scholarly journals Transforming growth factor ? induces fibroblast fibrillin-1 matrix formation

2002 ◽  
Vol 46 (11) ◽  
pp. 3000-3009 ◽  
Author(s):  
Eugene Y. Kissin ◽  
Raphael Lemaire ◽  
Joseph H. Korn ◽  
Robert Lafyatis
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Fibrillin 1

scholarly journals Induction and Coexpression of Latent Transforming Growth Factor β-Binding Protein-1 and Fibrillin-1 in Experimental Glomerulonephritis

2005 ◽  
Vol 102 (3-4) ◽  
pp. e99-e104 ◽  
Author(s):  
Markus Porst ◽  
Christoph Daniel ◽  
Christian Plank ◽  
Harald O. Schocklmann ◽  
Dieter P. Reinhardt ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Transforming Growth Factor Β ◽  
Experimental Glomerulonephritis ◽  
Fibrillin 1

scholarly journals Bovine latent transforming growth factor beta 1-binding protein 2: molecular cloning, identification of tissue isoforms, and immunolocalization to elastin-associated microfibrils.

1995 ◽  
Vol 15 (12) ◽  
pp. 6932-6942 ◽  
Author(s):  
M A Gibson ◽  
G Hatzinikolas ◽  
E C Davis ◽  
E Baker ◽  
G R Sutherland ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor Beta ◽  
Transforming Growth Factor ◽  
Binding Protein ◽  
Elastic Tissue ◽  
Tgf Beta ◽  
Fibrillin 1 ◽  
Growth Factor Beta ◽  
Nuchal Ligament ◽  
Cysteine Motifs

Monoclonal antibodies to fibrillin 1 (MP340), a component of elastin-associated microfibrils, were used to screen cDNA libraries made from bovine nuchal ligament mRNA. One of the selected clones (cL9; 1.2 kb) hybridized on Northern (RNA) blotting with nuchal ligament mRNA to two abundant mRNAs of 9.0 and 7.5 kb, which were clearly distinct from fibrillin mRNA (10 kb). Further library screening and later reverse transcription PCR by the rapid amplification of cDNA ends (RACE) technique resulted in the isolation of additional overlapping cDNAs corresponding to about 6.7 kb of the mRNA. The encoded protein exhibited sequence similarity of around 80% with a recently identified human protein named latent transforming growth factor beta 1 (TGF-beta 1)-binding protein 2 (LTBP-2), indicating that the new protein was bovine LTBP-2. This was confirmed by the specific localization of bovine LTBP-2 cDNA probes to human chromosome 14q24.3, which is the locus of the human LTBP-2 gene. The domain structure of bovine LTBP-2 is very similar to that of the human LTBP-2, containing 20 examples of 6-cysteine epidermal growth factor-like repeats, 16 of which have the consensus sequence for calcium binding, together with 4 examples of 8-cysteine motifs characteristic of fibrillins and LTBP-1. A 4-cysteine sequence which is unique to bovine LTBP-2 and which has similarity to the 8-cysteine motifs was also present. Antibodies raised to two unique bovine LTBP-2 peptides specifically localized in tissue sections to the elastin-associated microfibrils, indicating that LTBP-2 is closely associated with these structures. Immunoblotting experiments identified putative LTBP-2 isoforms as a 260-kDa species released into the medium by cultured elastic tissue cells and as larger 290- and 310-kDa species in tissue extracts. A major proportion of tissue-derived LTBP-2 required treatment with 6 M guanidine for solubilization, indicating that the protein was strongly bound to the microfibrils. Most of the guanidine-solubilized LTBP-2 appeared to be monomeric, indicating that it was not involved in disulfide-bonded aggregation either with itself or with latent TGF-beta. Additional LTBP-2 was resistant to solubilization with 6 M guanidine but was readily extracted with a reductive saline solution. This treatment is relatively specific for solubilization of microfibrillar constituents including fibrillin 1 and microfibril-associated glycoprotein. Therefore, it can be inferred that some LTBP-2 is bound covalently to the microfibrils by reducible disulfide linkages. The evidence suggests that LTBP-2 has a direct role in elastic fiber structure and assembly which may be independent of its growth factor-binding properties. Thus, LTBP-2 appears to share functional characteristics with both LTBP-1 and fibrillins.

