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J. Biol. Chem., Vol. 280, Issue 6, 5022-5031, February 11, 2005

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Local Activation of Rap1 Contributes to Directional Vascular Endothelial Cell Migration Accompanied by Extension of Microtubules on Which RAPL, a Rap1-associating Molecule, Localizes^*

Hisakazu Fujita, Shigetomo Fukuhara, Atsuko Sakurai, Akiko Yamagishi, Yuji Kamioka, Yoshikazu Nakaoka, Michitaka Masuda, and Naoki Mochizuki

From the Department of Structural Analysis, National Cardiovascular Center Research Institute, Suita, Osaka 565-8565, Japan

Endothelial cell migration is promoted by chemoattractants and is accompanied with microtubule extension toward the leading edge. Cytoskeletal microtubules polarize to function as rails for delivering a variety of molecules by motor proteins during cell migration. It remains, however, unclear how directional migration with polarized extension of microtubules is regulated. Here we report that Rap1 controls the migration of vascular endothelial cells. We found that Rap1-associating molecule, RAPL, which belongs to the Ras association domain family (Rassf), localized on microtubules and that activated Rap1 induced dissociation of RAPL from microtubules. A Rap1 activation-monitoring probe based on the fluorescence resonance energy transfer enabled us to demonstrate that local Rap1 activation occurs at the leading edge of the cells under the two types of cell migration, chemotaxis and wound healing. Time lapse imaging of microtubules marked by enhanced green fluorescent protein-RAPL showed the directional growth of microtubules toward the leading edge of the migrating cells. Using adenovirus, inactivation of Rap1 by expression of rap1GAPII inhibited wound healing. In addition, disconnection of Rap1 and RAPL by expression of a RAPL mutant also perturbed wound healing. Collectively, the locally activated Rap1 and its association with RAPL controls the directional migration of vascular endothelial cells.

Received for publication, August 24, 2004 , and in revised form, November 23, 2004.

^* This work was supported by grants from the Ministry of Health, Labor, and Welfare of Japan; from the Promotion of Fundamental Studies in Health Science of the Organization for Pharmaceutical Safety and Research of Japan; from the Ministry of Education, Science, Sports and Culture of Japan; from the Cell Science Research Foundation; and from the Mochida Memorial Foundation for Medical and Pharmaceutical Research. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains two additional figures and eight videos.

To whom correspondence should be addressed: Dept. of Structural Analysis, National Cardiovascular Center Research Institute, 5-7-1 Fujishirodai, Suita, Osaka 565-8565, Japan. Tel.: 81-6-6833-5012 (ext. 2508); Fax: 81-6-6835-5461; E-mail: nmochizu{at}ri.ncvc.go.jp.

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