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. 2003 Jun 1;372(Pt 2):503–515. doi: 10.1042/BJ20030174

The structure and regulation of the human and mouse matrix metalloproteinase-21 gene and protein.

George N Marchenko 1, Natalia D Marchenko 1, Alex Y Strongin 1
PMCID: PMC1223413  PMID: 12617721

Abstract

Matrix metalloproteinases (MMPs) play key roles in tissue remodelling under normal development and, especially, in diseases ranging from malignancies to stroke. We cloned and thoroughly characterized the novel human and mouse MMP gene encoding MMP-21. MMP-21 is the last uncharacterized MMP coded by the human genome. Human and mouse MMP-21 is the orthologue of Xenopus laevis X-MMP. The latent proenzyme of MMP-21 (569 amino acid residues) consists of the prodomain, the catalytic domain and the haemopexin-like domain, and is potentially capable of being activated in its secretory pathway to the extracellular milieu by furin-like proprotein convertases. Human MMP-21 is the probable target gene of the Wnt pathway. In addition, the expression of MMP-21 is controlled uniquely by Pax and Notch transcription factors known to be critical for organogenesis. MMP-21 is expressed transiently in mouse embryogenesis and increased in embryonic neuronal tissues. Our observations clearly indicate that there is an important specific function for MMP-21 in embryogenesis, especially in neuronal cells.

