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doi: 10.1242/10.1242/jcs.00145
Research Article |
8ß1 mediates adhesion to LAP-TGFß1
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
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 8ß1 binds to several ligands such as fibronectin and
vitronectin through the RGD sequence. Recent reports demonstrate that the
integrins vß1, vß6 and vß8 adhere to
LAP-TGFß1 through the RGD site. Therefore, we asked whether
LAP-TGFß1 might be a ligand for 8ß1 and whether this may be
important in the development of fibrosis. We found that cell lines transfected
with 8 subunit were able to spread on and adhere to recombinant
LAP-TGFß1 significantly better than mock transfected cell lines.
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 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. 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
8ß1 and interaction of 8ß1 with LAP-TGFß1 may
influence cell behavior.
Key words: Integrin, LAP-TGF-ß, 8ß1, Cell signaling
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