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Gene Review

MMP14  -  matrix metallopeptidase 14 (membrane...

Homo sapiens

Synonyms: MMP-14, MMP-X1, MT-MMP, MT-MMP 1, MT1-MMP, ...
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Disease relevance of MMP14


Psychiatry related information on MMP14


High impact information on MMP14

  • We find that the matrix metalloproteinase, MT1-MMP, confers tumor cells with a distinct 3D growth advantage in vitro and in vivo [6].
  • These studies suggest that therapeutic interventions designed to target MT1-MMP could prove beneficial in a range of human vascular disease states associated with the destructive remodeling of the vessel wall extracellular matrix [7].
  • Here, we report that HIV-infected macrophages secrete the zymogen matrix metalloproteinase-2 (MMP-2), which is activated by exposure to MT1-MMP on neurons [8].
  • Recent studies have further revealed that the function of MT1-MMP is modified and regulated by O-glycosylation, interaction with CD44, internalization and recycling [9].
  • MT1-MMP modifies various cellular functions and it is, sthus, regulated precisely as a proteinase and as a membrane protein [9].

Chemical compound and disease context of MMP14


Biological context of MMP14


Anatomical context of MMP14


Associations of MMP14 with chemical compounds


Physical interactions of MMP14

  • TIMP-2 complex also serves to reduce the intermolecular autocatalytic turnover of MT1-MMP, resulting in accumulation of active MT1-MMP (57 kDa) on the cell surface [26].
  • We then assessed the effect of fibronectin on the components of the putative MT1-MMP/TIMP-2 'receptor' complex implicated in MMP-2 activation [27].
  • Furthermore, disruption of the CD44H/MT1-MMP complex by overexpressing the HPX fragments resulted in inhibition of the shedding [28].
  • Thus, MTCBP-1 isolated as a binding protein for MT1-MMP was demonstrated to function as an ARD-like enzyme in the MTA cycle in yeast [29].
  • The major MT1-MMP cleavage site (Gly(79) down arrow Gln(80)) is localized within the structurally disordered loop connecting the beta(3) and the beta(4) strands of gC1qR [30].

Enzymatic interactions of MMP14

  • GL-A activation is mediated by a membrane-type MMP (MT-MMP) that cleaves the GL-A propeptide [31].
  • The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3 [32].
  • Recombinant syndecan-1 core protein was shown to be cleaved by recombinant MT1-MMP or MT3-MMP preferentially at the Gly245-Leu246 peptide bond [22].
  • MT1-MMP hydrolyzes a variety of extracellular matrix components and is a physiological activator of pro-MMP-2, another MMP involved in malignancy [26].
  • Most interestingly, the association of MT1-MMP with phosphorylated caveolin-1 induced the recruitment of Src and a concomitant inhibition of the kinase activity of the enzyme, suggesting that this complex may be involved in the negative regulation of Src activity [33].

Co-localisations of MMP14

  • MT1-MMP was co-localized with claudin-1 not only at cell-cell borders, but also at other parts of the cells [34].
  • MMP-2 was colocalized with MT1-MMP and TIMP-2, which are an activator and an activation-enhancing factor, respectively, for proMMP-2 [35].
  • We show here that TIMP-2 co-localizes with MT1-MMP and MMP-2 at lamellipodia but not with that of invadopodia [36].

