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Biochem J. May 1, 1998; 331(Pt 3): 965–972.
PMCID: PMC1219442

Activation of gelatinase-tissue-inhibitors-of-metalloproteinase complexes by matrilysin.


Matrilysin, gelatinase A and gelatinase B are matrix metalloproteinases (MMPs) implicated in normal and pathological processes that require remodelling of the extracellular matrix. In human prostate tissue, matrilysin is synthesized in ducts surrounded by inflammatory cells, and focally in prostate carcinoma, but not in normal glands. Gelatinase B expression is restricted to inflammatory cells. Gelatinase A can be found in both benign and malignant prostate tissue. MMP activities are regulated by their transition from latent to activated forms, as well as by the presence of tissue inhibitors of metalloproteinases (TIMPs). We investigated whether matrilysin can activate progelatinases A and B in the presence of their bound inhibitors TIMP2 and TIMP1 respectively. Incubation of progelatinase B-TIMP1 complex with active matrilysin resulted in 78 and 68 kDa active forms, as measured by SDS-PAGE and enzyme activity assays. TIMP-free gelatinase B was also activated by matrilysin. In addition, activation of progelatinase B by matrilysin was demonstrated in the conditioned medium of phorbol ester-treated HT1080 cells, confirming the results obtained in the in vitro experiments. In contrast, matrilysin did not proteolytically cleave gelatinase A-TIMP2 complex, but led to a transient increase in gelatinolytic activity of the proenzyme. Matrilysin did not enhance the autocatalytic conversion of its own proform. The data presented here suggest that matrilysin participates in a proteolytic cascade and can activate gelatinases in the presence of TIMPs.

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Selected References

These references are in PubMed. This may not be the complete list of references from this article.
  • Nagase H. Activation mechanisms of matrix metalloproteinases. Biol Chem. 1997 Mar-Apr;378(3-4):151–160. [PubMed]
  • Coussens LM, Werb Z. Matrix metalloproteinases and the development of cancer. Chem Biol. 1996 Nov;3(11):895–904. [PubMed]
  • Birkedal-Hansen H. Proteolytic remodeling of extracellular matrix. Curr Opin Cell Biol. 1995 Oct;7(5):728–735. [PubMed]
  • Basset P, Wolf C, Chambon P. Expression of the stromelysin-3 gene in fibroblastic cells of invasive carcinomas of the breast and other human tissues: a review. Breast Cancer Res Treat. 1993;24(3):185–193. [PubMed]
  • Dean DD, Martel-Pelletier J, Pelletier JP, Howell DS, Woessner JF., Jr Evidence for metalloproteinase and metalloproteinase inhibitor imbalance in human osteoarthritic cartilage. J Clin Invest. 1989 Aug;84(2):678–685. [PMC free article] [PubMed]
  • Park AJ, Matrisian LM, Kells AF, Pearson R, Yuan ZY, Navre M. Mutational analysis of the transin (rat stromelysin) autoinhibitor region demonstrates a role for residues surrounding the "cysteine switch". J Biol Chem. 1991 Jan 25;266(3):1584–1590. [PubMed]
  • Okada Y, Gonoji Y, Naka K, Tomita K, Nakanishi I, Iwata K, Yamashita K, Hayakawa T. Matrix metalloproteinase 9 (92-kDa gelatinase/type IV collagenase) from HT 1080 human fibrosarcoma cells. Purification and activation of the precursor and enzymic properties. J Biol Chem. 1992 Oct 25;267(30):21712–21719. [PubMed]
  • Fridman R, Toth M, Peña D, Mobashery S. Activation of progelatinase B (MMP-9) by gelatinase A (MMP-2). Cancer Res. 1995 Jun 15;55(12):2548–2555. [PubMed]
  • Imai K, Yokohama Y, Nakanishi I, Ohuchi E, Fujii Y, Nakai N, Okada Y. Matrix metalloproteinase 7 (matrilysin) from human rectal carcinoma cells. Activation of the precursor, interaction with other matrix metalloproteinases and enzymic properties. J Biol Chem. 1995 Mar 24;270(12):6691–6697. [PubMed]
