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The RGD sequence in fibrillin-1 regulates miRNA expression

ABSTRACT: Fibrillins are the major components of microfibrils in the extracellular matrix of elastic and non-elastic tissues. Fibrillin-1 contains one evolutionarily conserved Arg-Gly-Asp (RGD) sequence which mediates cell-matrix interactions through cell-surface integrins. Mutations in close vicinity to the RDG sequence lead to heritable disorders, including Marfan syndrome and stiff skin syndrome. Two recombinant fibrillin-1 fragments were produced, one wild-type RGD-containing fragment and one fragment containing a mutant RGA sequence, which has been previously shown to abolish interactions with integrins. To determine the differential regulation of signaling pathways, microarray analysis of microRNA expression was conducted using Affymetrix miRNA3.0 chips. The microRNA expression levels were compared after 24 hours of interaction between human skin fibroblasts (HSFs) and the RGD- and RGA-containing fibrillin-1 fragments.

ORGANISM(S): synthetic construct Homo sapiens

PROVIDER: GSE82083 | GEO | 2018/12/10

REPOSITORIES: GEO

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The RGD sequence in fibrillin-1 regulates mRNA expression

Project description:Fibrillins are the major components of microfibrils in the extracellular matrix of elastic and non-elastic tissues. Fibrillin-1 contains one evolutionarily conserved Arg-Gly-Asp (RGD) sequence which mediates cell-matrix interactions through cell-surface integrins. Mutations in close vicinity to the RDG sequence lead to heritable disorders, including Marfan syndrome and stiff skin syndrome. Two recombinant fibrillin-1 fragments were produced, one wild-type RGD-containing fragment and one fragment containing a mutant RGA sequence, which has been previously shown to abolish interactions with integrins. To determine the differential regulation of signaling pathways, microarray analysis of mRNA expression was conducted using Affymetrix Human Gene 2.0 ST chips. The mRNA expression levels were compared after 24 hours of interaction between human skin fibroblasts (HSFs) and the RGD- and RGA-containing fibrillin-1 fragments.

2018-12-10 | GSE82079 | GEO

The RGD sequence in fibrillin-1 regulates mRNA and miRNA expression

Project description:The RGD sequence in fibrillin-1 regulates mRNA and miRNA expression

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Project description:The RGD sequence in fibrillin-1 regulates miRNA expression

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Project description:Mutations in the fibrillin-1 gene result in cardiovascular, ocular, and skeletal abnormalities in Marfan syndrome. Here we show that a fibrillin-1 mutation also alters the neovessel formation. In the mouse retina vascularization model, fibrillin-1 is detected at the basement membrane underlying the angiogenic front and around arterioles. In Fbn1C1041G/+ mice, a model of Marfan disease, the microvasculature is altered at these sites. At the front, endothelial tip-cell sprouting and branching are decreased, and we show that mutant fibrillin-1 delays angiogenesis by affecting Notch signalling. Supplying the growing vasculature of Fbn1C1041G/+ mice with a C-terminal fragment of fibrillin-1 corrects all defects. In vitro, the C-terminal fragment of fibrillin-1 also displays pro-angiogenic activities on microvascular endothelial cell. Our data establish that fibrillin-1 performs essential functions in microvessel formation and integrity and that mutant fibrillin-1-induced defects can be rescued pharmacologically.

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Evolutionarily conserved sequence motif analysis guided development of chemically defined hydrogels for therapeutic angiogenesis

Project description:Biologically ligands (e.g., RGDS from fibronectin: Fn-RGD) play a critical role in the development of chemically defined biomaterials. However, there has been limited progress in recent decades towards discovering novel extracellular-matrix-protein-derived ligands for translational applications. Here, by combining motif analysis of evolutionarily conserved RGD-containing regions in laminin (Ln) with functional microarray screening, we identified a Ln-derived angiogenic peptide (LDAP) that showed enhanced proangiogenic activities over commonly used Fn-RGD. Mechanistic studies using RNA-sequencing of LDAP functionalized hydrogels showed an improved angiogenic transcriptome over Fn-RGD functionalized hydrogels and high similarity to Matrigel, attributed to the ability of LDAP to engage both Ln- and Fn-binding integrins. Injectable hydrogels functionalized with LDAP, along with MMP-QK (a VEGF-mimetic peptide), exhibited increased functional recovery over decellularized extracellular matrix (dECM) and alginates functionalized with Fn-RGD and MMP-QK in a mouse ischemic hindlimb model, illustrating the power of the strategy to rapidly develop potent chemically-defined biomaterials for therapeutic applications.

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Proteolysis of fibrillin-2 microfibrils is essential for normal skeletal development

Project description:Analysis of mouse Adamts6 and Adamts10 mutant embryos, lacking these homologous secreted metalloproteases individually and in combination, along with in vitro analysis of microfibrils, measurement of ADAMTS6-fibrillin affinities and N-terminomics determination of ADAMTS6-cleaved sites, demonstrates a transcriptionally adapted system for fibrillin-2 proteolysis that contributes to postnatal fibrillin-1 dominance. The lack of ADAMTS6, alone and in combination with ADAMTS10 led to excess fibrillin-2 in perichondrium, with impaired skeletal development. Although ADAMTS6 cleaves fibrillin-1 and fibrillin-2 as well as fibronectin, which provides the initial scaffold for microfibril assembly, primacy of the protease-substrate relationship between ADAMTS6 and fibrillin-2 was unequivocally established by reversal of these defects in Adamts6-/- embryos by genetic reduction of Fbn2, but not Fbn1.

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Project description:Fibrillin-1 (FBN1) is the major component of extracellular matrix microfibrils, which are required for proper development of elastic tissues including heart and lung. Through protein-protein interactions with latent TGF-beta binding protein 1 (LTBP1), microfibrils assist regulation of TGF-beta signaling. Mutations within the 47 epidermal growth factor-like (EGF) repeats of FBN1 cause autosomal dominant disorders including Marfan Syndrome that disrupt TGF-beta signaling. We recently identified 2 novel protein O-glucosyltransferases, Protein O-glucosyltransferase 2 (POGLUT2) and Protein O-glucosyltransferase 3 (POGLUT3), that modify a few EGF repeats on Notch. Here, using mass spectral analysis, we show that POGLUT2 and POGLUT3 also modify over half of the EGF repeats on FBN1, fibrillin-2 (FBN2), and LTBP1. While most sites are modified by both enzymes, some sites show a preference for either POGLUT2 or POGLUT3. POGLUT2 and POGLUT3 are homologs of POGLUT1, which stabilizes Notch proteins by addition of O-glucose to Notch EGF repeats. Like POGLUT1, POGLUT2 and 3 can discern a folded versus unfolded EGF repeat, suggesting POGLUT2 and 3 are involved in a protein folding pathway. In vitro secretion assays using recombinant FBN1 revealed reduced FBN1 secretion in POGLUT2 knockout, POGLUT3 knockout, and POGLUT2 and 3 double knockout HEK293T cells compared to wild type. These results illustrate that POGLUT2 and 3 function together to O-glycosylate protein targets, and that these modifications play a role in secretion of target proteins.

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