The world's first wiki where authorship really matters (Nature Genetics, 2008). Due credit and reputation for authors. Imagine a global collaborative knowledge base for original thoughts. Search thousands of articles and collaborate with scientists around the globe.

wikigene or wiki gene protein drug chemical gene disease author authorship tracking collaborative publishing evolutionary knowledge reputation system wiki2.0 global collaboration genes proteins drugs chemicals diseases compound
Hoffmann, R. A wiki for the life sciences where authorship matters. Nature Genetics (2008)



Gene Review

ADAMTS4  -  ADAM metallopeptidase with thrombospondin...

Homo sapiens

Synonyms: A disintegrin and metalloproteinase with thrombospondin motifs 4, ADAM-TS 4, ADAM-TS4, ADAMTS-2, ADAMTS-4, ...
Welcome! If you are familiar with the subject of this article, you can contribute to this open access knowledge base by deleting incorrect information, restructuring or completely rewriting any text. Read more.

Disease relevance of ADAMTS4

  • In transfected human chondrosarcoma cells, this process is not autoproteolytic because the same products form with an inactive mutant of ADAMTS4 (a disintegrin and metalloproteinase with thrombospondin-like motif 4) and truncation is completely blocked by tissue inhibitor of metalloproteinase-1 [1].
  • Conversely, ADAMTS4, 6, 14, and 20 are consistently up-regulated in breast carcinomas (P = 0.005, P < 0.0001, P = 0.003, and P = 0.001, respectively) [2].
  • Our results show that ADAMTS4 and 5 are upregulated on proliferating glioblastoma cells and these proteases may contribute to their invasive potential [3].
  • It is thought that ADAMTS4 plays a pivotal role in inflammatory joint diseases and cartilage degradation [4].
  • Role of aggrecanase 1 in Lyme arthritis [5].

High impact information on ADAMTS4

  • Our results are consistent with the presence in both normal and arthritic joint cartilage of proteolytic activity against aggrecan based on both classical MMPs and "aggrecanase."[6]
  • Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints [6].
  • To examine the activity of matrix metalloproteinases (MMPs) and aggrecanase in control and diseased human articular cartilage, metabolic fragments of aggrecan were detected with monospecific antipeptide antibodies [6].
  • The aggrecanase members of the ADAMTS (a disintegrin and metalloproteinase with thrombospondin motifs) family cleave a variety of proteins but do not seem to possess distinct sequence specificities [7].
  • In the present study, the topological substrate specificity of ADAMTS-4 (aggrecanase-1) was examined using triple-helical or single-stranded poly(Pro) II helical peptides [7].

Chemical compound and disease context of ADAMTS4

  • Kinetic analysis of the products present in rat chondrosarcoma cell cultures treated with interleukin-1b showed that the first aggrecanase-mediated cleavages occurred at the four sites within the CS attachment region to generate two stable intermediates, Val(1)-Glu(1459) and Val(1)-Glu(1274) [8].
  • Studies in vitro with retinoic acid-stimulated rat chondrosarcoma cells indicated that the rAgg1mut substrate was cleaved at the 'aggrecanase' site equivalent to Glu373-Ala374 (human aggrecan sequence enumeration) in its interglobular domain sequence segment [9].

Biological context of ADAMTS4


Anatomical context of ADAMTS4


Associations of ADAMTS4 with chemical compounds

  • In the present study, we further examined the susceptibility of the VEGF(165).CTGF complex to matrix metalloproteinases (MMP-1, -2, -3, -7, -9, and -13), ADAMTS4 (aggrecanase-1), and serine proteinases, and evaluated the recovery of the angiogenic activity of VEGF(165) after the treatment [17].
  • ADAMTS-5 was expressed constitutively in synovium with little or no transcriptional regulation by recombinant human interleukin-1 alpha or all-trans-retinoate, factors previously shown to upregulate aggrecanase activity in cartilage [18].
  • Further deletion of the cysteine-rich domain reduced the aggrecanase activity by 80% but did not alter the activity against Cm-Tf or fibromodulin [19].
  • Antioxidants and activating protein-1 transcription factor inhibitors, nordihydroguaiaretic acid and N-acetyl-L-cysteine (NAC) suppressed MMP and ADAM-TS4 genes [20].
  • RESULTS: Both aggrecanase-1 and aggrecanase-2 are able to cleave bovine and human biglycan at a site within their central leucine-rich repeat regions [21].
  • Although the spacer domain was critical for ADAMTS-4 localization in the matrix, the cysteine-rich domain influenced ADAMTS-5 localization [22].
  • This discrepancy is most likely due to selective inhibition of full-length ADAMTS-4 by heparin, particularly for cleavage at the Glu373-Ala374 bond [23].

