Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility

LI, Shi-Wu; ARITA, Machiko; FERTALA, Andrzej; BAO, Yunhua; KOPEN, Gene C.; Långsjö, Teemu K.; Hyttinen, Marko; Helminen, Heikki J.; Prockop, Darwin J.

doi:10.1042/bj3550271

Cited by 92 publications

(63 citation statements)

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“…However, significant levels were also detected in all tissues investigated, such as brain, spleen, and liver, indicating that Adamts-14 may have other functions. Similar findings have been reported for AD-AMTS-2 (14). As ADAMTS2 and -3, 3 ADAMTS14 is not transcriptionally regulated in fibroblasts by various soluble factors.…”

Section: Figsupporting

confidence: 77%

“…Aliquots of cell extracts were then stored at 4°C or incubated in presence of p-aminophenylmercuric acetate (0.3 mM for 15 min at 25°C) or trypsin (100 g/ml for 15 or 30 min at 37°C) followed by an incubation with soybean trypsin inhibitor (500 g/ml for 5 min at 37°C). The various samples of cell extracts were then assayed for their aminoprocollagen peptidase activity using 14 C-labeled pNI collagen as described earlier (10). Values determined for the cell transfected with the empty vector were considered as background and substracted from values obtained for cells expressing recombinant ADAMTS-2 or -14.…”

Section: Analysis Of Procollagen Processing In Vivo-for Evaluating Thmentioning

confidence: 99%

“…Ϫ/Ϫ mice (14), various organs and tissues were ground at liquid nitrogen temperature and extracted with 0.1 M acetic acid for 18 h at 4°C. After centrifugation, the supernatants were neutralized and ammonium sulfate was added (40% saturation).…”

Section: Analysis Of Procollagen Processing In Vivo-for Evaluating Thmentioning

confidence: 99%

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Cloning and Characterization of ADAMTS-14, a Novel ADAMTS Displaying High Homology with ADAMTS-2 and ADAMTS-3

Colige¹,

Vandenberghe²,

Thiry³

et al. 2002

Journal of Biological Chemistry

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186

129

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The processing of amino-and carboxyl-propeptides of fibrillar collagens is required to generate collagen monomers that correctly assemble into fibrils. Mutations in the ADAMTS2 gene, the aminopropeptidase of procollagen I and II, result in the accumulation of nonfully processed type I procollagen, causing human Ehlers-Danlos syndrome type VIIC and animal dermatosparaxis. In this study, we show that the aminopropeptide of type I procollagen can be cleaved in vivo in absence of ADAMTS-2 activity and that this processing is performed at the cleavage site for ADAMTS-2. In an attempt to identify the enzyme responsible for this alternative aminoprocollagen peptidase activity, we have cloned the cDNA and determined the primary structure of human and mouse ADAMTS-14, a novel ADAMTS displaying striking homologies with ADAMTS-2 and -3. The structure of the human gene, which maps to 10q21.3, and the mechanisms of generation of the various transcripts are described. The existence of two sites of initiation of transcription, in two different promoter contexts, suggests that transcripts resulting from these two sites can be differently regulated. The tissue distribution of AD-AMTS-14, the regulation of the gene expression by various cytokines and the activity of the recombinant enzyme are evaluated. The potential function of ADAMTS-14 as a physiological aminoprocollagen peptidase in vivo is discussed. ADAMTS1 (A Disintegrin and metalloprotease with thrombospondin type I repeats) is a novel family of metalloproteases found in vertebrates and invertebrates. These enzymes are related to ADAMs as judged from sequence homology and conserved domains such as a characteristic metalloprotease domain and a disintegrin-like module. However, they differ from ADAMs by their domain organization and the presence of distinct features. The most specific hallmark is the presence of a central thrombospondin type I repeat (TSPI) between the disintegrin-like module and the Cys-rich domain. All ADAMTS, except ADAMTS-4, contain also TSPI-like domains in varying numbers at the COOH terminus (1, 2). Currently, 12 ADAMTS from vertebrates and a few from invertebrates (Drosophila and Caenorhabditis elegans) have been described (1, 2). AD-AMTS-1, -4, and -5 are able to cleave proteoglycans and are probably involved in cartilage degradation during arthritis (3-5). ADAMTS-1 and -8 are potent anti-angiogenic molecules (6). Adamts1Ϫ/Ϫ mice display abnormal growth, defective fertility, and altered organ morphology and function (7). A C. elegans Adamts, gon-1, was found essential for gonadal morphogenesis (8). Both the metalloprotease domain and some TSPI-like repeats are required for the control of this process.The primarily described activity of ADAMTS-2 is to excise the aminopropeptide of type I and type II procollagens, explaining its former trivial name aminoprocollagen I/II peptidase (9, 10). Removal of the N-and C-propeptide of type I procollagen is required to generate collagen monomers able to assemble into elongated and cylindrical collagen fibers. H...

