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Published online 22 April 2002. doi:10.1083/jcb.200109100
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© The Rockefeller University Press, 0021-9525/2002/4/493 $5.00
The Journal of Cell Biology, Volume 157, Number 3, April 29, 2002 493-507

Article

The integrin {alpha}vß8 mediates epithelial homeostasis through MT1-MMP–dependent activation of TGF-ß1



Dezhi Mu1,2,5, Stephanie Cambier1,2,5, Lars Fjellbirkeland1,2,5, Jody L. Baron3, John S. Munger4, Hisaaki Kawakatsu5, Dean Sheppard2,5, V. Courtney Broaddus2,5 and Stephen L. Nishimura1,2,5

1 Department of Pathology, University of California at San Francisco, San Francisco, CA 94143
2 University of California at San Francisco/Mt. Zion Cancer Center, University of California at San Francisco, San Francisco, CA 94143
3 Department of Microbiology and Immunology, University of California at San Francisco, San Francisco, CA 94143
4 Department of Medicine and Cell Biology, New York University, New York, NY 10016
5 The Lung Biology Center and Pulmonary Division, San Francisco General Hospital, San Francisco, CA 94110

Address correspondence to Stephen L. Nishimura, Bldg. 3, Rm. 207, San Francisco General Hospital, 1001 Potrero Ave., San Francisco, CA 94110. Tel.: (415) 206-5906. Fax: (415) 206-3765. E-mail: cdog{at}itsa.ucsf.edu

Întegrins, matrix metalloproteases (MMPs), and the cytokine TGF-ß have each been implicated in homeostatic cell behaviors such as cell growth and matrix remodeling. TGF-ß exists mainly in a latent state, and a major point of homeostatic control is the activation of TGF-ß. Because the latent domain of TGF-ß1 possesses an integrin binding motif (RGD), integrins have the potential to sequester latent TGF-ß (SLC) to the cell surface where TGF-ß activation could be locally controlled. Here, we show that SLC binds to {alpha}vß8, an integrin expressed by normal epithelial and neuronal cells in vivo. This binding results in the membrane type 1 (MT1)-MMP–dependent release of active TGF-ß, which leads to autocrine and paracrine effects on cell growth and matrix production. These data elucidate a novel mechanism of cellular homeostasis achieved through the coordination of the activities of members of three major gene families involved in cell–matrix interactions.

Key Words: integrins; transforming growth factor ß; metalloprotease; cell cycle; homeostasis


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