title: Fibronectin is required for integrin alphavbeta6-mediated activation of latent TGF-beta complexes containing LTBP-1.
abstract: Transforming growth factor-betas (TGF-beta) are secreted as latent complexes consisting of the TGF-beta dimer, the TGF-beta propeptide dimer, and the latent TGF-beta binding protein (LTBP). Although the bonds between TGF-beta and its propeptide are cleaved intracellulary, the propeptide associates with TGF-beta by electrostatic interactions, thereby conferring latency to the complex. We reported that a specific sequence of LTBP-1 is required for latent TGF-beta activation by the integrin alphavbeta6. Here we describe a 24 amino acid sequence from the hinge domain required for activation. The LTBP-1 polypeptide rL1N, which includes the hinge, associates with fibronectin in binding assays. We present evidence that fibronectin null cells minimally activate latent TGF-beta and poorly incorporate the active hinge sequence into their matrix. In addition, cells missing the fibronectin receptor alpha5beta1 exhibit defective activation of latent TGF-beta by alphavbeta6 and decreased matrix incorporation. The results indicate specificity for integrin-mediated latent TGF-beta activation that include unique sequences in LTBP-1 and an appropriate matrix molecule.
authors.affiliation: Department of Cell Biology, New York University School of Medicine, New York, NY 10016, USA.
authors.forename: Laura
authors.initials: L
authors.lastname: Fontana
authors.forename: Yan
authors.initials: Y
authors.lastname: Chen
authors.forename: Petra
authors.initials: P
authors.lastname: Prijatelj
authors.forename: Takao
authors.initials: T
authors.lastname: Sakai
authors.forename: Reinhard
authors.initials: R
authors.lastname: Fässler
authors.forename: Lynn Y
authors.initials: LY
authors.lastname: Sakai
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
mesh_terms: D000595:Amino Acid Sequence; D000818:Animals; D000951:Antigens, Neoplasm / Q000737:chemistry* / Q000378:metabolism; D001681:Biological Assay; D015153:Blotting, Western; D016466:CHO Cells; D003101:Collodion / Q000737:chemistry; D006224:Cricetinae; D019281:Dimerization; D004591:Electrophoresis, Polyacrylamide Gel; D000939:Epitopes / Q000737:chemistry; D005353:Fibronectins / Q000737:chemistry / Q000502:physiology*; D005822:Genetic Vectors; D016023:Integrins / Q000737:chemistry* / Q000378:metabolism; D047908:Intracellular Signaling Peptides and Proteins / Q000737:chemistry* / Q000378:metabolism; D053779:Latent TGF-beta Binding Proteins; D008156:Luciferases / Q000378:metabolism; D051379:Mice; D008856:Microscopy, Fluorescence; D008969:Molecular Sequence Data; D010455:Peptides / Q000737:chemistry; D011485:Protein Binding; D017434:Protein Structure, Tertiary; D012333:RNA, Messenger / Q000378:metabolism; D020133:Reverse Transcriptase Polymerase Chain Reaction; D013997:Time Factors; D016212:Transforming Growth Factor beta / Q000378:metabolism*
chemical_list: D000951:Antigens, Neoplasm; D000939:Epitopes; D005353:Fibronectins; D016023:Integrins; D047908:Intracellular Signaling Peptides and Proteins; D053779:Latent TGF-beta Binding Proteins; C509033:Ltbp1 protein, mouse; D010455:Peptides; D012333:RNA, Messenger; D016212:Transforming Growth Factor beta; C073878:integrin alphavbeta6; D003101:Collodion; D008156:Luciferases