Physical interactions of ADAMTS4


Enzymatic interactions of ADAMTS4

  • ADAMTS4 cleaves at the aggrecanase site (Glu373-Ala374) and secondarily at the matrix metalloproteinase site (Asn341-Phe342) in the aggrecan interglobular domain [26].
  • It was further demonstrated that purified COMP was cleaved by ADAMTS-4, but not ADAMTS-1 or -5, to yield a fragment which co-migrated with Fragment-110 [27].
  • Time course studies indicated that only following depletion of substrate containing the preferred clip site did MMP-8 rapidly cleave at the aggrecanase site [28].
  • When tested, recombinant ADAMTS-4 effectively cleaved intact matrilin-3 at the predicted motif at Glu435/Ala436 generating two species of 45 and 5 kDa [29].

Regulatory relationships of ADAMTS4


Other interactions of ADAMTS4

  • The fold increase for ADAMTS9 mRNA was greater than that for mRNA of the other aggrecanase genes [33].
  • CONCLUSIONS: OSM+TNFalpha up regulates membrane associated aggrecanase activity and several ADAMTS aggrecanase mRNAs in chondrocytes [30].
  • We show here, in digests with native human aggrecan, that purified ADAMTS4 cleaves primarily at the Glu(373)-Ala(374) site, but also, albeit slowly and secondarily, at the Asn(341)-Phe(342) site [26].
  • Real-time PCR demonstrated that TGF-beta significantly increased aggrecanase-1 gene expression in FLS [31].
  • In addition, our evidence suggests that a furin-independent pathway may also contribute to the activation of ADAMTS4 [11].

