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Preclinical Models
Published in George C. Kagadis, Nancy L. Ford, Dimitrios N. Karnabatidis, George K. Loudos, Handbook of Small Animal Imaging, 2018
Irene Cuadrado, Jesús Egido, Jose Luis Zamorano, Carlos Zaragoza
Thoracic aortic aneurysm. Mouse models of disease contributed to significant progress in the understanding of thoracic aortic aneurysm (TAA). Marfan syndrome (MFS) is a common disorder of the connective tissue that involves the cardiovascular system and it is caused by mutations that affect the structure or expression of the extracellular matrix protein fibrillin-1, a glycoprotein that associates with extracellular proteins, including integrin receptors and insoluble elastin (Ramirez and Dietz 2007). Fibrillin-1 mutations in MFS decrease extracellular matrix sequestration of latent transforming growth factor-beta (TGFβ), thus rendering it more prone to or accessible for activation (Neptune et al. 2003; Habashi et al. 2006). TAA progression in MFS is driven by elastic fiber calcification, improper ECM proteins synthesis and matrix-degrading enzymes (matrix metalloproteinases), vascular wall inflammation, intimal hyperplasia, structural collapse of the vessel wall, as well as improper activation of MAP kinase signaling (Carta et al. 2009). In view of these results, systemic TGFβ antagonism is applied to mitigate vascular disease in mouse models of MFS and in children with severe and rapidly progressive MFS (Ramirez and Dietz 2007). In addition, murine models have recently shown that fibulin-4 and LRP1 are also associated to TAA (Boucher et al. 2007; Hanada et al. 2007).
Structure, Biochemical Properties, and Biological Functions of Integrin Cytoplasmic Domains
Published in Yoshikazu Takada, Integrins: The Biological Problems, 2017
Martin E. Hemler, Jonathan B. Weitzman, Renata Pasqualini, Satoshi Kawaguchi, Paul D. Kassner, Feodor B. Berdichevsky
As it becomes increasingly clear that integrins may participate in multiple signaling events, it is hypothesized that the diversity of cytoplasmic domain sequences might allow association with a number of distinct other molecules. However, unlike Cadherins which are tightly bound to intracellular proteins called catenins,48,49 most integrins do not appear to associate tightly with cytoplasmic or cytoskeletal proteins. In one attempt to identify proteins associated with the β1 cytoplasmic domain, a protein called fibulin was isolated from a β1 peptide affinity column,50 but later it was discovered that this binding was adventitious.51 Despite the technical difficulties, a few candidate integrin-associated molecules have been identified and are discussed below.
Integrin Expression in Tumor Progression — Role of Signaling Mechanisms
Published in Róza Ádány, Tumor Matrix Biology, 2017
The cytoplasmic domains of the integrins are short (50 amino acids), except β4, which is characterized by a 1000-amino acid long sequence containing a tyrosine phosphorylation sequence.2,13 The cytoplasmic domain of the integrins interacts with several linker proteins to form connections with the actin cytoskeleton. These linker molecules include α-actinin,17 talin,18 vinculin,19 and fibulin,20 as well as kinases such as protein kinase C (PKC), protein tyrosine kinase (PTK), and focal adhesion kinase (FAK).21 It is important to underline that the cytoplasmic interactions seem to be dependent on the cytoplasmic domain of the α chain, resulting in similar ligands recognizing heterodimers with altered cytoskeletal connections (α5β1/α3/β1 and αvβ3/αvβ5). Unlike most of the integrins interacting with actincytoskeleton, α6β4 exhibits specific interactions with intermediate filaments in hemidesmosomes, determined by its unique cytoplasmic domains.12 These cytoplasmic interactions are likely to mediate signal transduction from the exterior to the interior of the cell as well as from the interior to the exterior of the cell (i.e., outside-in and inside-out signalings).12,22 At present the function of the transmembrane domain is unknown besides its role as a linker between the extracellular and cytoplasmic domains.
Identification of novel combined biomarkers in the diagnosis of multiple myeloma
Published in Hematology, 2021
Yanxia Jin, Yuxing Liang, Yanting Su, Lingyun Hui, Hailing Liu, Lu Ding, Fuling Zhou
To determine whether these DEPs were artefacts or MM-related, we selected Fibulin-1 (FBLN1) for further validation. Fibulin-1 (FBLN1) is a secreted glycoprotein with 703 amino acids and a molecular weight of about 70 kDa. It was showed that the expression of FBLN1 was up-regulated in the plasma of MM patients compared to the control group in our MS detection (Supplementary information 1). It has been reported that the mRNA level of FBLN1 in MM cells and the protein expression in serum of MM patients are significantly increased, and FBLN1 was involved in the growth, invasion and migration of myeloma [27], which is consistent with our data. The interaction between FBLN1 protein and other DEPs was analysed by STRING software as shown in Figure 1(e), which found that FBLN1 could mainly interact with extracellular matrix protein 1 (ECM1). In addition, in our result, seven peptides from FBLN1 were enriched by the lectin AANL6 (Table 2), only the peptide CATPHGDN98ASLEATFVKR contain the N-glycosylation consensus sequence ‘N-X-S/T/C’, which has been reported in UniProt dataset (https://www.uniprot.org/uniprot/P23142). The peptide, DSSCGTGYELTEDN258SCK, this site was not reported in UniProt, but it contains the non-canonical sequences N-X-C motif [28], which will be a novel glycosylation site that enriched by AANL in this study, and the detailed structural data will need to be identified by HCD/ETD techniques.
Birt-Hogg-Dubé syndrome associated with chorioretinopathy and nyctalopia: a case report and review of the literature
Published in Ophthalmic Genetics, 2023
Eleni K. Konstantinou, Noreen Shaikh, David J. Ramsey
Clinical ophthalmic genetic testing using a commercially available inherited retinal disease panel of 293 genes (14) was negative for pathologic mutations associated with many other inherited retinal diseases, including the genes epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1) responsible for autosomal dominant macular and peripapillary drusen in Doyne honeycomb retinal dystrophy and tissue inhibitor of metalloproteinase-3 (TIMP3) responsible for Sorsby Fundus Dystrophy (Table 1). The only pathologic allele identified in this screen was a pathogenic variant of Cohen syndrome (VPS13B) for which our patient was heterozygous.
Fibulins: a new biomarker for pulmonary thromboembolism?
Published in The Aging Male, 2020
Murat Acat, Ozlem Sengoren Dikis, Seyhan Us Dulger, Ertan Akbay, Ekrem Karakaya, Ismail Haskul, Efsun Gonca Chousein
Fibulins are a family of eight extracellular matrix (ECM) glycoproteins, including fibulin-1 to -8, that are characterised by a modular structure [1]. Fibulin-1 and -2 constitute the subgroup of the “long fibulins” in being larger than the others with an extra domain including anaphylatoxin units [4,5]. Fibulin-3, -4, -5, and -7 belong to the second subgroup of the “short fibulins”. Short fibulins are monomers with structural similarities [6]. Fibulins, although sharing similarities of biochemical structures and location, have quite different functions and binding partners.