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Selected References

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  1. Ahokas Katja, Lohi Jouko, Lohi Hannes, Elomaa Outi, Karjalainen-Lindsberg Marja Liisa, Kere Juha, Saarialho-Kere Ulpu. Matrix metalloproteinase-21, the human orthologue for XMMP, is expressed during fetal development and in cancer. Gene. 2002 Nov 13;301(1-2):31–41. doi: 10.1016/s0378-1119(02)01088-0. [DOI] [PubMed] [Google Scholar]
  2. Allenspach Eric J., Maillard Ivan, Aster Jon C., Pear Warren S. Notch signaling in cancer. Cancer Biol Ther. 2002 Sep-Oct;1(5):466–476. doi: 10.4161/cbt.1.5.159. [DOI] [PubMed] [Google Scholar]
  3. Allman David, Aster Jon C., Pear Warren S. Notch signaling in hematopoiesis and early lymphocyte development. Immunol Rev. 2002 Sep;187:75–86. doi: 10.1034/j.1600-065x.2002.18707.x. [DOI] [PubMed] [Google Scholar]
  4. Barker N., Clevers H. Catenins, Wnt signaling and cancer. Bioessays. 2000 Nov;22(11):961–965. doi: 10.1002/1521-1878(200011)22:11<961::AID-BIES1>3.0.CO;2-T. [DOI] [PubMed] [Google Scholar]
  5. Baron M., Aslam H., Flasza M., Fostier M., Higgs J. E., Mazaleyrat S. L., Wilkin M. B. Multiple levels of Notch signal regulation (review). Mol Membr Biol. 2002 Jan-Mar;19(1):27–38. doi: 10.1080/09687680110112929. [DOI] [PubMed] [Google Scholar]
  6. Chi Neil, Epstein Jonathan A. Getting your Pax straight: Pax proteins in development and disease. Trends Genet. 2002 Jan;18(1):41–47. doi: 10.1016/s0168-9525(01)02594-x. [DOI] [PubMed] [Google Scholar]
  7. Damjanovski S., Amano T., Li Q., Pei D., Shi Y. B. Overexpression of matrix metalloproteinases leads to lethality in transgenic Xenopus laevis: implications for tissue-dependent functions of matrix metalloproteinases during late embryonic development. Dev Dyn. 2001 May;221(1):37–47. doi: 10.1002/dvdy.1123. [DOI] [PubMed] [Google Scholar]
  8. De Strooper B., Annaert W. Where Notch and Wnt signaling meet. The presenilin hub. J Cell Biol. 2001 Feb 19;152(4):F17–F20. doi: 10.1083/jcb.152.4.f17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  9. Egeblad Mikala, Werb Zena. New functions for the matrix metalloproteinases in cancer progression. Nat Rev Cancer. 2002 Mar;2(3):161–174. doi: 10.1038/nrc745. [DOI] [PubMed] [Google Scholar]
  10. Gu Zezong, Kaul Marcus, Yan Boxu, Kridel Steven J., Cui Jiankun, Strongin Alex, Smith Jeffrey W., Liddington Robert C., Lipton Stuart A. S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science. 2002 Aug 16;297(5584):1186–1190. doi: 10.1126/science.1073634. [DOI] [PubMed] [Google Scholar]
  11. Guidos Cynthia J. Notch signaling in lymphocyte development. Semin Immunol. 2002 Dec;14(6):395–404. doi: 10.1016/s104453230200074x. [DOI] [PubMed] [Google Scholar]
  12. Impola Ulla, Toriseva Mervi, Suomela Sari, Jeskanen Leila, Hieta Niina, Jahkola Tiina, Grenman Reidar, Kähäri Veli-Matti, Saarialho-Kere Ulpu. Matrix metalloproteinase-19 is expressed by proliferating epithelium but disappears with neoplastic dedifferentiation. Int J Cancer. 2003 Mar 1;103(6):709–716. doi: 10.1002/ijc.10902. [DOI] [PubMed] [Google Scholar]
  13. Kajita M., Itoh Y., Chiba T., Mori H., Okada A., Kinoh H., Seiki M. Membrane-type 1 matrix metalloproteinase cleaves CD44 and promotes cell migration. J Cell Biol. 2001 May 28;153(5):893–904. doi: 10.1083/jcb.153.5.893. [DOI] [PMC free article] [PubMed] [Google Scholar]
  14. Leontovich A. A., Zhang J., Shimokawa K., Nagase H., Sarras M. P., Jr A novel hydra matrix metalloproteinase (HMMP) functions in extracellular matrix degradation, morphogenesis and the maintenance of differentiated cells in the foot process. Development. 2000 Feb;127(4):907–920. doi: 10.1242/dev.127.4.907. [DOI] [PubMed] [Google Scholar]
  15. Llano E., Pendás A. M., Aza-Blanc P., Kornberg T. B., López-Otín C. Dm1-MMP, a matrix metalloproteinase from Drosophila with a potential role in extracellular matrix remodeling during neural development. J Biol Chem. 2000 Nov 17;275(46):35978–35985. doi: 10.1074/jbc.M006045200. [DOI] [PubMed] [Google Scholar]
