Skip to main content
PMC home page
Biochemical Journal logoLink to Biochemical Journal
. 2003 Oct 1;375(Pt 1):191–197. doi: 10.1042/BJ20030497

The mouse matrix metalloproteinase, epilysin (MMP-28), is alternatively spliced and processed by a furin-like proprotein convertase.

Sara A Illman 1, Jorma Keski-Oja 1, William C Parks 1, Jouko Lohi 1
PMCID: PMC1223653  PMID: 12803542

Abstract

Epilysin (MMP-28) is a recently identified member of the matrix metalloproteinase (MMP) family. To explore the expression of epilysin in vivo and to gain insight into its biological functions, we have cloned the mouse epilysin cDNA and determined its expression. The amino acid sequence of the mouse protein is 85% identical with the human sequence and contains conserved features such as an RKKR furin-activation sequence following the prodomain. Unexpectedly, we found two alternatively spliced forms of the epilysin mRNA lacking 30 and 72 nt at the beginning of the seventh exon coding for part of the haemopexin domain. Expression of recombinant epilysin in HT-1080 fibrosarcoma cells indicated that epilysin was secreted as a major 48 kDa form and a minor 58 kDa form. Expression of the 58 kDa form was increased by a synthetic furin inhibitor at the expense of the 48 kDa form, suggesting that furin cleaves and activates epilysin. Epilysin mRNA was detected in a number of mouse tissues, with the highest expression in the lung, placenta, heart and uterus, and lower levels in the testis and gastrointestinal tract. The wide expression of epilysin in intact, healthy tissues suggests that this MMP functions in physiological tissue homoeostasis and turnover.

Full Text

The Full Text of this article is available as a PDF (218.6 KB).

Selected References

These references are in PubMed. This may not be the complete list of references from this article.