Analytical, diagnostic and therapeutic context of ADAMTS4


  1. ADAMTS4 (aggrecanase-1) activation on the cell surface involves C-terminal cleavage by glycosylphosphatidyl inositol-anchored membrane type 4-matrix metalloproteinase and binding of the activated proteinase to chondroitin sulfate and heparan sulfate on syndecan-1. Gao, G., Plaas, A., Thompson, V.P., Jin, S., Zuo, F., Sandy, J.D. J. Biol. Chem. (2004) [Pubmed]
  2. Dysregulated expression of adamalysin-thrombospondin genes in human breast carcinoma. Porter, S., Scott, S.D., Sassoon, E.M., Williams, M.R., Jones, J.L., Girling, A.C., Ball, R.Y., Edwards, D.R. Clin. Cancer Res. (2004) [Pubmed]
  3. Matrix-degrading proteases ADAMTS4 and ADAMTS5 (disintegrins and metalloproteinases with thrombospondin motifs 4 and 5) are expressed in human glioblastomas. Held-Feindt, J., Paredes, E.B., Blömer, U., Seidenbecher, C., Stark, A.M., Mehdorn, H.M., Mentlein, R. Int. J. Cancer (2006) [Pubmed]
  4. Characterization of 5'-flanking region of human aggrecanase-1 (ADAMTS4) gene. Mizui, Y., Yamazaki, K., Kuboi, Y., Sagane, K., Tanaka, I. Mol. Biol. Rep. (2000) [Pubmed]
  5. Role of aggrecanase 1 in Lyme arthritis. Behera, A.K., Hildebrand, E., Szafranski, J., Hung, H.H., Grodzinsky, A.J., Lafyatis, R., Koch, A.E., Kalish, R., Perides, G., Steere, A.C., Hu, L.T. Arthritis Rheum. (2006) [Pubmed]
  6. Aggrecan degradation in human cartilage. Evidence for both matrix metalloproteinase and aggrecanase activity in normal, osteoarthritic, and rheumatoid joints. Lark, M.W., Bayne, E.K., Flanagan, J., Harper, C.F., Hoerrner, L.A., Hutchinson, N.I., Singer, I.I., Donatelli, S.A., Weidner, J.R., Williams, H.R., Mumford, R.A., Lohmander, L.S. J. Clin. Invest. (1997) [Pubmed]
  7. Substrate Conformation Modulates Aggrecanase (ADAMTS-4) Affinity and Sequence Specificity: SUGGESTION OF A COMMON TOPOLOGICAL SPECIFICITY FOR FUNCTIONALLY DIVERSE PROTEASES. Lauer-Fields, J.L., Minond, D., Sritharan, T., Kashiwagi, M., Nagase, H., Fields, G.B. J. Biol. Chem. (2007) [Pubmed]
  8. The intermediates of aggrecanase-dependent cleavage of aggrecan in rat chondrosarcoma cells treated with interleukin-1. Sandy, J.D., Thompson, V., Doege, K., Verscharen, C. Biochem. J. (2000) [Pubmed]
  9. Membrane type 1 matrix metalloproteinase (MT1-MMP) cleaves the recombinant aggrecan substrate rAgg1mut at the 'aggrecanase' and the MMP sites. Characterization of MT1-MMP catabolic activities on the interglobular domain of aggrecan. Büttner, F.H., Hughes, C.E., Margerie, D., Lichte, A., Tschesche, H., Caterson, B., Bartnik, E. Biochem. J. (1998) [Pubmed]
  10. ADAMTS4 (aggrecanase-1) interaction with the C-terminal domain of fibronectin inhibits proteolysis of aggrecan. Hashimoto, G., Shimoda, M., Okada, Y. J. Biol. Chem. (2004) [Pubmed]
  11. Proprotein convertase furin interacts with and cleaves pro-ADAMTS4 (Aggrecanase-1) in the trans-Golgi network. Wang, P., Tortorella, M., England, K., Malfait, A.M., Thomas, G., Arner, E.C., Pei, D. J. Biol. Chem. (2004) [Pubmed]
  12. Characterization of human aggrecanase 2 (ADAM-TS5): substrate specificity studies and comparison with aggrecanase 1 (ADAM-TS4). Tortorella, M.D., Liu, R.Q., Burn, T., Newton, R.C., Arner, E. Matrix Biol. (2002) [Pubmed]
  13. A quantitative assay for aggrecanase activity. Will, H., Dettloff, M., Bendzkô, P., Sveshnikov, P. Journal of biomolecular techniques : JBT. (2005) [Pubmed]
  14. Activation of the proteolytic activity of ADAMTS4 (aggrecanase-1) by C-terminal truncation. Gao, G., Westling, J., Thompson, V.P., Howell, T.D., Gottschall, P.E., Sandy, J.D. J. Biol. Chem. (2002) [Pubmed]
  15. Differential gene expression by endothelial cells in distinct angiogenic states. Glienke, J., Schmitt, A.O., Pilarsky, C., Hinzmann, B., Weiss, B., Rosenthal, A., Thierauch, K.H. Eur. J. Biochem. (2000) [Pubmed]
  16. Release of hyaluronan and hyaladherins (aggrecan G1 domain and link proteins) from articular cartilage exposed to ADAMTS-4 (aggrecanase 1) or ADAMTS-5 (aggrecanase 2). Chockalingam, P.S., Zeng, W., Morris, E.A., Flannery, C.R. Arthritis Rheum. (2004) [Pubmed]
  17. Matrix metalloproteinases cleave connective tissue growth factor and reactivate angiogenic activity of vascular endothelial growth factor 165. Hashimoto, G., Inoki, I., Fujii, Y., Aoki, T., Ikeda, E., Okada, Y. J. Biol. Chem. (2002) [Pubmed]
  18. Expression and activity of ADAMTS-5 in synovium. Vankemmelbeke, M.N., Holen, I., Wilson, A.G., Ilic, M.Z., Handley, C.J., Kelner, G.S., Clark, M., Liu, C., Maki, R.A., Burnett, D., Buttle, D.J. Eur. J. Biochem. (2001) [Pubmed]
  19. Altered proteolytic activities of ADAMTS-4 expressed by C-terminal processing. Kashiwagi, M., Enghild, J.J., Gendron, C., Hughes, C., Caterson, B., Itoh, Y., Nagase, H. J. Biol. Chem. (2004) [Pubmed]
