, H., Rueppel, A., Bos, J. L., Wittinghofer, A. (2003). Communication between the Regulatory and the Catalytic Region of the cAMP-responsive Guanine Nucleotide Exchange Factor Epac. J. Biol. Chem. 278: 23508-23514 [Abstract] [Full Text]  
• Zhang, W., Shao, Y., Fang, D., Huang, J., Jeon, M.-S., Liu, Y.-C. (2003). Negative Regulation of T Cell Antigen Receptor-mediated Crk-L-C3G Signaling and Cell Adhesion by Cbl-b. J. Biol. Chem. 278: 23978-23983 [Abstract] [Full Text]  
• de Bruyn, K. M. T., Zwartkruis, F. J. T., de Rooij, J., Akkerman, J.-W. N., Bos, J. L. (2003). The Small GTPase Rap1 Is Activated by Turbulence and Is Involved in Integrin {alpha}IIb{beta}3-mediated Cell Adhesion in Human Megakaryocytes. J. Biol. Chem. 278: 22412-22417 [Abstract] [Full Text]  
• Newman, P. J., Newman, D. K. (2003). Signal Transduction Pathways Mediated by PECAM-1: New Roles for an Old Molecule in Platelet and Vascular Cell Biology. Arterioscler. Thromb. Vasc. Bio. 23: 953-964 [Abstract] [Full Text]  
• Tohyama, Y., Katagiri, K., Pardi, R., Lu, C., Springer, T. A., Kinashi, T. (2003). The Critical Cytoplasmic Regions of the {alpha}L/{beta}2 Integrin in Rap1-induced Adhesion and Migration. Mol. Biol. Cell 14: 2570-2582 [Abstract] [Full Text]  
• Shimonaka, M., Katagiri, K., Nakayama, T., Fujita, N., Tsuruo, T., Yoshie, O., Kinashi, T. (2003). Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. JCB 161: 417-427 [Abstract] [Full Text]  
• Koopman, W. J. H., Bosch, R. R., van Emst-de Vries, S. E., Spaargaren, M., De Pont, J. J. H. H. M., Willems, P. H. G. M. (2003). R-Ras Alters Ca2+ Homeostasis by Increasing the Ca2+ Leak across the Endoplasmic Reticular Membrane. J. Biol. Chem. 278: 13672-13679 [Abstract] [Full Text]  
• Marchuk, D. A., Srinivasan, S., Squire, T. L., Zawistowski, J. S. (2003). Vascular morphogenesis: tales of two syndromes. Hum Mol Genet 12: R97-112 [Abstract] [Full Text]  
• O'Brien, C. D., Lim, P., Sun, J., Albelda, S. M. (2003). PECAM-1-dependent neutrophil transmigration is independent of monolayer PECAM-1 signaling or localization. Blood 101: 2816-2825 [Abstract] [Full Text]  
• Sakakibara, A., Ohba, Y., Kurokawa, K., Matsuda, M., Hattori, S. (2003). Novel function of Chat in controlling cell adhesion via Cas-Crk-C3G-pathway-mediated Rap1 activation. J. Cell Sci. 115: 4915-4924 [Abstract] [Full Text]  
• Chaves-Olarte, E., Freer, E., Parra, A., Guzman-Verri, C., Moreno, E., Thelestam, M. (2003). R-Ras Glucosylation and Transient RhoA Activation Determine the Cytopathic Effect Produced by Toxin B Variants from Toxin A-negative Strains of Clostridium difficile. J. Biol. Chem. 278: 7956-7963 [Abstract] [Full Text]  
• Rangarajan, S., Enserink, J. M., Kuiperij, H. B., de Rooij, J., Price, L. S., Schwede, F., Bos, J. L. (2003). Cyclic AMP induces integrin-mediated cell adhesion through Epac and Rap1 upon stimulation of the {beta}2-adrenergic receptor. JCB 160: 487-493 [Abstract] [Full Text]  
• Larson, M. K., Chen, H., Kahn, M. L., Taylor, A. M., Fabre, J.-E., Mortensen, R. M., Conley, P. B., Parise, L. V. (2003). Identification of P2Y12-dependent and -independent mechanisms of glycoprotein VI-mediated Rap1 activation in platelets. Blood 101: 1409-1415 [Abstract] [Full Text]  
• Caron, E. (2003). Cellular functions of the Rap1 GTP-binding protein: a pattern emerges. J. Cell Sci. 116: 435-440 [Abstract] [Full Text]  
• Singh, L., Gao, Q., Kumar, A., Gotoh, T., Wazer, D. E., Band, H., Feig, L. A., Band, V. (2003). The High-Risk Human Papillomavirus Type 16 E6 Counters the GAP Function of E6TP1 toward Small Rap G Proteins. J. Virol. 77: 1614-1620 [Abstract] [Full Text]  

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