The Journal of Experimental Medicine
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© The Rockefeller University Press, 0022-1007/1997/10/1347/ $5.00
The Journal of Experimental Medicine, Volume 186, Number 8, October 20, 1997 1347-1355

Articles

Mutational Evidence for Control of Cell Adhesion Through Integrin Diffusion/Clustering, Independent of Ligand Binding

Robert L. Yauch*, Dan P. Felsenfeld§, Stine-Kathrein Kraeft{ddagger}, Lan Bo Chen{ddagger}, Michael P. Sheetz§, and Martin E. Hemler*

From the * Division of Tumor Virology, and the {ddagger} Division of Molecular and Cellular Biology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115; and the § Department of Cell Biology, Duke University Medical Center, Durham, North Carolina 27710

Previous studies have shown that integrin {alpha} chain tails make strong positive contributions to integrin-mediated cell adhesion. We now show here that integrin {alpha}4 tail deletion markedly impairs static cell adhesion by a mechanism that does not involve altered binding of soluble vascular cell adhesion molecule 1 ligand. Instead, truncation of the {alpha}4 cytoplasmic domain caused a severe deficiency in integrin accumulation into cell surface clusters, as induced by ligand and/ or antibodies. Furthermore, {alpha}4 tail deletion also significantly decreased the membrane diffusivity of {alpha}4β1, as determined by a single particle tracking technique. Notably, low doses of cytochalasin D partially restored the deficiency in cell adhesion seen upon {alpha}4 tail deletion. Together, these results suggest that {alpha}4 tail deletion exposes the β1 cytoplasmic domain, leading to cytoskeletal associations that apparently restrict integrin lateral diffusion and accumulation into clusters, thus causing reduced static cell adhesion. Our demonstration of integrin adhesive activity regulated through receptor diffusion/clustering (rather than through altered ligand binding affinity) may be highly relevant towards the understanding of inside–out signaling mechanisms for β1 integrins.

Address correspondence to Martin E. Hemler, Rm. M-613, Dana-Farber Cancer Institute, 44 Binney St., Boston, MA 02115.

1 Abbreviations used in this paper: AP, alkaline phosphatase; CHO, Chinese hamster ovary; FBS, fetal bovine serum; MSD, mean square displacement; rsVCAM, recombinant soluble vascular cell adhesion molecule; TBS, Tris-buffered saline; VCAM, vascular cell adhesion molecule.


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