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doi: 10.1242/10.1242/jcs.00145

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Journal of Cell Science 115, 4641-4648 (2002)
doi: 10.1242/jcs.00145

Research Article

Integrin {alpha}8ß1 mediates adhesion to LAP-TGFß1

Min Lu1, John S. Munger2, Melissa Steadele3, Christina Busald3, Marinka Tellier1 and Lynn M. Schnapp1,3,*

1 Pulmonary and Critical Care Medicine, Department of Medicine, Mount Sinai School of Medicine, New York, NY 10029, USA
2 Departments of Medicine and Cell Biology, NYU School of Medicine, New York, NY 10016, USA
3 Pulmonary and Critical Care Medicine, Harborview Medical Center, University of Washington, Seattle, WA 98104, USA

* Author for correspondence (e-mail: lschnapp{at}u.washington.edu)

Accepted 3 September 2002

The development of fibrosis is a common response to a variety of injuries and results in the net accumulation of matrix proteins and impairment of normal organ function. We previously reported that the integrin {alpha}8ß1 is expressed by alveolar interstitial cells in normal lung and is upregulated during the development of fibrosis. TGFß1 is an important mediator of the inflammatory response in pulmonary fibrosis. TGFß1 is secreted as a latent protein that is non-covalently associated with latency-associated peptide (LAP) and requires activation to exert its effects. LAP-TGFß1 and LAP-TGFß3 contain the tripeptide sequence, arginine-glycine-aspartic acid (RGD), a known integrin recognition motif. The integrin {alpha}8ß1 binds to several ligands such as fibronectin and vitronectin through the RGD sequence. Recent reports demonstrate that the integrins {alpha}vß1, {alpha}vß6 and {alpha}vß8 adhere to LAP-TGFß1 through the RGD site. Therefore, we asked whether LAP-TGFß1 might be a ligand for {alpha}8ß1 and whether this may be important in the development of fibrosis. We found that cell lines transfected with {alpha}8 subunit were able to spread on and adhere to recombinant LAP-TGFß1 significantly better than mock transfected cell lines. {alpha}8-transfected cells were also able to adhere to LAP-TGFß3 significantly better than mock transfected cells. Adhesion to LAP-TGFß1 was enhanced by activation of {alpha}8ß1 by Mn2+, or 8A2, an integrin ß1 activating antibody. Furthermore, cell adhesion was abolished when we used a recombinant LAP-TGFß1 protein in which the RGD site was mutated to RGE. {alpha}8ß1 binding to LAP-TGFß1 increased cell proliferation and phosphorylation of FAK and ERK, but did not activate of TGFß1. These data strongly suggest that LAP-TGFß1 is a ligand of {alpha}8ß1 and interaction of {alpha}8ß1 with LAP-TGFß1 may influence cell behavior.

Key words: Integrin, LAP-TGF-ß, {alpha}8ß1, Cell signaling




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