  20. Interleukin-17 signal transduction pathways implicated in inducing matrix metalloproteinase-3, -13 and aggrecanase-1 genes in articular chondrocytes. Sylvester, J., Liacini, A., Li, W.Q., Zafarullah, M. Cell. Signal. (2004) [Pubmed]
  21. The cleavage of biglycan by aggrecanases. Melching, L.I., Fisher, W.D., Lee, E.R., Mort, J.S., Roughley, P.J. Osteoarthr. Cartil. (2006) [Pubmed]
  22. Proteolytic activities of human ADAMTS-5: comparative studies with ADAMTS-4. Gendron, C., Kashiwagi, M., Lim, N.H., Enghild, J.J., Thøgersen, I.B., Hughes, C., Caterson, B., Nagase, H. J. Biol. Chem. (2007) [Pubmed]
  23. Functional differences of the catalytic and non-catalytic domains in human ADAMTS-4 and ADAMTS-5 in aggrecanolytic activity. Fushimi, K., Troeberg, L., Nakamura, H., Lim, N.H., Nagase, H. J. Biol. Chem. (2008) [Pubmed]
  24. Glycosaminoglycan-binding properties and aggrecanase activities of truncated ADAMTSs: comparative analyses with ADAMTS-5, -9, -16 and -18. Zeng, W., Corcoran, C., Collins-Racie, L.A., Lavallie, E.R., Morris, E.A., Flannery, C.R. Biochim. Biophys. Acta (2006) [Pubmed]
  25. Autocatalytic cleavage of ADAMTS-4 (Aggrecanase-1) reveals multiple glycosaminoglycan-binding sites. Flannery, C.R., Zeng, W., Corcoran, C., Collins-Racie, L.A., Chockalingam, P.S., Hebert, T., Mackie, S.A., McDonagh, T., Crawford, T.K., Tomkinson, K.N., LaVallie, E.R., Morris, E.A. J. Biol. Chem. (2002) [Pubmed]
  26. ADAMTS4 cleaves at the aggrecanase site (Glu373-Ala374) and secondarily at the matrix metalloproteinase site (Asn341-Phe342) in the aggrecan interglobular domain. Westling, J., Fosang, A.J., Last, K., Thompson, V.P., Tomkinson, K.N., Hebert, T., McDonagh, T., Collins-Racie, L.A., LaVallie, E.R., Morris, E.A., Sandy, J.D. J. Biol. Chem. (2002) [Pubmed]
  27. Cleavage of cartilage oligomeric matrix protein (thrombospondin-5) by matrix metalloproteinases and a disintegrin and metalloproteinase with thrombospondin motifs. Dickinson, S.C., Vankemmelbeke, M.N., Buttle, D.J., Rosenberg, K., Heinegård, D., Hollander, A.P. Matrix Biol. (2003) [Pubmed]
  28. Cleavage of native cartilage aggrecan by neutrophil collagenase (MMP-8) is distinct from endogenous cleavage by aggrecanase. Arner, E.C., Decicco, C.P., Cherney, R., Tortorella, M.D. J. Biol. Chem. (1997) [Pubmed]
  29. Identification of an ADAMTS-4 cleavage motif using phage display leads to the development of fluorogenic peptide substrates and reveals matrilin-3 as a novel substrate. Hills, R., Mazzarella, R., Fok, K., Liu, M., Nemirovskiy, O., Leone, J., Zack, M.D., Arner, E.C., Viswanathan, M., Abujoub, A., Muruganandam, A., Sexton, D.J., Bassill, G.J., Sato, A.K., Malfait, A.M., Tortorella, M.D. J. Biol. Chem. (2007) [Pubmed]
  30. Oncostatin M in combination with tumour necrosis factor {alpha} induces a chondrocyte membrane associated aggrecanase that is distinct from ADAMTS aggrecanase-1 or -2. Hui, W., Barksby, H.E., Young, D.A., Cawston, T.E., McKie, N., Rowan, A.D. Ann. Rheum. Dis. (2005) [Pubmed]
  31. Expression and regulation of aggrecanase in arthritis: the role of TGF-beta. Yamanishi, Y., Boyle, D.L., Clark, M., Maki, R.A., Tortorella, M.D., Arner, E.C., Firestein, G.S. J. Immunol. (2002) [Pubmed]
  32. Metalloproteinase expression in PMA-stimulated THP-1 cells. Effects of peroxisome proliferator-activated receptor-gamma (PPAR gamma) agonists and 9-cis-retinoic acid. Worley, J.R., Baugh, M.D., Hughes, D.A., Edwards, D.R., Hogan, A., Sampson, M.J., Gavrilovic, J. J. Biol. Chem. (2003) [Pubmed]
  33. ADAMTS-9 is synergistically induced by interleukin-1beta and tumor necrosis factor alpha in OUMS-27 chondrosarcoma cells and in human chondrocytes. Demircan, K., Hirohata, S., Nishida, K., Hatipoglu, O.F., Oohashi, T., Yonezawa, T., Apte, S.S., Ninomiya, Y. Arthritis Rheum. (2005) [Pubmed]
  34. Brain-enriched hyaluronan binding (BEHAB)/brevican cleavage in a glioma cell line is mediated by a disintegrin and metalloproteinase with thrombospondin motifs (ADAMTS) family member. Matthews, R.T., Gary, S.C., Zerillo, C., Pratta, M., Solomon, K., Arner, E.C., Hockfield, S. J. Biol. Chem. (2000) [Pubmed]
  35. Purification of an insect derived recombinant human ADAMTS-1 reveals novel gelatin (type I collagen) degrading activities. Lind, T., Birch, M.A., McKie, N. Mol. Cell. Biochem. (2006) [Pubmed]
  36. Aggrecanase-1 (ADAMTS-4) interacts with alpha1-antitrypsin. Yoshida, K., Suzuki, Y., Saito, A., Fukuda, K., Hamanishi, C., Munakata, H. Biochim. Biophys. Acta (2005) [Pubmed]
  37. Utilization of a recombinant substrate rAgg1 to study the biochemical properties of aggrecanase in cell culture systems. Hughes, C.E., Büttner, F.H., Eidenmüller, B., Caterson, B., Bartnik, E. J. Biol. Chem. (1997) [Pubmed]
WikiGenes - Universities