  • Willenbrock F, Murphy G. Structure-function relationships in the tissue inhibitors of metalloproteinases. Am J Respir Crit Care Med. 1994 Dec;150(6 Pt 2):S165–S170. [PubMed]
  • Wilson CL, Heppner KJ, Rudolph LA, Matrisian LM. The metalloproteinase matrilysin is preferentially expressed by epithelial cells in a tissue-restricted pattern in the mouse. Mol Biol Cell. 1995 Jul;6(7):851–869. [PMC free article] [PubMed]
  • Wilhelm SM, Collier IE, Marmer BL, Eisen AZ, Grant GA, Goldberg GI. SV40-transformed human lung fibroblasts secrete a 92-kDa type IV collagenase which is identical to that secreted by normal human macrophages. J Biol Chem. 1989 Oct 15;264(29):17213–17221. [PubMed]
  • Goldberg GI, Marmer BL, Grant GA, Eisen AZ, Wilhelm S, He CS. Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2. Proc Natl Acad Sci U S A. 1989 Nov;86(21):8207–8211. [PMC free article] [PubMed]
  • Howard EW, Banda MJ. Binding of tissue inhibitor of metalloproteinases 2 to two distinct sites on human 72-kDa gelatinase. Identification of a stabilization site. J Biol Chem. 1991 Sep 25;266(27):17972–17977. [PubMed]
  • MacNaul KL, Chartrain N, Lark M, Tocci MJ, Hutchinson NI. Discoordinate expression of stromelysin, collagenase, and tissue inhibitor of metalloproteinases-1 in rheumatoid human synovial fibroblasts. Synergistic effects of interleukin-1 and tumor necrosis factor-alpha on stromelysin expression. J Biol Chem. 1990 Oct 5;265(28):17238–17245. [PubMed]
  • Campbell CE, Flenniken AM, Skup D, Williams BR. Identification of a serum- and phorbol ester-responsive element in the murine tissue inhibitor of metalloproteinase gene. J Biol Chem. 1991 Apr 15;266(11):7199–7206. [PubMed]
  • Huhtala P, Tuuttila A, Chow LT, Lohi J, Keski-Oja J, Tryggvason K. Complete structure of the human gene for 92-kDa type IV collagenase. Divergent regulation of expression for the 92- and 72-kilodalton enzyme genes in HT-1080 cells. J Biol Chem. 1991 Sep 5;266(25):16485–16490. [PubMed]
  • Baragi VM, Fliszar CJ, Conroy MC, Ye QZ, Shipley JM, Welgus HG. Contribution of the C-terminal domain of metalloproteinases to binding by tissue inhibitor of metalloproteinases. C-terminal truncated stromelysin and matrilysin exhibit equally compromised binding affinities as compared to full-length stromelysin. J Biol Chem. 1994 Apr 29;269(17):12692–12697. [PubMed]
  • Pajouh MS, Nagle RB, Breathnach R, Finch JS, Brawer MK, Bowden GT. Expression of metalloproteinase genes in human prostate cancer. J Cancer Res Clin Oncol. 1991;117(2):144–150. [PubMed]
  • McDonnell S, Navre M, Coffey RJ, Jr, Matrisian LM. Expression and localization of the matrix metalloproteinase pump-1 (MMP-7) in human gastric and colon carcinomas. Mol Carcinog. 1991;4(6):527–533. [PubMed]
  • Karelina TV, Goldberg GI, Eisen AZ. Matrix metalloproteinases in blood vessel development in human fetal skin and in cutaneous tumors. J Invest Dermatol. 1995 Sep;105(3):411–417. [PubMed]
  • Knox JD, Wolf C, McDaniel K, Clark V, Loriot M, Bowden GT, Nagle RB. Matrilysin expression in human prostate carcinoma. Mol Carcinog. 1996 Jan;15(1):57–63. [PubMed]
  • Rodgers WH, Matrisian LM, Giudice LC, Dsupin B, Cannon P, Svitek C, Gorstein F, Osteen KG. Patterns of matrix metalloproteinase expression in cycling endometrium imply differential functions and regulation by steroid hormones. J Clin Invest. 1994 Sep;94(3):946–953. [PMC free article] [PubMed]
  • Bruner KL, Rodgers WH, Gold LI, Korc M, Hargrove JT, Matrisian LM, Osteen KG. Transforming growth factor beta mediates the progesterone suppression of an epithelial metalloproteinase by adjacent stroma in the human endometrium. Proc Natl Acad Sci U S A. 1995 Aug 1;92(16):7362–7366. [PMC free article] [PubMed]
  • Sopata I, Dancewicz AM. Presence of a gelatin-specific proteinase and its latent form in human leucocytes. Biochim Biophys Acta. 1974 Dec 29;370(2):510–523. [PubMed]
  • Potts JR, Campbell ID. Fibronectin structure and assembly. Curr Opin Cell Biol. 1994 Oct;6(5):648–655. [PubMed]
