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Published 7 June 2004. doi:10.1083/jcb.200312172
The Rockefeller University Press, 0021-9525 $8.00
JCB, Volume 165, Number 5, 723-734
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Article

 Integrin {alpha}Vß6-mediated activation of latent TGF-ß requires the latent TGF-ß binding protein-1

Justin P. Annes1, Yan Chen1, John S. Munger1,2, and Daniel B. Rifkin1,2

1 Department of Cell Biology, New York University School of Medicine, New York, NY 10016
2 Department of Medicine, New York University School of Medicine, New York, NY 10016

Address correspondence to Daniel B. Rifkin, Dept. of Cell Biology, New York University School of Medicine, 550 First Ave., New York, NY 10016. Tel.: (212) 263-5109. Fax: (212) 263-0595. email: rifkid01{at}med.nyu.edu

Transforming growth factor-ßs (TGF-ß) are secreted as inactive complexes containing the TGF-ß, the TGF-ß propeptide, also called the latency-associated protein (LAP), and the latent TGF-ß binding protein (LTBP). Extracellular activation of this complex is a critical but incompletely understood step in TGF-ß regulation. We have investigated the role of LTBP in modulating TGF-ß generation by the integrin {alpha}Vß6. We show that even though {alpha}vß6 recognizes an RGD on LAP, LTBP-1 is required for {alpha}Vß6-mediated latent TGF-ß activation. The domains of LTBP-1 necessary for activation include the TGF-ß propeptide-binding domain and a basic amino acid sequence (hinge domain) with ECM targeting properties. Our results demonstrate an LTBP-1 isoform-specific function in {alpha}Vß6-mediated latent TGF-ß activation; LTBP-3 is unable to substitute for LTBP-1 in this assay. The results reveal a functional role for LTBP-1 in latent TGF-ß activation and suggest that activation of specific latent complexes is regulated by distinct mechanisms that may be determined by the LTBP isoform and its potential interaction with the matrix.

Key Words: LTBP; TGF-ß; integrin; {alpha}vß6; latent TGF-ß

Abbreviations used in this paper: CR, cysteine rich; CR3, third CR; DMEM, Dulbecco's minimum essential medium; LAP, latency-associated protein; LLC, large latent complex; LTBP, latent TGF-ß binding protein; SLC, small latent complex; TMLC, transformed mink lung cells; tTGase; tissue transglutaminase.


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