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J. Biol. Chem., Vol. 283, Issue 8, 5014-5022, February 22, 2008

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Immediate-Early Signaling Induced by E-cadherin Engagement and Adhesion^*

Tomas D. Perez¹, Masako Tamada², Michael P. Sheetz, and W. James Nelson^¶3

From the Departments of Molecular and Cellular Physiology and ^¶Biological Sciences, Stanford University, Stanford, California 94305-5430 and the Department of Biological Sciences, Columbia University, New York, New York 10027

Epithelial cell-cell interactions require localized adhesive interactions between E-cadherin on opposing membranes and the activation of downstream signaling pathways that affect membrane and actin dynamics. However, it is not known whether E-cadherin engagement and activation of these signaling pathways are locally coordinated or whether signaling is sustained or locally down-regulated like other receptor-mediated pathways. To obtain high spatiotemporal resolution of immediate-early signaling events upon E-cadherin engagement, we used laser tweezers to place beads coated with functional E-cadherin extracellular domain on cells. We show that cellular E-cadherin accumulated rapidly around beads, reaching a sustained plateau level in 1-3 min. Phosphoinositides and Rac1 co-accumulated with E-cadherin, reached peak levels with E-cadherin, but then rapidly dispersed. Both E-cadherin and Rac1 accumulated independently of Rac1 GTP binding/hydrolysis, but these activities were required for Rac1 dispersal. E-cadherin accumulation was dependent on membrane dynamics and actin polymerization, but actin did not stably co-accumulate with E-cadherin; mathematical modeling showed that diffusion-mediated trapping could account for the initial E-cadherin accumulation. We propose that initial E-cadherin accumulation requires active membrane dynamics and involves diffusion-mediated trapping at contact sites; to propagate further contacts, phosphatidylinositol 3-kinase and Rac1 are transiently activated by E-cadherin engagement and initiate a new round of membrane dynamics, but they are subsequently suppressed at that site to allow maintenance of weak E-cadherin mediated adhesion.

Received for publication, June 25, 2007 , and in revised form, November 15, 2007.

^* This work was supported by National Institutes of Health Grant GM35527 (to M. P. S. and to W. J. N.) and by a predoctoral fellowship from the Howard Hughes Medical Institute (to T. D. P.). 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 supplemental Figs. S1-S3.

¹ Present address: Columbia University, Sherman Fairchild Center, Rm. 715, MC 2416, 1212 Amsterdam Ave., New York, NY, 10027.

² Present address: Developmental Biology Program, Sloan-Kettering Institute, New York, NY 10021.

³ To whom correspondence should be addressed: The James H. Clark Center, The Bio-X program, 318 Campus Dr., E200-B, Stanford University, Stanford, CA 94305-5430. Tel.: 650-725-7596; Fax: 650-724-4927; E-mail: wjnelson{at}stanford.edu.

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