title: Integrin alphaVbeta6-mediated activation of latent TGF-beta requires the latent TGF-beta binding protein-1.
abstract: Transforming growth factor-betas (TGF-beta) are secreted as inactive complexes containing the TGF-beta, the TGF-beta propeptide, also called the latency-associated protein (LAP), and the latent TGF-beta binding protein (LTBP). Extracellular activation of this complex is a critical but incompletely understood step in TGF-beta regulation. We have investigated the role of LTBP in modulating TGF-beta generation by the integrin alphaVbeta6. We show that even though alphavbeta6 recognizes an RGD on LAP, LTBP-1 is required for alphaVbeta6-mediated latent TGF-beta activation. The domains of LTBP-1 necessary for activation include the TGF-beta 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 alphaVbeta6-mediated latent TGF-beta 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-beta 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.
authors.affiliation: Department of Cell Biology, New York University School of Medicine, 550 First Ave., New York, NY 10016, USA.
authors.forename: Justin P
authors.initials: JP
authors.lastname: Annes
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: John S
authors.initials: JS
authors.lastname: Munger
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
mesh_terms: D000595:Amino Acid Sequence / Q000502:physiology; D000818:Animals; D000951:Antigens, Neoplasm / Q000378:metabolism*; D016466:CHO Cells; D002352:Carrier Proteins / Q000378:metabolism*; D002462:Cell Membrane / Q000378:metabolism*; D006224:Cricetinae; D005109:Extracellular Matrix / Q000378:metabolism*; D016023:Integrins / Q000378:metabolism*; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D008969:Molecular Sequence Data; D010455:Peptides / Q000378:metabolism; D020033:Protein Isoforms / Q000378:metabolism; D017434:Protein Structure, Tertiary / Q000502:physiology; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D002352:Carrier Proteins; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; D010455:Peptides; D020033:Protein Isoforms; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6