Three cases of Japanese acromicric/geleophysic dysplasia with FBN1 mutations: a comparison of clinical and radiological features

2017 ◽  
Vol 30 (1) ◽  
Author(s):  
Kosei Hasegawa ◽  
Chikahiko Numakura ◽  
Hiroyuki Tanaka ◽  
Mahoko Furujo ◽  
Toshihide Kubo ◽  
...  
Keyword(s):  
Growth Factor ◽  
Respiratory Distress ◽  
Transforming Growth Factor ◽  
Radiological Findings ◽  
Skeletal Dysplasias ◽  
Radiological Features ◽  
Fibrillin 1 ◽  
Hands And Feet ◽  
Tubular Bones ◽  
Acromicric Dysplasia

AbstractAcromicric dysplasia (AD) and geleophysic dysplasia (GD) are rare skeletal dysplasias characterized by short stature, acromelia, joint contracture, hepatomegaly, hoarseness and respiratory distress. Compared with GD, AD presents with milder clinical and radiological features. Radiological findings of AD and GD consist of shortened tubular bones of the hands and feet, and deformed capital femoral epiphyses. The genetic cause of AD and some cases of GD was shown to be mutations in the transforming growth factor (TGF) β-binding protein-like domain 5 of the fibrillin 1 gene (

Isolation of rat fibrillin-1 cDNA and its relevance in metanephric development

1998 ◽  
Vol 275 (5) ◽  
pp. F710-F723 ◽  
Author(s):  
Yashpal S. Kanwar ◽  
Kosuke Ota ◽  
Qiwei Yang ◽  
Anil Kumar ◽  
Jun Wada ◽  
...  
Keyword(s):  
Growth Factor ◽  
Transforming Growth Factor ◽  
Rat Kidney ◽  
Transforming Growth Factor Β ◽  
Antisense Oligodeoxynucleotide ◽  
Metanephric Mesenchyme ◽  
Developmentally Regulated ◽  
Protein Motifs ◽  
Spatiotemporal Expression ◽  
Fibrillin 1

The role of fibrillin-1 in metanephrogenesis was investigated. Fibrillin-1 cDNA was isolated from the rat kidney cDNA library and sequenced, and its spatiotemporal expression was studied. It had ∼88% homology with human fibrillin-1 and had Ca2+ binding epidermal growth factor-like domains, transforming growth factor-β binding protein motifs, and an RGD binding site. Northern blot analysis revealed an ∼10-kb transcript, and fibrillin-1 expression was developmentally regulated. In situ hybridization and immunofluorescence studies indicated that at day 15 of gestation, fibrillin-1 is expressed in the metanephric mesenchyme. At day 18, its expression was confined to nascent blood vessels and glomeruli, and it increased in the newborn and neonatal kidneys. Immunoprecipitation revealed an ∼300-kDa band by SDS-PAGE. Treatment with fibrillin-1 antisense oligodeoxynucleotide induced marked dysmorphogenesis of the embryonic metanephroi. Concomitantly, the fibrillin-1 mRNA, antibody reactivity in the metanephroi, and fibrillin-1-specific radioincorporation were reduced. These data indicate that, like αvβ3integrin, a known morphogen and a putative receptor of fibrillin-1, the fibrillin-1 modulates events related to early organogenesis and possibly also the vascularization of the rat kidney.

Fibrillin–integrin interactions in health and disease

2008 ◽  
Vol 36 (2) ◽  
pp. 257-262 ◽  
Author(s):  
Jelena Jovanović ◽  
Sarah Iqbal ◽  
Sacha Jensen ◽  
Helen Mardon ◽  
Penny Handford
Keyword(s):  
Growth Factor ◽  
Cell Biology ◽  
Transforming Growth Factor ◽  
Integrin Αvβ3 ◽  
Human Keratinocytes ◽  
Modular Organization ◽  
Binding Motif ◽  
Structural Protein ◽  
Tetragonal Pyramid ◽  
Fibrillin 1

Human fibrillin-1 is the major structural protein of extracellular matrix 10–12 nm microfibrils. It has a disulfide-rich modular organization which consists primarily of cbEGF (Ca2+-binding epidermal growth factor-like) domains and TB (transforming growth factor β-binding protein-like) domains. TB4 contains an RGD (Arg-Gly-Asp) integrin-binding motif. The atomic structure of this region has been solved by X-ray crystallography and shows the TB4 and flanking cbEGF domains to be arranged as a tetragonal pyramid with N- and C-termini exposed at opposite ends of the fragment. The RGD integrin-binding motif is located within a flexible loop. We have used a variety of biophysical, biochemical and cell biology methods to investigate the molecular properties of integrin–fibrillin-1 interactions and have demonstrated that recombinant fibrillin-1 domain fragments mediate binding to integrins αVβ3, α5β1 and αVβ6. Integrin αVβ3 is a high-affinity fibrillin-1 receptor (Kd ∼40 nM), whereas integrins αVβ6 and α5β1 show moderate-affinity (Kd ∼450 nM) and low-affinity (Kd >1 μM) binding respectively. Different patterns of α5β1 distribution are seen when human keratinocytes and fibroblasts are plated on to fibrillin domain fragments compared with those seen for fibronectin, suggesting that fibrillin may cause a lesser degree or different type of intracellular signalling. A number of disease-causing mutations which affect the TB4 domain have been identified. These are being investigated for their effects on integrin binding and/or changes in intramolecular structure.

