Determinants of Versican-V1 Proteoglycan Processing by the Metalloproteinase ADAMTS5

Foulcer, Simon J.; Nelson, Courtney M.; Quintero, Maritza; Kuberan, Balagurunathan; Larkin, J.; Dours-Zimmermann, Marı́a T.; Zimmermann, Dieter R.; Apte, Suneel S.

doi:10.1074/jbc.m114.573287

Cited by 52 publications

(63 citation statements)

References 70 publications

Supporting

Mentioning

Contrasting

Order By: Relevance

“…As ADAMTS1 and ADAMTS5 are required for processing the proteoglycan versican during cardiac development, we next examined versican processing using antibodies to stain for total versican (intact and cleaved) and cleaved versican (DPEAAE neoepitope) only [ 15 , 23 ]. As seen in Fig.…”

Section: Resultsmentioning

confidence: 99%

“…In addition to changes in BMP and MAPK signaling, we detected changes in the level of proteases known to remodel the matrix as well as changes in the abundance of certain matrix proteins. Decreases in ADAMTS1 and ADAMTS5, both of which are known to cleave versican [ 15 , 16 , 23 ], are likely responsible for decreased versican cleavage seen in the developing valves of Galnt1 nulls. As versican remodeling is required for proper cardiac development [ 15 , 16 ], these changes likely contribute to the valve phenotypes observed.…”

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Galnt1 Is Required for Normal Heart Valve Development and Cardiac Function

et al. 2015

View full text Add to dashboard Cite

Congenital heart valve defects in humans occur in approximately 2% of live births and are a major source of compromised cardiac function. In this study we demonstrate that normal heart valve development and cardiac function are dependent upon Galnt1, the gene that encodes a member of the family of glycosyltransferases (GalNAc-Ts) responsible for the initiation of mucin-type O-glycosylation. In the adult mouse, compromised cardiac function that mimics human congenital heart disease, including aortic and pulmonary valve stenosis and regurgitation; altered ejection fraction; and cardiac dilation, was observed in Galnt1 null animals. The underlying phenotype is aberrant valve formation caused by increased cell proliferation within the outflow tract cushion of developing hearts, which is first detected at developmental stage E11.5. Developing valves from Galnt1 deficient animals displayed reduced levels of the proteases ADAMTS1 and ADAMTS5, decreased cleavage of the proteoglycan versican and increased levels of other extracellular matrix proteins. We also observed increased BMP and MAPK signaling. Taken together, the ablation of Galnt1 appears to disrupt the formation/remodeling of the extracellular matrix and alters conserved signaling pathways that regulate cell proliferation. Our study provides insight into the role of this conserved protein modification in cardiac valve development and may represent a new model for idiopathic valve disease.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Galnt1 Is Required for Normal Heart Valve Development and Cardiac Function

et al. 2015

View full text Add to dashboard Cite

show abstract

“…It has been reported that in several EOC cell lines, including SKOV3 and OVCAR3, V2 isoform is not expressed (37). In addition, V1 isoform can be processed into smaller fragments (40). Thus, it is possible that miR-590-3p and FOXA2 regulate the expression of V1, and possibly V0.…”

Section: Discussionmentioning

confidence: 99%

miR-590-3p Promotes Ovarian Cancer Growth and Metastasis via a Novel FOXA2–Versican Pathway

et al. 2018

View full text Add to dashboard Cite

miRNAs play important roles in gene regulation, and their dysregulation is associated with many diseases, including epithelial ovarian cancer (EOC). In this study, we determined the expression and function of miR-590-3p in EOC. miR-590-3p levels were higher in high-grade carcinoma when compared with low-grade or tumors with low malignant potential. Interestingly, plasma levels of miR-590-3p were significantly higher in patients with EOC than in subjects with benign gynecologic disorders. Transient transfection of miR-590-3p mimics or stable transfection of mir-590 increased cell proliferation, migration, and invasion. studies revealed that mir-590 accelerated tumor growth and metastasis. Using a cDNA microarray, we identified forkhead box A2 (FOXA2) and versican (VCAN) as top downregulated and upregulated genes by mir-590, respectively. miR-590-3p targeted FOXA2 3' UTR to suppress its expression. In addition, knockdown or knockout of FOXA2 enhanced cell proliferation, migration, and invasion. Overexpression of FOXA2 decreased, whereas knockout of FOXA2 increased VCAN mRNA and protein levels, which was due to direct binding and regulation of the VCAN gene by FOXA2. Interrogation of the TCGA ovarian cancer database revealed a negative relationship between FOXA2 and VCAN mRNA levels in EOC tumors, and high FOXA2/low VCAN mRNA levels in tumors positively correlated with patient survival. Finally, overexpression of FOXA2 or silencing of VCAN reversed the effects of mir-590. These findings demonstrate that miR-590-3p promotes EOC development via a novel FOXA2-VCAN pathway. Low FOXA2/high VCAN levels mediate the tumor-promoting effects of miR-590-3p and negatively correlate with ovarian cancer survival. .

show abstract

“…for 1 hour at room temperature, and stained with antibodies against versican (anti-VC), which detects intact and cleaved versican (cleavage at the E 441 -A 442 peptide bond; V1 isoform enumeration) (44), and aggrecan (polyclonal AB1031, and mouse monoclonal MCA1454G). Rabbit polyclonal antibodies against an ADAMTS protease-generated aggrecan neoepitope (NITEGE 393 ) and versican neoepitope (DPEAAE 441 ; V1 enumeration) were used to localize aggrecan and versican cleavage, respectively.…”

Section: Methodsmentioning

confidence: 99%

Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection

et al. 2018

Self Cite

View full text Add to dashboard Cite

Proteoglycan accumulation is a hallmark of medial degeneration in thoracic aortic aneurysm and dissection (TAAD). Here, we defined the aortic proteoglycanome using mass spectrometry, and based on the findings, investigated the large aggregating proteoglycans aggrecan and versican in human ascending TAAD and a mouse model of severe Marfan syndrome. The aortic proteoglycanome comprises 20 proteoglycans including aggrecan and versican. Antibodies against these proteoglycans intensely stained medial degeneration lesions in TAAD, contrasting with modest intralamellar staining in controls. Aggrecan, but not versican, was increased in longitudinal analysis of Fbn1mgR/mgR aortas. TAAD and Fbn1mgR/mgR aortas had increased aggrecan and versican mRNAs, and reduced expression of a key proteoglycanase gene, ADAMTS5, was seen in TAAD. Fbn1mgR/mgR mice with ascending aortic dissection and/or rupture had dramatically increased aggrecan staining compared with mice without these complications. Thus, aggrecan and versican accumulation in ascending TAAD occurs via increased synthesis and/or reduced proteolytic turnover, and correlates with aortic dissection/rupture in Fbn1mgR/mgR mice. Tissue swelling imposed by aggrecan and versican is proposed to be profoundly deleterious to aortic wall mechanics and smooth muscle cell homeostasis, predisposing to type-A dissections. These proteoglycans provide potential biomarkers for refined risk stratification and timing of elective aortic aneurysm repair.

show abstract

Determinants of Versican-V1 Proteoglycan Processing by the Metalloproteinase ADAMTS5

Cited by 52 publications

References 70 publications

Galnt1 Is Required for Normal Heart Valve Development and Cardiac Function

Galnt1 Is Required for Normal Heart Valve Development and Cardiac Function

miR-590-3p Promotes Ovarian Cancer Growth and Metastasis via a Novel FOXA2–Versican Pathway

Massive aggrecan and versican accumulation in thoracic aortic aneurysm and dissection

Contact Info

Product

Resources

About