Regulatory relationships of MMP14


Other interactions of MMP14


Analytical, diagnostic and therapeutic context of MMP14


  1. The hepatitis B virus X protein promotes tumor cell invasion by inducing membrane-type matrix metalloproteinase-1 and cyclooxygenase-2 expression. Lara-Pezzi, E., Gómez-Gaviro, M.V., Gálvez, B.G., Mira, E., Iñiguez, M.A., Fresno, M., Martínez-A, C., Arroyo, A.G., López-Cabrera, M. J. Clin. Invest. (2002) [Pubmed]
  2. Membrane-type matrix metalloproteinase-mediated angiogenesis in a fibrin-collagen matrix. Collen, A., Hanemaaijer, R., Lupu, F., Quax, P.H., van Lent, N., Grimbergen, J., Peters, E., Koolwijk, P., van Hinsbergh, V.W. Blood (2003) [Pubmed]
  3. Enhanced production and activation of progelatinase A mediated by membrane-type 1 matrix metalloproteinase in human papillary thyroid carcinomas. Nakamura, H., Ueno, H., Yamashita, K., Shimada, T., Yamamoto, E., Noguchi, M., Fujimoto, N., Sato, H., Seiki, M., Okada, Y. Cancer Res. (1999) [Pubmed]
  4. Membrane-type 1 matrix metalloproteinase expression is regulated by zonula occludens-1 in human breast cancer cells. Polette, M., Gilles, C., Nawrocki-Raby, B., Lohi, J., Hunziker, W., Foidart, J.M., Birembaut, P. Cancer Res. (2005) [Pubmed]
  5. White matter microglia produce membrane-type matrix metalloprotease, an activator of gelatinase A, in human brain tissues. Yamada, T., Yoshiyama, Y., Sato, H., Seiki, M., Shinagawa, A., Takahashi, M. Acta Neuropathol. (1995) [Pubmed]
  6. Membrane type I matrix metalloproteinase usurps tumor growth control imposed by the three-dimensional extracellular matrix. Hotary, K.B., Allen, E.D., Brooks, P.C., Datta, N.S., Long, M.W., Weiss, S.J. Cell (2003) [Pubmed]
  7. MT1-matrix metalloproteinase directs arterial wall invasion and neointima formation by vascular smooth muscle cells. Filippov, S., Koenig, G.C., Chun, T.H., Hotary, K.B., Ota, I., Bugge, T.H., Roberts, J.D., Fay, W.P., Birkedal-Hansen, H., Holmbeck, K., Sabeh, F., Allen, E.D., Weiss, S.J. J. Exp. Med. (2005) [Pubmed]
  8. HIV-induced metalloproteinase processing of the chemokine stromal cell derived factor-1 causes neurodegeneration. Zhang, K., McQuibban, G.A., Silva, C., Butler, G.S., Johnston, J.B., Holden, J., Clark-Lewis, I., Overall, C.M., Power, C. Nat. Neurosci. (2003) [Pubmed]
  9. MT1-MMP: an enzyme with multidimensional regulation. Itoh, Y., Seiki, M. Trends Biochem. Sci. (2004) [Pubmed]
  10. Phosphoinositide 3-kinase regulates membrane Type 1-matrix metalloproteinase (MMP) and MMP-2 activity during melanoma cell vasculogenic mimicry. Hess, A.R., Seftor, E.A., Seftor, R.E., Hendrix, M.J. Cancer Res. (2003) [Pubmed]
  11. Localization of MT1-MMP, TIMP-1, TIMP-2, and TIMP-3 messenger RNA in normal, hyperplastic, and neoplastic endometrium. Enhanced expression by endometrial adenocarcinomas is associated with low differentiation. Määttä, M., Soini, Y., Liakka, A., Autio-Harmainen, H. Am. J. Clin. Pathol. (2000) [Pubmed]
  12. Ovarian carcinoma regulation of matrix metalloproteinase-2 and membrane type 1 matrix metalloproteinase through beta1 integrin. Ellerbroek, S.M., Fishman, D.A., Kearns, A.S., Bafetti, L.M., Stack, M.S. Cancer Res. (1999) [Pubmed]
