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J. Biol. Chem., Vol. 282, Issue 48, 35361-35372, November 30, 2007

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Lateral Compartmentalization of T Cell Receptor Versus CD45 by Galectin-N-Glycan Binding and Microfilaments Coordinate Basal and Activation Signaling^*

I-Ju Chen, Hung-Lin Chen, and Michael Demetriou¹

From the Department of Neurology and Department of Microbiology and Molecular Genetics, University of California, Irvine, California 92697

Lateral compartmentalization of membrane proteins into microdomains regulates signal transduction; however, structural determinants are incompletely understood. Membrane glycoproteins bind galectins in proportion to the number (i.e. NX(S/T) sites) and degree of GlcNAc branching within attached N-glycans, forming a molecular lattice that negatively regulates T cell function and autoimmunity. We find that in resting T cells, partition of CD45 inside and T cell receptor (TCR)/CD4-Lck/Zap-70 outside microdomains is positively and negatively regulated by the galectin lattice and actin cytoskeleton, respectively. In the absence of TCR ligands, the galectin lattice counteracts F-actin to retain CD45 in microdomains while concurrently blocking TCR/CD4-Lck/Zap-70 partition to microdomains by preventing a conformational change in the TCR that recruits Nck/Wiscott Aldrich Syndrome (WASp)/SLP76/F-actin/CD4 to TCR. The counterbalancing activities of the galectin lattice and actin cytoskeleton negatively and positively regulate Lck activity in resting cells and CD45 versus TCR clustering and signaling at the early immune synapse, respectively. Microdomain-localized CD45 inactivates Lck and inhibits TCR signaling at the early immune synapse. Thus, the galectin lattice and actin cytoskeleton interact on opposing sides of the plasma membrane to control microdomain structure and function, coupling basal growth signaling with thresholds to activation.

Received for publication, August 20, 2007 , and in revised form, September 18, 2007.

^* This research was supported by a grant from NIAID, National Institutes of Health (to M. D.). 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. 1-5.

¹ To whom correspondence should be addressed: Depts. of Neurology and Microbiology and Molecular Genetics, University of California, 250 Sprague Hall, Irvine, CA 92697. Tel.: 949-824-9775; Fax: 949-824-9847; E-mail: mdemetri{at}uci.edu.

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