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J. Biol. Chem., Vol. 278, Issue 40, 38174-38182, October 3, 2003

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₄₁ Integrin Affinity Changes Govern Cell Adhesion^*

Alexandre Chigaev  , Gordon Zwartz , Steven W. Graves , Denise C. Dwyer , Hisashi Tsuji , Terry D. Foutz , Bruce S. Edwards , Eric R. Prossnitz ¶, Richard S. Larson  || and Larry A. Sklar   **

From the Department of Pathology and Cancer Center, University of New Mexico HSC, Albuquerque, New Mexico 87131, the ^¶Department of Cell Biology and Physiology, University of New Mexico HSC, Albuquerque, New Mexico 87131, and National Flow Cytometry Resource, Los Alamos National Laboratory, Los Alamos, New Mexico 87545

Integrin ₄₁ is a receptor for vascular cell adhesion molecule-1 and fibronectin. It is important in lymphopoiesis, inflammatory recruitment of leukocytes, and other situations that require cell adhesion to the vascular endothelium. The avidity of the cells expressing ₄₁ integrin can be rapidly changed by chemokines and chemoattractants. Different mechanisms, including changes in the number of interacting molecules due to the alteration of the receptor topology or changes in the affinity of the individual bonds, have been proposed to explain the nature of these fast changes in avidity. Recently, we described a fluorescent LDV-containing small molecule, which we used to monitor the affinity changes on live cells in real time (Chigaev, A., Blenc, A. M., Braaten, J. V., Kumaraswamy, N., Kepley, C. L., Andrews, R. P., Oliver, J. M., Edwards, B. S., Prossnitz, E. R., Larson, R. S. et al. (2001) J. Biol. Chem. 276, 48670–48678). Here we show that the affinity of the small molecule probe as well as the native ligand vascular cell adhesion molecule-1 varies in parallel when the integrin is modulated with divalent cations and that the affinity modulation leads to the changes in cell avidity. Using formyl peptide receptor-transfected U937 cells, we further show that the time course of avidity changes in response to the receptor activation coincides with the time course of the affinity changes. Taken together, these data are consistent with the idea that affinity regulation is a major factor that governs the avidity of cell adhesion mediated by the ₄ integrin.

Received for publication, October 11, 2002 , and in revised form, July 1, 2003.

^* This work was supported by National Institutes of Health Grants RR14175, HL56384 (to L. A. S.), and RR01315 (to S. W. G.) and in part by American Heart Association Grant 990318Z and American Cancer Society (ACS) Grant RPG-00-096-01-LBC (to R. S. L.). 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.

^|| Supported in part as the designated investigator for the ACS Hoops for Lymphoma and Coaches against Cancer in memory of Fred Hartman.

^** To whom correspondence and reprint requests should be addressed: Dept. of Pathology and Cancer Center, University of New Mexico HSC, Albuquerque, NM 87131. Tel.: 505-272-6892; Fax: 505-272-6995; E-mail: lsklar{at}salud.unm.edu.

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