HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

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

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 280/6/5022    most recent M409701200v1 Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Fujita, H. Articles by Mochizuki, N. Search for Related Content PubMed PubMed Citation Articles by Fujita, H. Articles by Mochizuki, N. Social Bookmarking                      What's this?

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.

CiteULike    Complore    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				J. Yan, F. Li, D. A. Ingram, and L. A. Quilliam Rap1a Is a Key Regulator of Fibroblast Growth Factor 2-Induced Angiogenesis and Together with Rap1b Controls Human Endothelial Cell Functions Mol. Cell. Biol., September 15, 2008; 28(18): 5803 - 5810. [Abstract] [Full Text] [PDF]

				C. J. Foley, H. Freedman, S. L. Choo, C. Onyskiw, N. Y. Fu, V. C. Yu, J. Tuszynski, J. C. Pratt, and S. Baksh Dynamics of RASSF1A/MOAP-1 Association with Death Receptors Mol. Cell. Biol., July 15, 2008; 28(14): 4520 - 4535. [Abstract] [Full Text] [PDF]

				M. Takahashi, Y. Rikitake, Y. Nagamatsu, T. Hara, W. Ikeda, K.-i. Hirata, and Y. Takai Sequential activation of Rap1 and Rac1 small G proteins by PDGF locally at leading edges of NIH3T3 cells. Genes Cells, June 1, 2008; 13(6): 549 - 569. [Abstract] [Full Text] [PDF]

				S. Sehrawat, X. Cullere, S. Patel, J. Italiano Jr., and T. N. Mayadas Role of Epac1, an Exchange Factor for Rap GTPases, in Endothelial Microtubule Dynamics and Barrier Function Mol. Biol. Cell, March 1, 2008; 19(3): 1261 - 1270. [Abstract] [Full Text] [PDF]

				M. Chrzanowska-Wodnicka, A. E. Kraus, D. Gale, G. C. White II, and J. VanSluys Defective angiogenesis, endothelial migration, proliferation, and MAPK signaling in Rap1b-deficient mice Blood, March 1, 2008; 111(5): 2647 - 2656. [Abstract] [Full Text] [PDF]

				G. W. Tew, E. L. Lorimer, T. J. Berg, H. Zhi, R. Li, and C. L. Williams SmgGDS Regulates Cell Proliferation, Migration, and NF-{kappa}B Transcriptional Activity in Non-small Cell Lung Carcinoma J. Biol. Chem., January 11, 2008; 283(2): 963 - 976. [Abstract] [Full Text] [PDF]

				M. Miertzschke, P. Stanley, T. D. Bunney, F. Rodrigues-Lima, N. Hogg, and M. Katan Characterization of Interactions of Adapter Protein RAPL/Nore1B with RAP GTPases and Their Role in T Cell Migration J. Biol. Chem., October 19, 2007; 282(42): 30629 - 30642. [Abstract] [Full Text] [PDF]

				O. M. Tsygankova, G. V. Prendergast, K. Puttaswamy, Y. Wang, M. D. Feldman, H. Wang, M. S. Brose, and J. L. Meinkoth Downregulation of Rap1GAP Contributes to Ras Transformation Mol. Cell. Biol., October 1, 2007; 27(19): 6647 - 6658. [Abstract] [Full Text] [PDF]

				M. J. Lorenowicz, M. Fernandez-Borja, and P. L. Hordijk cAMP Signaling in Leukocyte Transendothelial Migration Arterioscler. Thromb. Vasc. Biol., May 1, 2007; 27(5): 1014 - 1022. [Abstract] [Full Text] [PDF]

				T. J. Jeon, D.-J. Lee, S. Merlot, G. Weeks, and R. A. Firtel Rap1 controls cell adhesion and cell motility through the regulation of myosin II J. Cell Biol., March 26, 2007; 176(7): 1021 - 1033. [Abstract] [Full Text] [PDF]

				P. J. S. Stork and T. J. Dillon Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions Blood, November 1, 2005; 106(9): 2952 - 2961. [Abstract] [Full Text] [PDF]