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J Biol Chem, Vol. 275, Issue 10, 7052-7059, March 10, 2000

The alpha 4 Integrin Subunit Tyr187 Has a Key Role in alpha 4beta 7-Dependent Cell Adhesion*

Natividad Ruiz-VelascoDagger , Mercedes Guerrero-EsteoDagger , Michael J. Briskin§, and Joaquín TeixidóDagger

From the Dagger  Department of Immunology, Centro de Investigaciones Biológicas, Velázquez 144, 28006 Madrid, Spain and § LeukoSite Inc., Cambridge, Massachusetts 02142

The integrin alpha 4beta 7 is the cell adhesion receptor for the mucosal vascular addressin MAdCAM-1, and this interaction is dominant in lymphocyte homing to Peyer's patch high endothelial venules, and plays key roles in lymphocyte recruitment at sites of inflammation. To identify alpha 4 subunit amino acids important for alpha 4beta 7/MAdCAM-1 interaction, we expressed mutant alpha 4 and wild type beta 7 chains in K562 cells and analyzed the effect of the mutations on cell adhesion to a soluble MAdCAM-1 (sMAdCAM-1-Ig). Transfectants expressing mutated alpha 4 at Tyr187 displayed a substantial decrease in adhesion to this ligand, which was associated with a reduced alpha 4beta 7/sMAdCAM-1-Ig interaction, as determined by soluble binding assays. Addition of Mn2+ to the adhesion assays did not restore the impaired adhesion. Mutations at alpha 4 Gln152Asp153 also affected transfectant adhesion to sMAdCAM-1-Ig, but did not involve an alteration of alpha 4beta 7/MAdCAM-1 binding, and adhesion was restored by Mn2+. Instead, mutations at alpha 4 Asn123Glu124 did not affect this adhesion. Mutation of alpha 4 Tyr187 abolished alpha 4beta 7-mediated cell adhesion to CS-1/fibronectin, an additional ligand for alpha 4beta 7, while alpha 4 Gln152Asp153 transfectant mutants showed a reduced adhesion. These results identify alpha 4 Tyr187 as a key residue during receptor alpha 4beta 7/ligand interactions, indicating that it plays important roles in alpha 4beta 7-mediated leukocyte adhesion, and provide a potential target for therapeutic intervention in several inflammatory pathologies.

* This work was supported by Grants PM95-0017 and SAF99-0057 from the plan General del Conocimiento-Ministerio de Educaciòn y Ciencia (Spain).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

To whom correspondence should be addressed. Tel.: 34-91-5611800; Fax: 34-91-5627518; E-mail: joaquint@cib.csic.es.

Copyright © 2000 by The American Society for Biochemistry and Molecular Biology, Inc.
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