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J. Cell Biol. 161 (2): 417-427

Copyright © 2003 by the Rockefeller University Press.


Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow

Mika Shimonaka1,2, Koko Katagiri1, Toshinori Nakayama3, Naoya Fujita4, Takashi Tsuruo4, Osamu Yoshie5, and Tatsuo Kinashi1

1 Bayer-chair, Department of Molecular Immunology and Allergy
2 Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
3 Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba 263-8522, Japan
4 Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8654, Japan
5 Department of Microbiology and Internal Medicine III, Kinki University School of Medicine, Osaka 589-0014, Japan

Address correspondence to Dr. Tatsuo Kinashi, Bayer-chair, Dept. of Molecular Immunology and Allergy, Graduate School of Medicine, Kyoto University, Yoshida-konoe, Sakyo-ku, Kyoto 606-8501, Japan. Tel.: 81-75-771-8159. Fax: 81-75-771-8184. E-mail: tkinashi{at}

Abstract: Chemokines arrest circulating lymphocytes within the vasculature through the rapid up-regulation of leukocyte integrin adhesive activity, promoting subsequent lymphocyte transmigration. However, the key regulatory molecules regulating this process have remained elusive. Here, we demonstrate that Rap1 plays a pivotal role in chemokine-induced integrin activation and migration. Rap1 was activated by secondary lymphoid tissue chemokine (SLC; CCL21) and stromal-derived factor 1 (CXCL4) treatment in lymphocytes within seconds. Inhibition of Rap1 by Spa1, a Rap1-specific GTPase-activating protein, abrogated chemokine-stimulated lymphocyte rapid adhesion to endothelial cells under flow via intercellular adhesion molecule 1. Expression of a dominant active Rap1V12 in lymphocytes stimulated shear-resistant adhesion, robust cell migration on immobilized intercellular adhesion molecule 1 and vascular cell adhesion molecule 1, and transendothelial migration under flow. We also demonstrated that Rap1V12 expression in lymphocytes induced a polarized morphology, accompanied by the redistribution of CXCR4 and CD44 to the leading edge and uropod, respectively. Spa1 effectively suppressed this polarization after SLC treatment. This unique characteristic of Rap1 may control chemokine-induced lymphocyte extravasation.

Key Words: chemokines; LFA-1; ICAM-1; lymphocyte; transmigration

The online version of this article includes supplemental material.

* Abbreviations used in this paper: HUVEC, human umbilical vascular endothelial cells; ICAM-1, intercellular adhesion molecule 1; LFA-1, lymphocyte function–associated antigen 1; LN, lymph node; PTX, pertussis toxin; SDF-1, stromal-derived factor 1; SLC, secondary lymphoid tissue chemokine; VCAM-1, vascular cell adhesion molecule 1; VLA-4, very late antigen 4.

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W. P.-v. Berkel, M.H.G. Verheijen, E. Cuppen, M. Asahina, J. de Rooij, G. Jansen, R.H.A. Plasterk, J. L. Bos, and F.J.T. Zwartkruis (2005)
Mol. Biol. Cell 16, 106-116
   Abstract »    Full Text »    PDF »
Coordinated Redistribution of Leukocyte LFA-1 and Endothelial Cell ICAM-1 Accompany Neutrophil Transmigration.
S. K. Shaw, S. Ma, M. B. Kim, R. M. Rao, C. U. Hartman, R. M. Froio, L. Yang, T. Jones, Y. Liu, A. Nusrat, et al. (2004)
J. Exp. Med. 200, 1571-1580
   Abstract »    Full Text »    PDF »
Chemoattractant Signals and {beta}2 Integrin Occupancy at Apical Endothelial Contacts Combine with Shear Stress Signals to Promote Transendothelial Neutrophil Migration.
G. Cinamon, V. Shinder, R. Shamri, and R. Alon (2004)
J. Immunol. 173, 7282-7291
   Abstract »    Full Text »    PDF »
Common Cues in Vascular and Axon Guidance.
G. Serini and F. Bussolino (2004)
Physiology 19, 348-354
   Abstract »    Full Text »    PDF »
Elastase Release by Transmigrating Neutrophils Deactivates Endothelial-bound SDF-1{alpha} and Attenuates Subsequent T Lymphocyte Transendothelial Migration.
R. M. Rao, T. V. Betz, D. J. Lamont, M. B. Kim, S. K. Shaw, R. M. Froio, F. Baleux, F. Arenzana-Seisdedos, R. Alon, and F. W. Luscinskas (2004)
J. Exp. Med. 200, 713-724
   Abstract »    Full Text »    PDF »
Contribution of Protease-activated Receptors 1 and 4 and Glycoprotein Ib-IX-V in the Gi-independent Activation of Platelet Rap1B by Thrombin.
P. Lova, F. Campus, R. Lombardi, M. Cattaneo, F. Sinigaglia, C. Balduini, and M. Torti (2004)
J. Biol. Chem. 279, 25299-25306
   Abstract »    Full Text »    PDF »
Signaling in Leukocyte Transendothelial Migration.
J. D. van Buul and P. L. Hordijk (2004)
Arterioscler Thromb Vasc Biol 24, 824-833
   Abstract »    Full Text »
The Rap GTPases Regulate Integrin-mediated Adhesion, Cell Spreading, Actin Polymerization, and Pyk2 Tyrosine Phosphorylation in B Lymphocytes.
S. J. McLeod, A. J. Shum, R. L. Lee, F. Takei, and M. R. Gold (2004)
J. Biol. Chem. 279, 12009-12019
   Abstract »    Full Text »    PDF »
Rap1-mediated Lymphocyte Function-associated Antigen-1 Activation by the T Cell Antigen Receptor Is Dependent on Phospholipase C-{gamma}1.
K. Katagiri, M. Shimonaka, and T. Kinashi (2004)
J. Biol. Chem. 279, 11875-11881
   Abstract »    Full Text »    PDF »
LAD-III, a leukocyte adhesion deficiency syndrome associated with defective Rap1 activation and impaired stabilization of integrin bonds.
T. Kinashi, M. Aker, M. Sokolovsky-Eisenberg, V. Grabovsky, C. Tanaka, R. Shamri, S. Feigelson, A. Etzioni, and R. Alon (2004)
Blood 103, 1033-1036
   Abstract »    Full Text »    PDF »
T-cell integrins: more than just sticking points.
N. Hogg, M. Laschinger, K. Giles, and A. McDowall (2003)
J. Cell Sci. 116, 4695-4705
   Abstract »    Full Text »    PDF »
Rap1 GTPase: Functions, Regulation, and Malignancy.
M. Hattori and N. Minato (2003)
J. Biochem. 134, 479-484
   Abstract »    Full Text »    PDF »
The Critical Cytoplasmic Regions of the {alpha}L/{beta}2 Integrin in Rap1-induced Adhesion and Migration.
Y. Tohyama, K. Katagiri, R. Pardi, C. Lu, T. A. Springer, and T. Kinashi (2003)
Mol. Biol. Cell 14, 2570-2582
   Abstract »    Full Text »    PDF »

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