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Section: Figsupporting

confidence: 77%

Section: Analysis Of Procollagen Processing In Vivo-for Evaluating Thmentioning

confidence: 99%

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Cloning and Characterization of ADAMTS-14, a Novel ADAMTS Displaying High Homology with ADAMTS-2 and ADAMTS-3

Colige¹,

Vandenberghe²,

Thiry³

et al. 2002

Journal of Biological Chemistry

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186

129

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“…This inherited connective tissue disorder arises as a result of accumulation of incorrectly processed aminoprocollagen and its cardinal feature is an extreme skin fragility. Adamts2 knockout mice have been created [23]. In addition to skin fragility, male infertility was related to altered maturation of spermatogonia, suggesting that ADAMTS-2 may have functions other than procollagen processing.…”

Section: Introductionmentioning

confidence: 99%

ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

Dubail¹,

Kesteloot²,

Deroanne³

et al. 2010

Cell. Mol. Life Sci.

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ADAMTS-2 is a metalloproteinase that plays a key role in the processing of fibrillar procollagen precursors into mature collagen molecules by excising the amino-propeptide. We demonstrate that recombinant ADAMTS-2 is also able to reduce proliferation of endothelial cells, and to induce their retraction and detachment from the substrate resulting in apoptosis. Dephosphorylation of Erk1/2 and MLC largely precedes the ADAMTS-2 induced morphological alterations. In 3-D culture models, ADAMTS-2 strongly reduced branching of capillarylike structures formed by endothelial cells and their long-term maintenance and inhibited vessels formation in embryoid bodies (EB). Growth and vascularization of tumors formed in nude mice by HEK 293-EBNA cells expressing ADAMTS-2 were drastically reduced. A similar anti-tumoral activity was observed when using cells expressing recombinant deleted forms of ADAMTS-2, including catalytically inactive enzyme. Nucleolin, a nuclear protein also found to be associated with the cell membrane, was identified as a potential receptor mediating the antiangiogenic properties of ADAMTS-2.

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“…Adamts1-null mice have abnormal adipogenesis, defective angiogenesis in the adrenal gland, and a defect of ureteric ECM turnover, leading to hydronephrosis (14). Adamts2-null mice have fragile skin, and males are infertile (15). Many other ADAMTS enzymes have been discovered through molecular cloning, and their functions are presently unknown.…”

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confidence: 99%

Characterization of ADAMTS-9 and ADAMTS-20 as a Distinct ADAMTS Subfamily Related to Caenorhabditis elegans GON-1

Somerville

Longpré

Jungers

et al. 2003

Journal of Biological Chemistry

308

332

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We demonstrate that in humans, two metalloproteases, ADAMTS-9 (1935 amino acids) and ADAMTS-20 (1911 amino acids) are orthologs of GON-1, an ADAMTS protease required for gonadal morphogenesis in Caenorhabditis elegans. ADAMTS-9 and ADAMTS-20 have an identical modular structure, are distinct in possessing 15 TSRs and a unique C-terminal domain, and have a similar gene structure, suggesting that they comprise a new subfamily of human ADAMTS proteases. AD-AMTS20 is very sparingly expressed, although it is detectable in epithelial cells of the breast and lung. However, ADAMTS9 is highly expressed in embryonic and adult tissues, and therefore we characterized the AD-AMTS-9 protein further. Although the ADAMTS-9 zymogen has many proprotein convertase processing sites, pulse-chase analysis, site-directed mutagenesis, and amino acid sequencing demonstrated that maturation to the active form occurs by selective proprotein convertase (e.g. furin) cleavage of the Arg 287 -Phe 288 bond. Although lacking a transmembrane sequence, ADAMTS-9 is retained near the cell surface as well as in the ECM of transiently transfected COS-1 and 293 cells. COS-1 cells transfected with ADAMTS9 (but not vector-transfected cells) proteolytically cleaved bovine versican and aggrecan core proteins at the Glu 441 -Ala 442 bond of versican V1 and the Glu 1771 -Ala 1772 bond of aggrecan, respectively. In contrast, the ADAMTS-9 catalytic domain alone was neither localized to the cell surface nor able to confer these proteolytic activities on cells, demonstrating that the ancillary domains of ADAMTS-9, including the TSRs, are required both for specific extracellular localization and for its versicanase and aggrecanase activities.

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Transgenic mice with inactive alleles for procollagen N-proteinase (ADAMTS-2) develop fragile skin and male sterility

Cited by 92 publications

References 0 publications

Cloning and Characterization of ADAMTS-14, a Novel ADAMTS Displaying High Homology with ADAMTS-2 and ADAMTS-3

Cloning and Characterization of ADAMTS-14, a Novel ADAMTS Displaying High Homology with ADAMTS-2 and ADAMTS-3

ADAMTS-2 functions as anti-angiogenic and anti-tumoral molecule independently of its catalytic activity

Characterization of ADAMTS-9 and ADAMTS-20 as a Distinct ADAMTS Subfamily Related to Caenorhabditis elegans GON-1

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