  16. Llano E., Pendás A. M., Freije J. P., Nakano A., Knäuper V., Murphy G., López-Otin C. Identification and characterization of human MT5-MMP, a new membrane-bound activator of progelatinase a overexpressed in brain tumors. Cancer Res. 1999 Jun 1;59(11):2570–2576. [PubMed] [Google Scholar]
  17. Lohi J., Wilson C. L., Roby J. D., Parks W. C. Epilysin, a novel human matrix metalloproteinase (MMP-28) expressed in testis and keratinocytes and in response to injury. J Biol Chem. 2000 Dec 19;276(13):10134–10144. doi: 10.1074/jbc.M001599200. [DOI] [PubMed] [Google Scholar]
  18. Marchenko G. N., Ratnikov B. I., Rozanov D. V., Godzik A., Deryugina E. I., Strongin A. Y. Characterization of matrix metalloproteinase-26, a novel metalloproteinase widely expressed in cancer cells of epithelial origin. Biochem J. 2001 Jun 15;356(Pt 3):705–718. doi: 10.1042/0264-6021:3560705. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Marchenko G. N., Strongin A. Y. MMP-28, a new human matrix metalloproteinase with an unusual cysteine-switch sequence is widely expressed in tumors. Gene. 2001 Mar 7;265(1-2):87–93. doi: 10.1016/s0378-1119(01)00360-2. [DOI] [PubMed] [Google Scholar]
  20. Marchenko George N., Marchenko Natalia D., Leng Jay, Strongin Alex Y. Promoter characterization of the novel human matrix metalloproteinase-26 gene: regulation by the T-cell factor-4 implies specific expression of the gene in cancer cells of epithelial origin. Biochem J. 2002 Apr 15;363(Pt 2):253–262. doi: 10.1042/0264-6021:3630253. [DOI] [PMC free article] [PubMed] [Google Scholar]
  21. Marchenko Natalia D., Marchenko George N., Strongin Alex Y. Unconventional activation mechanisms of MMP-26, a human matrix metalloproteinase with a unique PHCGXXD cysteine-switch motif. J Biol Chem. 2002 Mar 11;277(21):18967–18972. doi: 10.1074/jbc.M201197200. [DOI] [PubMed] [Google Scholar]
  22. Massova I., Kotra L. P., Fridman R., Mobashery S. Matrix metalloproteinases: structures, evolution, and diversification. FASEB J. 1998 Sep;12(12):1075–1095. [PubMed] [Google Scholar]
  23. Mauch Simon, Kolb Cornelia, Kolb Birgit, Sadowski Thorsten, Sedlacek Radislav. Matrix metalloproteinase-19 is expressed in myeloid cells in an adhesion-dependent manner and associates with the cell surface. J Immunol. 2002 Feb 1;168(3):1244–1251. doi: 10.4049/jimmunol.168.3.1244. [DOI] [PubMed] [Google Scholar]
  24. McQuibban G. A., Gong J. H., Tam E. M., McCulloch C. A., Clark-Lewis I., Overall C. M. Inflammation dampened by gelatinase A cleavage of monocyte chemoattractant protein-3. Science. 2000 Aug 18;289(5482):1202–1206. doi: 10.1126/science.289.5482.1202. [DOI] [PubMed] [Google Scholar]
  25. Nagase H., Woessner J. F., Jr Matrix metalloproteinases. J Biol Chem. 1999 Jul 30;274(31):21491–21494. doi: 10.1074/jbc.274.31.21491. [DOI] [PubMed] [Google Scholar]
  26. Ohnishi J., Ohnishi E., Jin M., Hirano W., Nakane D., Matsui H., Kimura A., Sawa H., Nakayama K., Shibuya H. Cloning and characterization of a rat ortholog of MMP-23 (matrix metalloproteinase-23), a unique type of membrane-anchored matrix metalloproteinase and conditioned switching of its expression during the ovarian follicular development. Mol Endocrinol. 2001 May;15(5):747–764. doi: 10.1210/mend.15.5.0638. [DOI] [PubMed] [Google Scholar]
  27. Overall Christopher Mark, López-Otín Carlos. Strategies for MMP inhibition in cancer: innovations for the post-trial era. Nat Rev Cancer. 2002 Sep;2(9):657–672. doi: 10.1038/nrc884. [DOI] [PubMed] [Google Scholar]
  28. Park H. I., Ni J., Gerkema F. E., Liu D., Belozerov V. E., Sang Q. X. Identification and characterization of human endometase (Matrix metalloproteinase-26) from endometrial tumor. J Biol Chem. 2000 Jul 7;275(27):20540–20544. doi: 10.1074/jbc.M002349200. [DOI] [PubMed] [Google Scholar]
  29. Park Hyun I., Turk Benjamin E., Gerkema Ferry E., Cantley Lewis C., Sang Qing-Xiang Amy. Peptide substrate specificities and protein cleavage sites of human endometase/matrilysin-2/matrix metalloproteinase-26. J Biol Chem. 2002 Jul 15;277(38):35168–35175. doi: 10.1074/jbc.M205071200. [DOI] [PubMed] [Google Scholar]
