title: Specificity of latent TGF-β binding protein (LTBP) incorporation into matrix: role of fibrillins and fibronectin.
abstract: Fibrillin microfibrils are extracellular matrix structures with essential functions in the development and the organization of tissues including blood vessels, bone, limbs and the eye. Fibrillin-1 and fibrillin-2 form the core of fibrillin microfibrils, to which multiple proteins associate to form a highly organized structure. Defining the components of this structure and their interactions is crucial to understand the pathobiology of microfibrillopathies associated with mutations in fibrillins and in microfibril-associated molecules. In this study, we have analyzed both in vitro and in vivo the role of fibrillin microfibrils in the matrix deposition of latent TGF-β binding protein 1 (LTBP-1), -3 and -4; the three LTBPs that form a complex with TGF-β. In Fbn1(-/-) ascending aortas and lungs, LTBP-3 and LTBP-4 are not incorporated into a matrix lacking fibrillin-1 microfibrils, whereas LTBP-1 is still deposited. In addition, in cultures of Fbn1(-/-) smooth muscle cells or lung fibroblasts, LTBP-3 and LTBP-4 are not incorporated into a matrix lacking fibrillin-1 microfibrils, whereas LTBP-1 is still deposited. Fibrillin-2 is not involved in the deposition of LTBP-1 in Fbn1(-/-) extracellular matrix as cells deficient for both fibrillin-1 and fibrillin-2 still incorporate LTBP-1 in their matrix. However, blocking the formation of the fibronectin network in Fbn1(-/-) cells abrogates the deposition of LTBP-1. Together, these data indicate that LTBP-3 and LTBP-4 association with the matrix depends on fibrillin-1 microfibrils, whereas LTBP-1 association depends on a fibronectin network.
authors.affiliation: Department of Cell Biology, New York University Langone School of Medicine, New York, New York 10016, USA.
authors.forename: Lior
authors.initials: L
authors.lastname: Zilberberg
authors.forename: Vesna
authors.initials: V
authors.lastname: Todorovic
authors.forename: Branka
authors.initials: B
authors.lastname: Dabovic
authors.forename: Masahito
authors.initials: M
authors.lastname: Horiguchi
authors.forename: Thomas
authors.initials: T
authors.lastname: Couroussé
authors.forename: Lynn Y
authors.initials: LY
authors.lastname: Sakai
authors.forename: Daniel B
authors.initials: DB
authors.lastname: Rifkin
mesh_terms: D000818:Animals; D018076:DNA, Complementary / Q000235:genetics / Q000378:metabolism; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005347:Fibroblasts / Q000378:metabolism; D005353:Fibronectins / Q000235:genetics / Q000378:metabolism*; D005786:Gene Expression Regulation / Q000502:physiology*; D053779:Latent TGF-beta Binding Proteins / Q000235:genetics / Q000378:metabolism*; D008168:Lung / Q000166:cytology; D051379:Mice; D018345:Mice, Knockout; D008840:Microfilament Proteins / Q000235:genetics / Q000378:metabolism*; D009131:Muscle, Smooth, Vascular / Q000166:cytology; D032389:Myocytes, Smooth Muscle / Q000378:metabolism; D012313:RNA / Q000235:genetics / Q000378:metabolism; D060888:Real-Time Polymerase Chain Reaction; D054392:Adipokines
chemical_list: D018076:DNA, Complementary; D000071838:Fibrillin-1; D000071840:Fibrillin-2; D000071837:Fibrillins; D005353:Fibronectins; D053779:Latent TGF-beta Binding Proteins; D008840:Microfilament Proteins; D012313:RNA; C000605724:Fbn1 protein, mouse; D054392:Adipokines; C000605728:Fbn2 protein, mouse