Alpha4beta1 integrin affinity changes govern cell adhesion.
Integrin alpha4beta1 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 alpha4beta1 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 alpha4 integrin.
Chigaev
Alexandre
A
Department of Pathology and Cancer Center, University of New Mexico HSC, Albuquerque, New Mexico 87131, USA.
Zwartz
Gordon
G
Graves
Steven W
SW
Dwyer
Denise C
DC
Tsuji
Hisashi
H
Foutz
Terry D
TD
Edwards
Bruce S
BS
Prossnitz
Eric R
ER
Larson
Richard S
RS
Sklar
Larry A
LA
D000818:Animals; D001667:Binding, Competitive; D002118:Calcium / Q000378:metabolism; D002138:Calibration; D002412:Cations; D002448:Cell Adhesion; D002850:Chromatography, Gel; D003432:Cross-Linking Reagents / Q000494:pharmacology; D004305:Dose-Response Relationship, Drug; D005434:Flow Cytometry; D006801:Humans; D039041:Integrin alpha4beta1 / Q000737:chemistry* / Q000378:metabolism; D007700:Kinetics; D008024:Ligands; D008274:Magnesium / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008956:Models, Chemical; D016297:Mutagenesis, Site-Directed; D011485:Protein Binding; D013997:Time Factors; D014162:Transfection; D014407:Tumor Cells, Cultured; D020298:U937 Cells; D019010:Vascular Cell Adhesion Molecule-1 / Q000737:chemistry / Q000378:metabolism
D002412:Cations; D003432:Cross-Linking Reagents; D039041:Integrin alpha4beta1; D008024:Ligands; D019010:Vascular Cell Adhesion Molecule-1; D008274:Magnesium; D002118:Calcium