  1. Afzal S., Lalani E. N., Poulsom R., Stubbs A., Rowlinson G., Sato H., Seiki M., Stamp G. W. MT1-MMP and MMP-2 mRNA expression in human ovarian tumors: possible implications for the role of desmoplastic fibroblasts. Hum Pathol. 1998 Feb;29(2):155–165. doi: 10.1016/s0046-8177(98)90226-x. [DOI] [PubMed] [Google Scholar]
  2. Boukamp P., Petrussevska R. T., Breitkreutz D., Hornung J., Markham A., Fusenig N. E. Normal keratinization in a spontaneously immortalized aneuploid human keratinocyte cell line. J Cell Biol. 1988 Mar;106(3):761–771. doi: 10.1083/jcb.106.3.761. [DOI] [PMC free article] [PubMed] [Google Scholar]
  3. Cao J., Drews M., Lee H. M., Conner C., Bahou W. F., Zucker S. The propeptide domain of membrane type 1 matrix metalloproteinase is required for binding of tissue inhibitor of metalloproteinases and for activation of pro-gelatinase A. J Biol Chem. 1998 Dec 25;273(52):34745–34752. doi: 10.1074/jbc.273.52.34745. [DOI] [PubMed] [Google Scholar]
  4. Hobbs S., Jitrapakdee S., Wallace J. C. Development of a bicistronic vector driven by the human polypeptide chain elongation factor 1alpha promoter for creation of stable mammalian cell lines that express very high levels of recombinant proteins. Biochem Biophys Res Commun. 1998 Nov 18;252(2):368–372. doi: 10.1006/bbrc.1998.9646. [DOI] [PubMed] [Google Scholar]
  5. Hofmann M. C., Narisawa S., Hess R. A., Millán J. L. Immortalization of germ cells and somatic testicular cells using the SV40 large T antigen. Exp Cell Res. 1992 Aug;201(2):417–435. doi: 10.1016/0014-4827(92)90291-f. [DOI] [PubMed] [Google Scholar]
  6. Hu S. I., Klein M., Carozza M., Rediske J., Peppard J., Qi J. S. Identification of a splice variant of neutrophil collagenase (MMP-8). FEBS Lett. 1999 Jan 22;443(1):8–10. doi: 10.1016/s0014-5793(98)01654-8. [DOI] [PubMed] [Google Scholar]
  7. Illman S. A., Keski-Oja J., Lohi J. Promoter characterization of the human and mouse epilysin (MMP-28) genes. Gene. 2001 Sep 5;275(1):185–194. doi: 10.1016/s0378-1119(01)00664-3. [DOI] [PubMed] [Google Scholar]
  8. Kang Tiebang, Nagase Hideaki, Pei Duanqing. Activation of membrane-type matrix metalloproteinase 3 zymogen by the proprotein convertase furin in the trans-Golgi network. Cancer Res. 2002 Feb 1;62(3):675–681. [PubMed] [Google Scholar]
  9. Lehti K., Lohi J., Valtanen H., Keski-Oja J. Proteolytic processing of membrane-type-1 matrix metalloproteinase is associated with gelatinase A activation at the cell surface. Biochem J. 1998 Sep 1;334(Pt 2):345–353. doi: 10.1042/bj3340345. [DOI] [PMC free article] [PubMed] [Google Scholar]
  10. Li Qing-Lei, Illman Sara A., Wang Hong-Mei, Liu Dong-Lin, Lohi Jouko, Zhu Cheng. Matrix metalloproteinase-28 transcript and protein are expressed in rhesus monkey placenta during early pregnancy. Mol Hum Reprod. 2003 Apr;9(4):205–211. doi: 10.1093/molehr/gag028. [DOI] [PubMed] [Google Scholar]
  11. Liu Z., Zhou X., Shapiro S. D., Shipley J. M., Twining S. S., Diaz L. A., Senior R. M., Werb Z. The serpin alpha1-proteinase inhibitor is a critical substrate for gelatinase B/MMP-9 in vivo. Cell. 2000 Sep 1;102(5):647–655. doi: 10.1016/s0092-8674(00)00087-8. [DOI] [PubMed] [Google Scholar]
  12. 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]
  13. Luo Daochun, Mari Bernard, Stoll Isabelle, Anglard Patrick. Alternative splicing and promoter usage generates an intracellular stromelysin 3 isoform directly translated as an active matrix metalloproteinase. J Biol Chem. 2002 May 2;277(28):25527–25536. doi: 10.1074/jbc.M202494200. [DOI] [PubMed] [Google Scholar]
  14. Maquoi E., Noël A., Frankenne F., Angliker H., Murphy G., Foidart J. M. Inhibition of matrix metalloproteinase 2 maturation and HT1080 invasiveness by a synthetic furin inhibitor. FEBS Lett. 1998 Mar 13;424(3):262–266. doi: 10.1016/s0014-5793(98)00187-2. [DOI] [PubMed] [Google Scholar]
  15. 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]
  16. Matsumoto S., Katoh M., Saito S., Watanabe T., Masuho Y. Identification of soluble type of membrane-type matrix metalloproteinase-3 formed by alternatively spliced mRNA. Biochim Biophys Acta. 1997 Nov 1;1354(2):159–170. doi: 10.1016/s0167-4781(97)00120-6. [DOI] [PubMed] [Google Scholar]
  17. 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]
  18. Pei D., Weiss S. J. Transmembrane-deletion mutants of the membrane-type matrix metalloproteinase-1 process progelatinase A and express intrinsic matrix-degrading activity. J Biol Chem. 1996 Apr 12;271(15):9135–9140. doi: 10.1074/jbc.271.15.9135. [DOI] [PubMed] [Google Scholar]
  19. Pendás A. M., Knäuper V., Puente X. S., Llano E., Mattei M. G., Apte S., Murphy G., López-Otín C. Identification and characterization of a novel human matrix metalloproteinase with unique structural characteristics, chromosomal location, and tissue distribution. J Biol Chem. 1997 Feb 14;272(7):4281–4286. doi: 10.1074/jbc.272.7.4281. [DOI] [PubMed] [Google Scholar]
  20. Ravanti L., Kähäri V. M. Matrix metalloproteinases in wound repair (review). Int J Mol Med. 2000 Oct;6(4):391–407. [PubMed] [Google Scholar]
  21. 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]
  22. Sato H., Kinoshita T., Takino T., Nakayama K., Seiki M. Activation of a recombinant membrane type 1-matrix metalloproteinase (MT1-MMP) by furin and its interaction with tissue inhibitor of metalloproteinases (TIMP)-2. FEBS Lett. 1996 Sep 9;393(1):101–104. doi: 10.1016/0014-5793(96)00861-7. [DOI] [PubMed] [Google Scholar]
  23. Sternlicht M. D., Werb Z. How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol. 2001;17:463–516. doi: 10.1146/annurev.cellbio.17.1.463. [DOI] [PMC free article] [PubMed] [Google Scholar]
  24. Taipale J., Keski-Oja J. Growth factors in the extracellular matrix. FASEB J. 1997 Jan;11(1):51–59. doi: 10.1096/fasebj.11.1.9034166. [DOI] [PubMed] [Google Scholar]
  25. Wilson C. L., Ouellette A. J., Satchell D. P., Ayabe T., López-Boado Y. S., Stratman J. L., Hultgren S. J., Matrisian L. M., Parks W. C. Regulation of intestinal alpha-defensin activation by the metalloproteinase matrilysin in innate host defense. Science. 1999 Oct 1;286(5437):113–117. doi: 10.1126/science.286.5437.113. [DOI] [PubMed] [Google Scholar]

Articles from Biochemical Journal are provided here courtesy of The Biochemical Society

RESOURCES