  • Mainardi CL, Hibbs MS, Hasty KA, Seyer JM. Purification of a type V collagen degrading metalloproteinase from rabbit alveolar macrophages. Coll Relat Res. 1984 Dec;4(6):479–492. [PubMed]
  • Hibbs MS. Expression of 92 kDa phagocyte gelatinase by inflammatory and connective tissue cells. Matrix Suppl. 1992;1:51–57. [PubMed]
  • Moll UM, Youngleib GL, Rosinski KB, Quigley JP. Tumor promoter-stimulated Mr 92,000 gelatinase secreted by normal and malignant human cells: isolation and characterization of the enzyme from HT1080 tumor cells. Cancer Res. 1990 Oct 1;50(19):6162–6170. [PubMed]
  • Morodomi T, Ogata Y, Sasaguri Y, Morimatsu M, Nagase H. Purification and characterization of matrix metalloproteinase 9 from U937 monocytic leukaemia and HT1080 fibrosarcoma cells. Biochem J. 1992 Jul 15;285(Pt 2):603–611. [PMC free article] [PubMed]
  • Sehgal I, Baley PA, Thompson TC. Transforming growth factor beta1 stimulates contrasting responses in metastatic versus primary mouse prostate cancer-derived cell lines in vitro. Cancer Res. 1996 Jul 15;56(14):3359–3365. [PubMed]
  • Bernhard EJ, Gruber SB, Muschel RJ. Direct evidence linking expression of matrix metalloproteinase 9 (92-kDa gelatinase/collagenase) to the metastatic phenotype in transformed rat embryo cells. Proc Natl Acad Sci U S A. 1994 May 10;91(10):4293–4297. [PMC free article] [PubMed]
  • Goldberg GI, Strongin A, Collier IE, Genrich LT, Marmer BL. Interaction of 92-kDa type IV collagenase with the tissue inhibitor of metalloproteinases prevents dimerization, complex formation with interstitial collagenase, and activation of the proenzyme with stromelysin. J Biol Chem. 1992 Mar 5;267(7):4583–4591. [PubMed]
  • Stetler-Stevenson WG, Krutzsch HC, Liotta LA. TIMP-2: identification and characterization of a new member of the metalloproteinase inhibitor family. Matrix Suppl. 1992;1:299–306. [PubMed]
  • Stetler-Stevenson WG. Type IV collagenases in tumor invasion and metastasis. Cancer Metastasis Rev. 1990 Dec;9(4):289–303. [PubMed]
  • Emonard HP, Remacle AG, Noël AC, Grimaud JA, Stetler-Stevenson WG, Foidart JM. Tumor cell surface-associated binding site for the M(r) 72,000 type IV collagenase. Cancer Res. 1992 Oct 15;52(20):5845–5848. [PubMed]
  • Strongin AY, Collier I, Bannikov G, Marmer BL, Grant GA, Goldberg GI. Mechanism of cell surface activation of 72-kDa type IV collagenase. Isolation of the activated form of the membrane metalloprotease. J Biol Chem. 1995 Mar 10;270(10):5331–5338. [PubMed]
  • Nguyen Q, Willenbrock F, Cockett MI, O'Shea M, Docherty AJ, Murphy G. Different domain interactions are involved in the binding of tissue inhibitors of metalloproteinases to stromelysin-1 and gelatinase A. Biochemistry. 1994 Mar 1;33(8):2089–2095. [PubMed]
  • Bergmann U, Tuuttila A, Stetler-Stevenson WG, Tryggvason K. Autolytic activation of recombinant human 72 kilodalton type IV collagenase. Biochemistry. 1995 Mar 7;34(9):2819–2825. [PubMed]
  • Crabbe T, Smith B, O'Connell J, Docherty A. Human progelatinase A can be activated by matrilysin. FEBS Lett. 1994 May 23;345(1):14–16. [PubMed]
  • Barnett J, Straub K, Nguyen B, Chow J, Suttman R, Thompson K, Tsing S, Benton P, Schatzman R, Chen M, et al. Production, purification, and characterization of human matrilysin (PUMP) from recombinant Chinese hamster ovary cells. Protein Expr Purif. 1994 Feb;5(1):27–36. [PubMed]
  • Howard EW, Bullen EC, Banda MJ. Preferential inhibition of 72- and 92-kDa gelatinases by tissue inhibitor of metalloproteinases-2. J Biol Chem. 1991 Jul 15;266(20):13070–13075. [PubMed]
  • Howard EW, Bullen EC, Banda MJ. Regulation of the autoactivation of human 72-kDa progelatinase by tissue inhibitor of metalloproteinases-2. J Biol Chem. 1991 Jul 15;266(20):13064–13069. [PubMed]
