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J. Biol. Chem., Vol. 281, Issue 49, 37904-37912, December 8, 2006

This Article Full Text Full Text (PDF) Supplemental Data All Versions of this Article: 281/49/37904    most recent M606888200v3 M606888200v2 M606888200v1 Submit a Letter to Editor Alert me when this article is cited Alert me when eLetters are posted 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 Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Yang, W. Articles by Springer, T. A. Search for Related Content PubMed PubMed Citation Articles by Yang, W. Articles by Springer, T. A. Social Bookmarking                      What's this?

A Small Molecule Agonist of an Integrin, _L2^*

Wei Yang¹, Christopher V. Carman¹, Minsoo Kim^¶2, Azucena Salas^¶3, Motomu Shimaoka^¶, and Timothy A. Springer⁴

From the CBR Institute for Biomedical Research, Departments of Pathology and ^¶Anesthesia, Harvard Medical School, Boston, Massachusetts 02115

The binding of integrin _L2 to its ligand intercellular adhesion molecule-1 is required for immune responses and leukocyte trafficking. Small molecule antagonists of _L2 are under intense investigation as potential anti-inflammatory drugs. We describe for the first time a small molecule integrin agonist. A previously described / I allosteric inhibitor, compound 4, functions as an agonist of _L2 in Ca²⁺ and Mg²⁺and as an antagonist in Mn²⁺. We have characterized the mechanism of activation and its competitive and noncompetitive inhibition by different compounds. Although it stimulates ligand binding, compound 4 nonetheless inhibits lymphocyte transendothelial migration. Agonism by compound 4 results in accumulation of _L2 in the uropod, extreme uropod elongation, and defective de-adhesion. Small molecule integrin agonists open up novel therapeutic possibilities.

Received for publication, July 19, 2006

^* This work was supported by National Institutes of Health Grants CA31798 (to T. A. S.) and AI63421 (to M. S.) and a grant from the Arthritis Foundation (to C. V. C.). 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 Videos 1 and 2.

¹ These authors contributed equally to this work.

² Current address: Division of Surgical Research, Rhode Island Hospital, Brown University School of Medicine, 593 Eddy Street, Middlehouse 207, Providence, RI 02903.

³ Current address: Instituto de Investigaciones Biomédicas de Barcelona-CSIC, Roselló 161, 7^a planta, 08036 Barcelona, Spain.

⁴ To whom correspondence should be addressed: The CBR Institute for Bio-medical Research, Dept. of Pathology, Harvard Medical School, 200 Long-wood Ave., Boston, MA 02115. Tel.: 617-278-3200; Fax: 617-278-3232; E-mail: springeroffice{at}cbr.med.harvard.edu.

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