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

J. Cell Biol., 28 April 2003
Vol. 161, Issue 2, p. 417-427
DOI: 10.1083/jcb.200301133

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

  1. Mika Shimonaka1,2,
  2. Koko Katagiri1,
  3. Toshinori Nakayama3,
  4. Naoya Fujita4,
  5. Takashi Tsuruo4,
  6. Osamu Yoshie5, and
  7. Tatsuo Kinashi1
  1. 1Bayer-chair, Department of Molecular Immunology and Allergy
  2. 2Department of Dermatology, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
  3. 3Department of Molecular Immunology, Graduate School of Medicine, Chiba University, Chiba 263-8522, Japan
  4. 4Institute of Molecular and Cellular Biosciences, University of Tokyo, Tokyo 113-8654, Japan
  5. 5Department of Microbiology and Internal Medicine III, Kinki University School of Medicine, Osaka 589-0014, Japan
  1. 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}


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.

  • chemokines; LFA-1; ICAM-1; lymphocyte; transmigration
  • Submitted: 30 January 2003
  • Revision received 7 March 2003
  • Accepted: 7 March 2003


M. Shimonaka, K. Katagiri, T. Nakayama, N. Fujita, T. Tsuruo, O. Yoshie, and T. Kinashi, Rap1 translates chemokine signals to integrin activation, cell polarization, and motility across vascular endothelium under flow. J. Cell Biol. 161, 417-427 (2003).

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Common Cues in Vascular and Axon Guidance
G. Serini, and F. Bussolino
Physiology 19, 348-354 (1 December 2004)

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, F. W. Luscinskas et al.
JEM 200, 713-724 (20 September 2004)

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
J Biol Chem 279, 25299-25306 (11 June 2004)

Signaling in Leukocyte Transendothelial Migration
J. D. van Buul, and P. L. Hordijk
Arterioscler. Thromb. Vasc. Bio. 24, 824-833 (1 May 2004)

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
J Biol Chem 279, 12009-12019 (26 March 2004)

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
J Biol Chem 279, 11875-11881 (19 March 2004)

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
Blood 103, 1033-1036 (1 February 2004)

T-cell integrins: more than just sticking points
N. Hogg, M. Laschinger, K. Giles, and A. McDowall
J. Cell Sci. 116, 4695-4705 (1 December 2003)

Rap1 GTPase: Functions, Regulation, and Malignancy
M. Hattori, and N. Minato
J Biochem 134, 479-484 (1 October 2003)

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
Mol. Biol. Cell 14, 2570-2582 (1 June 2003)

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