Betaglycan: A multifunctional accessory

Bilandzic, Maree; Stenvers, Kaye L.

doi:10.1016/j.mce.2011.04.014

Cited by 96 publications

(105 citation statements)

References 110 publications

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“…Loss of beta-glycan was confirmed using cultured microvascular EC from TSP-4 −/− mice and was associated with increased activity of two mediators of main pathways of TGFβ signaling (p38 and smad2) both in the tissues and in cultured EC. The role of beta-glycan as a TGFβ receptor is controversial: both activating and inhibiting activities on TGFβ have been ascribed (Bilandzic and Stenvers, 2011; Gatza et al, 2010). Our data suggest that beta-glycan has inhibiting effect on TGFβ signaling in skeletal muscle, and TSP-4 is required for its production/retention in the ECM.…”

Section: Discussionmentioning

confidence: 99%

Control of organization and function of muscle and tendon by thrombospondin-4

et al. 2014

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Thrombospondins (TSP) are multifunctional proteins that are deposited in the extracellular matrix where they directly affect the function of vascular and other cell types. TSP-4, one of the 5 TSP family members, is expressed abundantly in tendon and muscle. We have examined the effect of TSP-4 deficiency on tendon collagen and skeletal muscle morphology and function. In Thbs4−/− mice, tendon collagen fibrils are significantly larger than in wild-type mice, and there is no compensatory over-expression of TSP-3 and TSP-5, the two TSPs most highly homologous to TSP-4, in the deficient mice. TSP-4 is expressed in skeletal muscle, and higher levels of TSP-4 protein are associated with the microvasculature of red skeletal muscle with high oxidative metabolism. Lack of TSP-4 in Medial soleus, red skeletal muscle with predominant oxidative metabolism, is associated with decreased levels of several specific glycosaminoglycan modifications, decreased expression of a TGFβ receptor beta-glycan, decreased activity of lipoprotein lipase, which associates with vascular cell surfaces by binding to glycosaminoglycans, and decreased uptake of VLDL. The soleus muscle is smaller and hind- and fore-limb grip strength is reduced in Thbs4−/− mice compared to wild-type mice. These observations suggest that TSP-4 regulates the composition of the ECM at major sites of its deposition, tendon and muscle, and the absence of TSP-4 alters the organization, composition and physiological functions of these tissues.

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Section: Discussionmentioning

confidence: 99%

Control of organization and function of muscle and tendon by thrombospondin-4

et al. 2014

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“…23,24 Betaglycan is a TGFβ coreceptor that facilitates or inhibits signaling depending on the context. 25 The cytoplasmic domain facilitates signaling by TGFβ2 or TGFβ1, while the soluble, cleaved ectodomain can modulate TGFβ signaling by sequestering these growth factors. Betaglycan is expressed in interstitial and peritubular myoid cells in the fetal testes of mouse and human.…”

Section: Discussionmentioning

confidence: 99%

Phenotype Specific Association of the TGFBR3 Locus with Nonsyndromic Cryptorchidism

et al. 2015

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Purpose Based on a genome-wide association study (GWAS) of testicular dysgenesis syndrome (TDS) reporting possible association with TGFBR3, we analyzed GWAS data from a larger, phenotypically restricted cryptorchidism population for potential replication of this signal. Materials and Methods We excluded samples based on strict quality control criteria, leaving 844 cases and 2718 controls of European ancestry that were analyzed in 2 separate groups based on genotyping platform. Analyses included genotype imputation at the TGFBR3 locus, association analysis of imputed data with correction for population substructure, subsequent meta-analysis of Group 1 and 2 data and selective genotyping of independent cases (n=330) and controls (n=324) for replication. We also measured Tgfbr3 mRNA levels and performed TGFBR3/betaglycan immunostaining in rat fetal gubernaculum. Results We identified suggestive (p≤1×10−4) association of markers in/near TGFBR3 including rs9661103 (OR 1.40, 95% CI 1.20,1.64, p=2.71×10−5) and rs10782968 (OR 1.58, CI 1.26,1.98, p=9.36×10−5) in Groups 1 and 2, respectively. In subgroup analyses, we observed strongest association of rs17576372 (OR 1.42, CI 1.24,1.60; p=1.67×10−4) with proximal and rs11165059 (OR 1.32, CI 1.15,1.38; p=9.42×10−4) with distal testis position, signals in strong linkage disequilibrium with rs9661103 and rs10782968, respectively. Association of the prior GWAS signal (rs12082710) was marginal (OR 1.13, CI 0.99,1.28, p=0.09 for Group 1) and we were unable to replicate signals in our independent cohort. Tgfbr3/betaglycan was differentially expressed in wild type and cryptorchid rat fetal gubernaculum. Conclusions These data suggest complex or phenotype-specific association of cryptorchidism with TGFBR3 and the gubernaculum as a potential target of TGFβ signaling.

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“…This hexameric assembly permits interaction between the intracellular domains, with the constitutively active intracellular domain of type II receptor cross-phosphorylating the intracellular glycine-serine (GS) domain of type I receptor [2]. These receptor complexes can contain a type III receptor also termed a co-receptor (betaglycan [3], Endoglin [4] or RGM-a, b, c [5]) that modulates ligand affinity for its type I and type II receptors [6].…”

Section: Introductionmentioning

confidence: 99%

Bioinformatic Analysis of Pathogenic Missense Mutations of Activin Receptor Like Kinase 1 Ectodomain

et al. 2011

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Activin A receptor, type II-like kinase 1 (also called ALK1), is a serine-threonine kinase predominantly expressed on endothelial cells surface. Mutations in its ACVRL1 encoding gene (12q11-14) cause type 2 Hereditary Haemorrhagic Telangiectasia (HHT2), an autosomal dominant multisystem vascular dysplasia. The study of the structural effects of mutations is crucial to understand their pathogenic mechanism. However, while an X-ray structure of ALK1 intracellular domain has recently become available (PDB ID: 3MY0), structure determination of ALK1 ectodomain (ALK1EC) has been elusive so far. We here describe the building of a homology model for ALK1EC, followed by an extensive bioinformatic analysis, based on a set of 38 methods, of the effect of missense mutations at the sequence and structural level. ALK1EC potential interaction mode with its ligand BMP9 was then predicted combining modelling and docking data. The calculated model of the ALK1EC allowed mapping and a preliminary characterization of HHT2 associated mutations. Major structural changes and loss of stability of the protein were predicted for several mutations, while others were found to interfere mainly with binding to BMP9 or other interactors, like Endoglin (CD105), whose encoding ENG gene (9q34) mutations are known to cause type 1 HHT. This study gives a preliminary insight into the potential structure of ALK1EC and into the structural effects of HHT2 associated mutations, which can be useful to predict the potential effect of each single mutation, to devise new biological experiments and to interpret the biological significance of new mutations, private mutations, or non-synonymous polymorphisms.

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Betaglycan: A multifunctional accessory

Cited by 96 publications

References 110 publications

Control of organization and function of muscle and tendon by thrombospondin-4

Control of organization and function of muscle and tendon by thrombospondin-4

Phenotype Specific Association of the TGFBR3 Locus with Nonsyndromic Cryptorchidism

Bioinformatic Analysis of Pathogenic Missense Mutations of Activin Receptor Like Kinase 1 Ectodomain

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