scholarly journals Bone matrix to growth factors: location, location, location

2010 ◽  
Vol 190 (6) ◽  
pp. 949-951 ◽  
Author(s):  
Daniel B. Rifkin ◽  
Vesna Todorovic
Keyword(s):  
Extracellular Matrix ◽  
Growth Factors ◽  
Growth Factor ◽  
Transforming Growth Factor ◽  
Bone Matrix ◽  
Cell Behavior ◽  
Structural Support ◽  
Morphogenetic Protein ◽  
Fibrillin 1 ◽  
Osteoblast Maturation

The demonstration that fibrillin-1 mutations perturb transforming growth factor (TGF)–β bioavailability/signaling in Marfan syndrome (MFS) changed the view of the extracellular matrix as a passive structural support to a dynamic modulator of cell behavior. In this issue, Nistala et al. (2010. J. Cell Biol. doi: 10.1083/jcb.201003089) advance this concept by demonstrating how fibrillin-1 and -2 regulate TGF-β and bone morphogenetic protein (BMP) action during osteoblast maturation.

scholarly journals Steered molecular dynamic simulations reveal Marfan syndrome mutations disrupt fibrillin-1 cbEGF domain mechanosensitive calcium binding

2020 ◽  
Vol 10 (1) ◽  
Author(s):  
Stephen J. Haller ◽  
Adrian E. Roitberg ◽  
Andrew T. Dudley
Keyword(s):  
Extracellular Matrix ◽  
Growth Factor ◽  
Marfan Syndrome ◽  
Transforming Growth Factor Beta ◽  
Calcium Binding ◽  
Disulfide Bonds ◽  
Transforming Growth Factor ◽  
Connective Tissue Disorder ◽  
Dynamic Simulations ◽  
Fibrillin 1

Abstract Marfan syndrome (MFS) is a highly variable genetic connective tissue disorder caused by mutations in the calcium binding extracellular matrix glycoprotein fibrillin-1. Patients with the most severe form of MFS (neonatal MFS; nMFS) tend to have mutations that cluster in an internal region of fibrillin-1 called the neonatal region. This region is predominantly composed of eight calcium-binding epidermal growth factor-like (cbEGF) domains, each of which binds one calcium ion and is stabilized by three highly conserved disulfide bonds. Crucially, calcium plays a fundamental role in stabilizing cbEGF domains. Perturbed calcium binding caused by cbEGF domain mutations is thus thought to be a central driver of MFS pathophysiology. Using steered molecular dynamics (SMD) simulations, we demonstrate that cbEGF domain calcium binding decreases under mechanical stress (i.e. cbEGF domains are mechanosensitive). We further demonstrate the disulfide bonds in cbEGF domains uniquely orchestrate protein unfolding by showing that MFS disulfide bond mutations markedly disrupt normal mechanosensitive calcium binding dynamics. These results point to a potential mechanosensitive mechanism for fibrillin-1 in regulating extracellular transforming growth factor beta (TGFB) bioavailability and microfibril integrity. Such mechanosensitive “smart” features may represent novel mechanisms for mechanical hemostasis regulation in extracellular matrix that are pathologically activated in MFS.

Hereditäre Erkrankungen mit Gelenkhypermobilität

2009 ◽  
Vol 18 (04) ◽  
pp. 293-303
Author(s):  
D. Renz ◽  
L. Graul-Neumann ◽  
P. Robinson ◽  
G. Schwabe
Keyword(s):  
Growth Factor ◽  
Osteogenesis Imperfecta ◽  
Transforming Growth Factor ◽  
Tgf Beta ◽  
Fibrillin 1 ◽  
Hereditäre Erkrankungen

ZusammenfassungUnter Gelenkhypermobilität versteht man die Überbeweglichkeit eines oder mehrerer Gelenke. Hypermobilität ist oftmals mit extraartikulären Begleitmanifestationen vergesellschaftet und tritt gehäuft bei hereditären Erkrankungen des Bindegewebes und Skeletts, wie Marfan-Syndrom (MFS), marfanoiden Erkrankungen, Ehlers-Danlos-Syndrom (EDS), Osteogenesis imperfecta (OI) und weiteren Skelettdysplasien auf. Während das MFS durch Fibrillin-1 (FBN1)-Mutationen hervorgerufen wird, führen Mutationen in den TGFbeta-Rezeptoren TGFBR1 und TGFBR2 zum marfanähnlichen Loeys-Dietz-Syndrom (LDS). Untersuchungen an Mausmodellen und bei Patienten zeigen, dass eine erhöhte Verfügbarkeit von Transforming-Growth- Factor (TGF)-beta ein wichtiger Faktor bei der Pathogenese des MFS und LDS ist. Demgegenüber werden die unterschiedlichen EDS- und OI-Formen durch Mutationen verursacht, die die Synthese und Modifikation verschiedener fibrillärer Kollagene betreffen. In diesem Übersichtsartikel präsentieren wir eine aktuelle Zusammenfassung bedeutsamer klinischer und genetischer Erkenntnisse von hereditären Erkrankungen des Bindegewebes und Skeletts mit Gelenkhypermobilität.

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