  13. Neutrophil-derived serine proteinases enhance membrane type-1 matrix metalloproteinase-dependent tumor cell invasion. Shamamian, P., Pocock, B.J., Schwartz, J.D., Monea, S., Chuang, N., Whiting, D., Marcus, S.G., Galloway, A.C., Mignatti, P. Surgery (2000) [Pubmed]
  14. Genes of the membrane-type matrix metalloproteinase (MT-MMP) gene family, MMP14, MMP15, and MMP16, localize to human chromosomes 14, 16, and 8, respectively. Mattei, M.G., Roeckel, N., Olsen, B.R., Apte, S.S. Genomics (1997) [Pubmed]
  15. Membrane type 1 matrix metalloproteinase regulates collagen-dependent mitogen-activated protein/extracellular signal-related kinase activation and cell migration. Takino, T., Miyamori, H., Watanabe, Y., Yoshioka, K., Seiki, M., Sato, H. Cancer Res. (2004) [Pubmed]
  16. Apoptosis of human hepatic myofibroblasts promotes activation of matrix metalloproteinase-2. Preaux, A.M., D'ortho, M.P., Bralet, M.P., Laperche, Y., Mavier, P. Hepatology (2002) [Pubmed]
  17. Expression of membrane-type matrix metalloproteinase 1 (MT1-MMP) in tumor cells enhances pulmonary metastasis in an experimental metastasis assay. Tsunezuka, Y., Kinoh, H., Takino, T., Watanabe, Y., Okada, Y., Shinagawa, A., Sato, H., Seiki, M. Cancer Res. (1996) [Pubmed]
  18. Membrane-type matrix metalloproteinase-1 and -3 activity in primate smooth muscle cells. Shofuda, K.I., Hasenstab, D., Kenagy, R.D., Shofuda, T., Li, Z.Y., Lieber, A., Clowes, A.W. FASEB J. (2001) [Pubmed]
  19. Cellular mechanisms for human procollagenase-3 (MMP-13) activation. Evidence that MT1-MMP (MMP-14) and gelatinase a (MMP-2) are able to generate active enzyme. Knäuper, V., Will, H., López-Otin, C., Smith, B., Atkinson, S.J., Stanton, H., Hembry, R.M., Murphy, G. J. Biol. Chem. (1996) [Pubmed]
  20. Up-regulation of vascular endothelial growth factor-A by active membrane-type 1 matrix metalloproteinase through activation of Src-tyrosine kinases. Sounni, N.E., Roghi, C., Chabottaux, V., Janssen, M., Munaut, C., Maquoi, E., Galvez, B.G., Gilles, C., Frankenne, F., Murphy, G., Foidart, J.M., Noel, A. J. Biol. Chem. (2004) [Pubmed]
  21. Unveiling the surface epitopes that render tissue inhibitor of metalloproteinase-1 inactive against membrane type 1-matrix metalloproteinase. Lee, M.H., Rapti, M., Murphy, G. J. Biol. Chem. (2003) [Pubmed]
  22. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. Endo, K., Takino, T., Miyamori, H., Kinsen, H., Yoshizaki, T., Furukawa, M., Sato, H. J. Biol. Chem. (2003) [Pubmed]
  23. Inhibition of membrane-type 1 matrix metalloproteinase by hydroxamate inhibitors: an examination of the subsite pocket. Yamamoto, M., Tsujishita, H., Hori, N., Ohishi, Y., Inoue, S., Ikeda, S., Okada, Y. J. Med. Chem. (1998) [Pubmed]
  24. Prostate cancer-associated membrane type 1-matrix metalloproteinase: a pivotal role in bone response and intraosseous tumor growth. Bonfil, R.D., Dong, Z., Trindade Filho, J.C., Sabbota, A., Osenkowski, P., Nabha, S., Yamamoto, H., Chinni, S.R., Zhao, H., Mobashery, S., Vessella, R.L., Fridman, R., Cher, M.L. Am. J. Pathol. (2007) [Pubmed]
  25. Membrane type 1 matrix metalloproteinase is a crucial promoter of synovial invasion in human rheumatoid arthritis. Miller, M.C., Manning, H.B., Jain, A., Troeberg, L., Dudhia, J., Essex, D., Sandison, A., Seiki, M., Nanchahal, J., Nagase, H., Itoh, Y. Arthritis Rheum. (2009) [Pubmed]
