title: Fibrillin-1 regulates the bioavailability of TGFbeta1.
abstract: We have discovered that fibrillin-1, which forms extracellular microfibrils, can regulate the bioavailability of transforming growth factor (TGF) beta1, a powerful cytokine that modulates cell survival and phenotype. Altered TGFbeta signaling is a major contributor to the pathology of Marfan syndrome (MFS) and related diseases. In the presence of cell layer extracellular matrix, a fibrillin-1 sequence encoded by exons 44-49 releases endogenous TGFbeta1, thereby stimulating TGFbeta receptor-mediated Smad2 signaling. This altered TGFbeta1 bioavailability does not require intact cells, proteolysis, or the altered expression of TGFbeta1 or its receptors. Mass spectrometry revealed that a fibrillin-1 fragment containing the TGFbeta1-releasing sequence specifically associates with full-length fibrillin-1 in cell layers. Solid-phase and BIAcore binding studies showed that this fragment interacts strongly and specifically with N-terminal fibrillin-1, thereby inhibiting the association of C-terminal latent TGFbeta-binding protein 1 (a component of the large latent complex [LLC]) with N-terminal fibrillin-1. By releasing LLC from microfibrils, the fibrillin-1 sequence encoded by exons 44-49 can contribute to MFS and related diseases.
authors.affiliation: Wellcome Trust Centre for Cell-Matrix Research, UK Centre for Tissue Engineering, Faculty of Life Sciences, University of Manchester, Manchester M13 9PT, England, UK.
authors.forename: Shazia S
authors.initials: SS
authors.lastname: Chaudhry
authors.forename: Stuart A
authors.initials: SA
authors.lastname: Cain
authors.forename: Amanda
authors.initials: A
authors.lastname: Morgan
authors.forename: Sarah L
authors.initials: SL
authors.lastname: Dallas
authors.forename: C Adrian
authors.initials: CA
authors.lastname: Shuttleworth
authors.forename: Cay M
authors.initials: CM
authors.lastname: Kielty
mesh_terms: D030201:Activin Receptors, Type I / Q000378:metabolism; D002460:Cell Line; D000071838:Fibrillin-1; D000071837:Fibrillins; D015870:Gene Expression / Q000502:physiology; D006801:Humans; D008382:Marfan Syndrome / Q000378:metabolism; D013058:Mass Spectrometry; D020894:Microfibrils / Q000378:metabolism*; D008840:Microfilament Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D010446:Peptide Fragments / Q000378:metabolism; D011485:Protein Binding; D017346:Protein Serine-Threonine Kinases; D017434:Protein Structure, Tertiary; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta / Q000378:metabolism; D011994:Recombinant Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D051899:Smad2 Protein / Q000378:metabolism; D053773:Transforming Growth Factor beta1 / Q000378:metabolism*; D054392:Adipokines
chemical_list: D030201:Activin Receptors, Type I; D000071838:Fibrillin-1; D000071837:Fibrillins; D008840:Microfilament Proteins; D010446:Peptide Fragments; D017346:Protein Serine-Threonine Kinases; D000077293:Receptor, Transforming Growth Factor-beta Type I; D000077294:Receptor, Transforming Growth Factor-beta Type II; D018125:Receptors, Transforming Growth Factor beta; D011994:Recombinant Proteins; D051899:Smad2 Protein; D053773:Transforming Growth Factor beta1; C000605722:FBN1 protein, human; D054392:Adipokines; C497782:SMAD2 protein, human