  • Bullen EC, Longaker MT, Updike DL, Benton R, Ladin D, Hou Z, Howard EW. Tissue inhibitor of metalloproteinases-1 is decreased and activated gelatinases are increased in chronic wounds. J Invest Dermatol. 1995 Feb;104(2):236–240. [PubMed]
  • Gassmann M, Thömmes P, Weiser T, Hübscher U. Efficient production of chicken egg yolk antibodies against a conserved mammalian protein. FASEB J. 1990 May;4(8):2528–2532. [PubMed]
  • von Bredow DC, Nagle RB, Bowden GT, Cress AE. Degradation of fibronectin fibrils by matrilysin and characterization of the degradation products. Exp Cell Res. 1995 Nov;221(1):83–91. [PubMed]
  • Scharffetter-Kochanek K, Klein CE, Heinen G, Mauch C, Schaefer T, Adelmann-Grill BC, Goerz G, Fusenig NE, Krieg TM, Plewig G. Migration of a human keratinocyte cell line (HACAT) to interstitial collagen type I is mediated by the alpha 2 beta 1-integrin receptor. J Invest Dermatol. 1992 Jan;98(1):3–11. [PubMed]
  • Laemmli UK. Cleavage of structural proteins during the assembly of the head of bacteriophage T4. Nature. 1970 Aug 15;227(5259):680–685. [PubMed]
  • Stetler-Stevenson WG. Progelatinase A activation during tumor cell invasion. Invasion Metastasis. 1994;14(1-6):259–268. [PubMed]
  • McDonnell S, Wright JH, Gaire M, Matrisian LM. Expression and regulation of stromelysin and matrilysin by growth factors and oncogenes. Biochem Soc Trans. 1994 Feb;22(1):58–63. [PubMed]
  • Freestone T, Turner RJ, Coady A, Higman DJ, Greenhalgh RM, Powell JT. Inflammation and matrix metalloproteinases in the enlarging abdominal aortic aneurysm. Arterioscler Thromb Vasc Biol. 1995 Aug;15(8):1145–1151. [PubMed]
  • Zucker S, Lysik RM, Zarrabi MH, Greenwald RA, Gruber B, Tickle SP, Baker TS, Docherty AJ. Elevated plasma stromelysin levels in arthritis. J Rheumatol. 1994 Dec;21(12):2329–2333. [PubMed]
  • Brown PD, Levy AT, Margulies IM, Liotta LA, Stetler-Stevenson WG. Independent expression and cellular processing of Mr 72,000 type IV collagenase and interstitial collagenase in human tumorigenic cell lines. Cancer Res. 1990 Oct 1;50(19):6184–6191. [PubMed]
  • Lokeshwar BL, Selzer MG, Block NL, Gunja-Smith Z. Secretion of matrix metalloproteinases and their inhibitors (tissue inhibitor of metalloproteinases) by human prostate in explant cultures: reduced tissue inhibitor of metalloproteinase secretion by malignant tissues. Cancer Res. 1993 Oct 1;53(19):4493–4498. [PubMed]
  • O'Connell JP, Willenbrock F, Docherty AJ, Eaton D, Murphy G. Analysis of the role of the COOH-terminal domain in the activation, proteolytic activity, and tissue inhibitor of metalloproteinase interactions of gelatinase B. J Biol Chem. 1994 May 27;269(21):14967–14973. [PubMed]
  • Hayakawa T, Yamashita K, Tanzawa K, Uchijima E, Iwata K. Growth-promoting activity of tissue inhibitor of metalloproteinases-1 (TIMP-1) for a wide range of cells. A possible new growth factor in serum. FEBS Lett. 1992 Feb 17;298(1):29–32. [PubMed]
  • Hayakawa T, Yamashita K, Ohuchi E, Shinagawa A. Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). J Cell Sci. 1994 Sep;107(Pt 9):2373–2379. [PubMed]
  • Turck J, Pollock AS, Lee LK, Marti HP, Lovett DH. Matrix metalloproteinase 2 (gelatinase A) regulates glomerular mesangial cell proliferation and differentiation. J Biol Chem. 1996 Jun 21;271(25):15074–15083. [PubMed]
  • Miyazaki K, Umenishi F, Funahashi K, Koshikawa N, Yasumitsu H, Umeda M. Activation of TIMP-2/progelatinase A complex by stromelysin. Biochem Biophys Res Commun. 1992 Jun 30;185(3):852–859. [PubMed]
  • Newell KJ, Witty JP, Rodgers WH, Matrisian LM. Expression and localization of matrix-degrading metalloproteinases during colorectal tumorigenesis. Mol Carcinog. 1994 Aug;10(4):199–206. [PubMed]
  • Karelina TV, Hruza GJ, Goldberg GI, Eisen AZ. Localization of 92-kDa type IV collagenase in human skin tumors: comparison with normal human fetal and adult skin. J Invest Dermatol. 1993 Feb;100(2):159–165. [PubMed]

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