Transforming growth factor-β–induced protein (TGFBIp/β ig-h3) activates platelets and promotes thrombogenesis

Kim, Ha Jeong; Kim, Pan Kyung; Bae, Sang Mun; Son, Hyo Jung; Thoudam, Debraj Singh; Kim, Jung Eun; Lee, Byung Heon; Park, Rang Woon; Kim, In San

doi:10.1182/blood-2009-03-212415

Cited by 34 publications

(33 citation statements)

References 42 publications

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“…Neo-N terminal peptides of collagen α-1 (XVIII) commence at Glu 444 , Glu 679 and Asp 732 representing the P1′ residues in the cleavage site. TTGF-β-induced protein ig-h3 (TGFBI), an adhesion molecule that binds to type I fibrillar collagen [59] and is associated with bone formation, was also identified by TAILS as a meprin substrate (Table 5). …”

Section: Resultsmentioning

confidence: 99%

The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10

Jefferson

Keller

Bellac

et al. 2012

Cell. Mol. Life Sci.

113

133

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The in vivo roles of meprin metalloproteases in pathophysiological conditions remain elusive. Substrates define protease roles. Therefore, to identify natural substrates for human meprin α and β we employed TAILS (terminal amine isotopic labeling of substrates), a proteomics approach that enriches for N-terminal peptides of proteins and cleavage fragments. Of the 151 new extracellular substrates we identified, it was notable that ADAM10 (a disintegrin and metalloprotease domain-containing protein 10)—the constitutive α-secretase—is activated by meprin β through cleavage of the propeptide. To validate this cleavage event, we expressed recombinant proADAM10 and after preincubation with meprin β, this resulted in significantly elevated ADAM10 activity. Cellular expression in murine primary fibroblasts confirmed activation. Other novel substrates including extracellular matrix proteins, growth factors and inhibitors were validated by western analyses and enzyme activity assays with Edman sequencing confirming the exact cleavage sites identified by TAILS. Cleavages in vivo were confirmed by comparing wild-type and meprin−/− mice. Our finding of cystatin C, elafin and fetuin-A as substrates and natural inhibitors for meprins reveal new mechanisms in the regulation of protease activity important for understanding pathophysiological processes.Electronic supplementary materialThe online version of this article (doi:10.1007/s00018-012-1106-2) contains supplementary material, which is available to authorized users.

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Section: Resultsmentioning

confidence: 99%

The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10

Jefferson

Keller

Bellac

et al. 2012

Cell. Mol. Life Sci.

113

133

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“…Plasma levels of TGF-β1 and TGF-β2 isoforms are significantly lower in patients with recurrent VTE (43). Potential mechanisms of TGF-β signalling dysregulation in the causative pathway to VTE include suppressed expression of heme oxygenase-1 (44, 45) and promotion of monocyte adhesion, migration and chemotaxis, platelet activation and thrombogenesis by TGF-β-induced protein (TGFBIp/β ig-h3) (46). …”

Section: Discussionmentioning

confidence: 99%

Identification of unique venous thromboembolism-susceptibility variants in African-Americans

et al. 2017

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Summary To identify novel single nucleotide polymorphisms (SNPs) associated with venous thromboembolism (VTE) in African-Americans (AAs), we performed a genome-wide association study (GWAS) of VTE in AAs using the Electronic Medical Records and Genomics (eMERGE) Network, comprised of seven sites each with DNA biobanks (total ~39,200 unique DNA samples) with genome-wide SNP data (imputed to 1000 Genomes Project cosmopolitan reference panel) and linked to electronic health records (EHRs). Using a validated EHR-driven phenotype extraction algorithm, we identified VTE cases and controls and tested for an association between each SNP and VTE using unconditional logistic regression, adjusted for age, sex, stroke, site-platform combination and sickle cell risk genotype. Among 393 AA VTE cases and 4,941 AA controls, three intragenic SNPs reached genome-wide significance: LEMD3 rs138916004 (OR=3.2; p=1.3E-08), LY86 rs3804476 (OR=1.8; p=2E-08) and LOC100130298 rs142143628 (OR=4.5; p=4.4E-08); all three SNPs validated using internal cross-validation, parametric bootstrap and meta-analysis methods. LEMD3 rs138916004 and LOC100130298 rs142143628 are only present in Africans (1000G data). LEMD3 showed a significant differential expression in both NCBI Gene Expression Omnibus (GEO) and the Mayo Clinic gene expression data, LOC100130298 showed a significant differential expression only in the GEO expression data, and LY86 showed a significant differential expression only in the Mayo expression data. LEMD3 encodes for an antagonist of TGF-β-induced cell proliferation arrest. LY86 encodes for MD-1 which down-regulates the pro-inflammatory response to lipopolysaccharide; LY86 variation was previously associated with VTE in white women; LOC100130298 is a non-coding RNA gene with unknown regulatory activity in gene expression and epigenetics.

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“…In the context of these previous studies, Tremmel et al not only provide further confirmation of the involvement of CD44 in tumor angiogenesis, but also present some additional mechanistic insights into the activity of endothelial CD44 in the formation of new vessels. 1 In their paper, Tremmel et al demonstrate that human ECs express CD44 isoforms bearing sequences coded by variant exon 6 (designated as CD44v6). Coimmunoprecipitation studies revealed a constitutive association between vascular endothelial growth factor-2 (VEGFR-2) and CD44v6 (unlike the inducible interaction between CD44v6 and c-Met, the receptor for hepatocyte growth factor [HGF]), which did not require heparan sulfate modification of CD44.…”

Section: Horace M Delisser University Of Pennsylvaniamentioning

confidence: 99%

TGFBIp: more than meets the eye?

Rowley

Weyrich

Campbell

2009

Blood

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Transforming growth factor-β–induced protein (TGFBIp/β ig-h3) activates platelets and promotes thrombogenesis

Cited by 34 publications

References 42 publications

The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10

The substrate degradome of meprin metalloproteases reveals an unexpected proteolytic link between meprin β and ADAM10

Identification of unique venous thromboembolism-susceptibility variants in African-Americans

TGFBIp: more than meets the eye?

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