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Gene Review

TIMP2  -  TIMP metallopeptidase inhibitor 2

Homo sapiens

Synonyms: CSC-21K, DDC8, Metalloproteinase inhibitor 2, TIMP-2, Tissue inhibitor of metalloproteinases 2
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Disease relevance of TIMP2


Psychiatry related information on TIMP2

  • Instead of TIMP-2, various MMP inhibitors (MMPI) such as BB-2516 have been investigated with regard to suppression of tumor progression and improvement of prognosis in patients with advanced cancers, which resulted in no clinical efficacy [7].

High impact information on TIMP2

  • The nonsense mutation effects a deletion of the substrate-binding and catalytic sites and the fibronectin type II-like and hemopexin/TIMP2 binding domains [8].
  • A similar but non-significant trend was seen for MMP-2 and cathepsin D. A non-significant trend in the opposite direction was seen for TIMP-1 and TIMP-2 [9].
  • Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3 [10].
  • The endothelial cell (EC)-derived tissue inhibitor of metalloproteinase-2 (TIMP-2) and pericyte-derived TIMP-3 are shown to coregulate human capillary tube stabilization following EC-pericyte interactions through a combined ability to block EC tube morphogenesis and regression in three-dimensional collagen matrices [10].
  • Furthermore, we show that EC tube morphogenesis (lumen formation and invasion) is primarily controlled by the TIMP-2 and -3 target membrane type (MT) 1 MMP [10].

Chemical compound and disease context of TIMP2


Biological context of TIMP2

  • MMP inhibitors, recombinant TIMP2, and synthetic BB94 inhibited collagen-induced platelet aggregation in a concentration-dependent manner, indicating the role of activated MT1-MMP in the modulation of platelet function [16].
  • Equally none of the mutants showed significant differences in K(I)(app) for the N-terminal inhibitory domain of TIMP2, again indicating that mutation or deletion of resides 163-170 has no major effect on the overall topology of the active site of MT1-MMP [17].
  • MMP2 genotypes were determined by PCR-based denaturing high performance liquid chromatography analysis and TIMP2 genotypes identified by a PCR-RFLP method in 462 breast cancer patients and 509 frequency matched control women [3].
  • Single nucleotide polymorphisms identified in the promoters of MMP2 (-1306C-->T) and TIMP2 (-418G-->C) abolish the Sp1-binding site and thus may down-regulate expression of the genes [3].
  • Both the nucleotide sequence and the conceptual translation product of the human TIMP3 cDNA have a high degree of similarity to ChIMP-3, a recently cloned metalloproteinase inhibitor in the chicken, and to the TIMP1 and TIMP2 gene products, including 12 conserved cysteinyl residues at the same relative positions [18].

Anatomical context of TIMP2


Associations of TIMP2 with chemical compounds

  • Similarly, the addition of epsilon-aminocaproic acid (a plasmin inhibitor) or tissue inhibitor of metalloprotease (TIMP2, a collagenase inhibitor) reduced the invasiveness of U251 cells from 42% to 14% and 10%, respectively [22].
  • Cyclosporine (but not tacrolimus) increased the expression of (alpha2)IV collagen and TIMP2 in isolated glomeruli [23].
  • VEGF/FGF-2-stimulated tube formation was dependent on metalloproteinase function [it is inhibited by the addition of tissue inhibitor of metalloproteinases-2 (TIMP-2)], whereas aprotinin, E64 [trans-epoxysuccinyl-L-leucylamido (4-guanidino)-butane] and pepstatin had no effect [24].
  • Messenger ribonucleic acids (mRNAs) for MMP-1, MMP-2, and TIMP-2 were localized to the connective tissue stroma and the thecal-lutein cells of the corpus luteum [25].
  • One tissue inhibitor of metalloproteinases, TIMP-2, was barely detectable under hyperglycaemic conditions (30 mM D-glucose) [26].
  • In vitro Matrigel invasion assays showed that re-expression of TIMP-2 after a combined treatment with 5-aza and trichostatin-A in metastatic prostate cells resulted in a significant reduction of tumor cell invasion [27].

Physical interactions of TIMP2


Enzymatic interactions of TIMP2


Regulatory relationships of TIMP2

  • These results suggest that TIMP-2 is not involved in cluadin-5-induced pro-MMP-2 activation by MT-MMPs [34].
  • RESULTS: When smooth muscle cells were cultured on collagen fibrils, pro-MMP-2 processing to active form was observed in the conditioned medium in coincidence with the increased MT1-MMP expression and the suppressed TIMP-2 production [35].
  • TIMP-3 (74+/-23%) was reduced compared with control values (P<0.05) and TIMP-2 was elevated (128+/-31%) compared with non-MFS (73+/-19%; P<0.05) [36].
  • Thus, timp-2 mRNA transcript levels are differentially regulated from timp-1 levels in vivo as well as in cell culture [37].
  • In a second approach, TIMP2 overproduction in MCF7 cells expressing hST3 was induced by retroviral infection [38].