  26. Tissue inhibitor of metalloproteinase (TIMP)-2 acts synergistically with synthetic matrix metalloproteinase (MMP) inhibitors but not with TIMP-4 to enhance the (Membrane type 1)-MMP-dependent activation of pro-MMP-2. Toth, M., Bernardo, M.M., Gervasi, D.C., Soloway, P.D., Wang, Z., Bigg, H.F., Overall, C.M., DeClerck, Y.A., Tschesche, H., Cher, M.L., Brown, S., Mobashery, S., Fridman, R. J. Biol. Chem. (2000) [Pubmed]
  27. The activation of ProMMP-2 (gelatinase A) by HT1080 fibrosarcoma cells is promoted by culture on a fibronectin substrate and is concomitant with an increase in processing of MT1-MMP (MMP-14) to a 45 kDa form. Stanton, H., Gavrilovic, J., Atkinson, S.J., d'Ortho, M.P., Yamada, K.M., Zardi, L., Murphy, G. J. Cell. Sci. (1998) [Pubmed]
  28. CD44 binding through the hemopexin-like domain is critical for its shedding by membrane-type 1 matrix metalloproteinase. Suenaga, N., Mori, H., Itoh, Y., Seiki, M. Oncogene (2005) [Pubmed]
  29. Membrane-type 1 matrix metalloproteinase cytoplasmic tail binding protein-1 (MTCBP-1) acts as an eukaryotic aci-reductone dioxygenase (ARD) in the methionine salvage pathway. Hirano, W., Gotoh, I., Uekita, T., Seiki, M. Genes Cells (2005) [Pubmed]
  30. The hemopexin-like C-terminal domain of membrane type 1 matrix metalloproteinase regulates proteolysis of a multifunctional protein, gC1qR. Rozanov, D.V., Ghebrehiwet, B., Postnova, T.I., Eichinger, A., Deryugina, E.I., Strongin, A.Y. J. Biol. Chem. (2002) [Pubmed]
  31. Gelatinase A activation is regulated by the organization of the polymerized actin cytoskeleton. Tomasek, J.J., Halliday, N.L., Updike, D.L., Ahern-Moore, J.S., Vu, T.K., Liu, R.W., Howard, E.W. J. Biol. Chem. (1997) [Pubmed]
  32. The soluble catalytic domain of membrane type 1 matrix metalloproteinase cleaves the propeptide of progelatinase A and initiates autoproteolytic activation. Regulation by TIMP-2 and TIMP-3. Will, H., Atkinson, S.J., Butler, G.S., Smith, B., Murphy, G. J. Biol. Chem. (1996) [Pubmed]
  33. Src-mediated tyrosine phosphorylation of caveolin-1 induces its association with membrane type 1 matrix metalloproteinase. Labrecque, L., Nyalendo, C., Langlois, S., Durocher, Y., Roghi, C., Murphy, G., Gingras, D., Béliveau, R. J. Biol. Chem. (2004) [Pubmed]
  34. Claudin promotes activation of pro-matrix metalloproteinase-2 mediated by membrane-type matrix metalloproteinases. Miyamori, H., Takino, T., Kobayashi, Y., Tokai, H., Itoh, Y., Seiki, M., Sato, H. J. Biol. Chem. (2001) [Pubmed]
  35. Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy. Noda, K., Ishida, S., Inoue, M., Obata, K., Oguchi, Y., Okada, Y., Ikeda, E. Invest. Ophthalmol. Vis. Sci. (2003) [Pubmed]
  36. Specialized surface protrusions of invasive cells, invadopodia and lamellipodia, have differential MT1-MMP, MMP-2, and TIMP-2 localization. Chen, W.T., Wang, J.Y. Ann. N. Y. Acad. Sci. (1999) [Pubmed]
  37. Tissue inhibitor of matrix metalloproteinase-2 regulates matrix metalloproteinase-2 activation by modulation of membrane-type 1 matrix metalloproteinase activity in high and low invasive melanoma cell lines. Kurschat, P., Zigrino, P., Nischt, R., Breitkopf, K., Steurer, P., Klein, C.E., Krieg, T., Mauch, C. J. Biol. Chem. (1999) [Pubmed]