  30. Pei D., Kang T., Qi H. Cysteine array matrix metalloproteinase (CA-MMP)/MMP-23 is a type II transmembrane matrix metalloproteinase regulated by a single cleavage for both secretion and activation. J Biol Chem. 2000 Oct 27;275(43):33988–33997. doi: 10.1074/jbc.M006493200. [DOI] [PubMed] [Google Scholar]
  31. Pei D., Weiss S. J. Furin-dependent intracellular activation of the human stromelysin-3 zymogen. Nature. 1995 May 18;375(6528):244–247. doi: 10.1038/375244a0. [DOI] [PubMed] [Google Scholar]
  32. Ratnikov Boris I., Rozanov Dmitri V., Postnova Tanya I., Baciu Peter G., Zhang Heying, DiScipio Richard G., Chestukhina Galina G., Smith Jeffrey W., Deryugina Elena I., Strongin Alex Y. An alternative processing of integrin alpha(v) subunit in tumor cells by membrane type-1 matrix metalloproteinase. J Biol Chem. 2001 Dec 10;277(9):7377–7385. doi: 10.1074/jbc.M109580200. [DOI] [PubMed] [Google Scholar]
  33. Rozanov Dmitry V., Ghebrehiwet Berhane, Ratnikov BorisI, Monosov Edward Z., Deryugina Elena I., Strongin Alex Y. The cytoplasmic tail peptide sequence of membrane type-1 matrix metalloproteinase (MT1-MMP) directly binds to gC1qR, a compartment-specific chaperone-like regulatory protein. FEBS Lett. 2002 Sep 11;527(1-3):51–57. doi: 10.1016/s0014-5793(02)03153-8. [DOI] [PubMed] [Google Scholar]
  34. Saarialho-Kere Ulpu, Kerkelä Erja, Jahkola Tiina, Suomela Sari, Keski-Oja Jorma, Lohi Jouko. Epilysin (MMP-28) expression is associated with cell proliferation during epithelial repair. J Invest Dermatol. 2002 Jul;119(1):14–21. doi: 10.1046/j.1523-1747.2002.01790.x. [DOI] [PubMed] [Google Scholar]
  35. Stracke J. O., Hutton M., Stewart M., Pendás A. M., Smith B., López-Otin C., Murphy G., Knäuper V. Biochemical characterization of the catalytic domain of human matrix metalloproteinase 19. Evidence for a role as a potent basement membrane degrading enzyme. J Biol Chem. 2000 May 19;275(20):14809–14816. doi: 10.1074/jbc.275.20.14809. [DOI] [PubMed] [Google Scholar]
  36. Suzuki A. S., Tadano Y., Yamamoto T., Abe S. I., Tajima T. Expression of a novel matrix metalloproteinase gene during Cynops early embryogenesis. Biochem Biophys Res Commun. 2001 Oct 26;288(2):380–384. doi: 10.1006/bbrc.2001.5784. [DOI] [PubMed] [Google Scholar]
  37. Uría J. A., López-Otín C. Matrilysin-2, a new matrix metalloproteinase expressed in human tumors and showing the minimal domain organization required for secretion, latency, and activity. Cancer Res. 2000 Sep 1;60(17):4745–4751. [PubMed] [Google Scholar]
  38. Velasco G., Cal S., Merlos-Suárez A., Ferrando A. A., Alvarez S., Nakano A., Arribas J., López-Otín C. Human MT6-matrix metalloproteinase: identification, progelatinase A activation, and expression in brain tumors. Cancer Res. 2000 Feb 15;60(4):877–882. [PubMed] [Google Scholar]
  39. Velasco G., Pendás A. M., Fueyo A., Knäuper V., Murphy G., López-Otín C. Cloning and characterization of human MMP-23, a new matrix metalloproteinase predominantly expressed in reproductive tissues and lacking conserved domains in other family members. J Biol Chem. 1999 Feb 19;274(8):4570–4576. doi: 10.1074/jbc.274.8.4570. [DOI] [PubMed] [Google Scholar]
  40. Westermarck J., Kähäri V. M. Regulation of matrix metalloproteinase expression in tumor invasion. FASEB J. 1999 May;13(8):781–792. [PubMed] [Google Scholar]
  41. Yang M., Murray M. T., Kurkinen M. A novel matrix metalloproteinase gene (XMMP) encoding vitronectin-like motifs is transiently expressed in Xenopus laevis early embryo development. J Biol Chem. 1997 May 23;272(21):13527–13533. doi: 10.1074/jbc.272.21.13527. [DOI] [PubMed] [Google Scholar]
  42. de Coignac A. B., Elson G., Delneste Y., Magistrelli G., Jeannin P., Aubry J. P., Berthier O., Schmitt D., Bonnefoy J. Y., Gauchat J. F. Cloning of MMP-26. A novel matrilysin-like proteinase. Eur J Biochem. 2000 Jun;267(11):3323–3329. doi: 10.1046/j.1432-1327.2000.01363.x. [DOI] [PubMed] [Google Scholar]

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