  38. Differential regulation of membrane type 1-matrix metalloproteinase activity by ERK 1/2- and p38 MAPK-modulated tissue inhibitor of metalloproteinases 2 expression controls transforming growth factor-beta1-induced pericellular collagenolysis. Munshi, H.G., Wu, Y.I., Mukhopadhyay, S., Ottaviano, A.J., Sassano, A., Koblinski, J.E., Platanias, L.C., Stack, M.S. J. Biol. Chem. (2004) [Pubmed]
  39. Glycation cross-links inhibit matrix metalloproteinase-2 activation in vascular smooth muscle cells cultured on collagen lattice. Kuzuya, M., Asai, T., Kanda, S., Maeda, K., Cheng, X.W., Iguchi, A. Diabetologia (2001) [Pubmed]
  40. Furin-like proprotein convertases are central regulators of the membrane type matrix metalloproteinase-pro-matrix metalloproteinase-2 proteolytic cascade in atherosclerosis. Stawowy, P., Meyborg, H., Stibenz, D., Borges Pereira Stawowy, N., Roser, M., Thanabalasingam, U., Veinot, J.P., Chrétien, M., Seidah, N.G., Fleck, E., Graf, K. Circulation (2005) [Pubmed]
  41. Visualization of polarized membrane type 1 matrix metalloproteinase activity in live cells by fluorescence resonance energy transfer imaging. Ouyang, M., Lu, S., Li, X.Y., Xu, J., Seong, J., Giepmans, B.N., Shyy, J.Y., Weiss, S.J., Wang, Y. J. Biol. Chem. (2008) [Pubmed]
  42. Increased extracellular matrix remodeling is associated with tumor progression in human hepatocellular carcinomas. Théret, N., Musso, O., Turlin, B., Lotrian, D., Bioulac-Sage, P., Campion, J.P., Boudjéma, K., Clément, B. Hepatology (2001) [Pubmed]
  43. Matrix metalloproteinases collagenase-2, macrophage elastase, collagenase-3, and membrane type 1-matrix metalloproteinase impair clotting by degradation of fibrinogen and factor XII. Hiller, O., Lichte, A., Oberpichler, A., Kocourek, A., Tschesche, H. J. Biol. Chem. (2000) [Pubmed]
  44. Suppression of membrane-type 1 matrix metalloproteinase (MMP)-mediated MMP-2 activation and tumor invasion by testican 3 and its splicing variant gene product, N-Tes. Nakada, M., Yamada, A., Takino, T., Miyamori, H., Takahashi, T., Yamashita, J., Sato, H. Cancer Res. (2001) [Pubmed]
  45. Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis. Deryugina, E.I., Soroceanu, L., Strongin, A.Y. Cancer Res. (2002) [Pubmed]
  46. Cooperative interactions of laminin 5 gamma2 chain, matrix metalloproteinase-2, and membrane type-1-matrix/metalloproteinase are required for mimicry of embryonic vasculogenesis by aggressive melanoma. Seftor, R.E., Seftor, E.A., Koshikawa, N., Meltzer, P.S., Gardner, L.M., Bilban, M., Stetler-Stevenson, W.G., Quaranta, V., Hendrix, M.J. Cancer Res. (2001) [Pubmed]
  47. Characterization of the distinct collagen binding, helicase and cleavage mechanisms of matrix metalloproteinase 2 and 14 (gelatinase A and MT1-MMP): the differential roles of the MMP hemopexin c domains and the MMP-2 fibronectin type II modules in collagen triple helicase activities. Tam, E.M., Moore, T.R., Butler, G.S., Overall, C.M. J. Biol. Chem. (2004) [Pubmed]
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