Other interactions of TIMP2


Analytical, diagnostic and therapeutic context of TIMP2


  1. 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]
  2. Expression of MMP2, MMP9, MT1-MMP, TIMP1, and TIMP2 mRNA in valvular lesions of the heart. Soini, Y., Satta, J., Määttä, M., Autio-Harmainen, H. J. Pathol. (2001) [Pubmed]
  3. Substantial reduction in risk of breast cancer associated with genetic polymorphisms in the promoters of the matrix metalloproteinase-2 and tissue inhibitor of metalloproteinase-2 genes. Zhou, Y., Yu, C., Miao, X., Tan, W., Liang, G., Xiong, P., Sun, T., Lin, D. Carcinogenesis (2004) [Pubmed]
  4. Metalloproteinase expression and prognosis in soft tissue sarcomas. Benassi, M.S., Gamberi, G., Magagnoli, G., Molendini, L., Ragazzini, P., Merli, M., Chiesa, F., Balladelli, A., Manfrini, M., Bertoni, F., Mercuri, M., Picci, P. Ann. Oncol. (2001) [Pubmed]
  5. Prognostic significance of matrix metalloproteinase 2 and tissue inhibitor of metalloproteinase 2 expression in prostate cancer. Ross, J.S., Kaur, P., Sheehan, C.E., Fisher, H.A., Kaufman, R.A., Kallakury, B.V. Mod. Pathol. (2003) [Pubmed]
  6. Conditionally replicating adenovirus expressing TIMP2 for ovarian cancer therapy. Yang, S.W., Cody, J.J., Rivera, A.A., Waehler, R., Wang, M., Kimball, K.J., Alvarez, R.A., Siegal, G.P., Douglas, J.T., Ponnazhagan, S. Clin. Cancer Res. (2011) [Pubmed]
  7. Recent advances in the regulation of matrix metalloproteinase 2 activation: from basic research to clinical implication (Review). Yoshizaki, T., Sato, H., Furukawa, M. Oncol. Rep. (2002) [Pubmed]
  8. Mutation of the matrix metalloproteinase 2 gene (MMP2) causes a multicentric osteolysis and arthritis syndrome. Martignetti, J.A., Aqeel, A.A., Sewairi, W.A., Boumah, C.E., Kambouris, M., Mayouf, S.A., Sheth, K.V., Eid, W.A., Dowling, O., Harris, J., Glucksman, M.J., Bahabri, S., Meyer, B.F., Desnick, R.J. Nat. Genet. (2001) [Pubmed]
  9. Expression of genes that contribute to proliferative and metastatic ability in breast cancer resected during various menstrual phases. Saad, Z., Bramwell, V.H., Wilson, S.M., O'Malley, F.P., Jeacock, J., Chambers, A.F. Lancet (1998) [Pubmed]
  10. Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3. Saunders, W.B., Bohnsack, B.L., Faske, J.B., Anthis, N.J., Bayless, K.J., Hirschi, K.K., Davis, G.E. J. Cell Biol. (2006) [Pubmed]
  11. Biophysical and functional characterization of full-length, recombinant human tissue inhibitor of metalloproteinases-2 (TIMP-2) produced in Escherichia coli. Comparison of wild type and amino-terminal alanine appended variant with implications for the mechanism of TIMP functions. Wingfield, P.T., Sax, J.K., Stahl, S.J., Kaufman, J., Palmer, I., Chung, V., Corcoran, M.L., Kleiner, D.E., Stetler-Stevenson, W.G. J. Biol. Chem. (1999) [Pubmed]
  12. Circulating matrix metalloproteinases 1, 2, 9 and their inhibitors TIMP-1 and TIMP-2 as serum markers of liver fibrosis in patients with chronic hepatitis C: comparison with PIIINP and hyaluronic acid. Leroy, V., Monier, F., Bottari, S., Trocme, C., Sturm, N., Hilleret, M.N., Morel, F., Zarski, J.P. Am. J. Gastroenterol. (2004) [Pubmed]
  13. Reconstitution of TIMP-2 expression in SH-SY5Y neuroblastoma cells by 5-azacytidine is mediated transcriptionally by NF-Y through an inverted CCAAT site. Cappabianca, L., Farina, A.R., Tacconelli, A., Mantovani, R., Gulino, A., Mackay, A.R. Exp. Cell Res. (2003) [Pubmed]
  14. Frequent hypermethylation of 5' flanking region of TIMP-2 gene in cervical cancer. Ivanova, T., Vinokurova, S., Petrenko, A., Eshilev, E., Solovyova, N., Kisseljov, F., Kisseljova, N. Int. J. Cancer (2004) [Pubmed]
  15. Synthesis and refolding of human TIMP-2 from E. coli, with specific activity for MMP-2. Negro, A., Onisto, M., Masiero, L., Garbisa, S. FEBS Lett. (1995) [Pubmed]
  16. Platelet release of trimolecular complex components MT1-MMP/TIMP2/MMP2: involvement in MMP2 activation and platelet aggregation. Kazes, I., Elalamy, I., Sraer, J.D., Hatmi, M., Nguyen, G. Blood (2000) [Pubmed]
  17. Characterization of the role of the "MT-loop": an eight-amino acid insertion specific to progelatinase A (MMP2) activating membrane-type matrix metalloproteinases. English, W.R., Holtz, B., Vogt, G., Knäuper, V., Murphy, G. J. Biol. Chem. (2001) [Pubmed]
  18. Cloning of the cDNA encoding human tissue inhibitor of metalloproteinases-3 (TIMP-3) and mapping of the TIMP3 gene to chromosome 22. Apte, S.S., Mattei, M.G., Olsen, B.R. Genomics (1994) [Pubmed]
  19. Soluble latent membrane-type 1 matrix metalloprotease secreted by human mesangial cells is activated by urokinase. Kazes, I., Delarue, F., Hagège, J., Bouzhir-Sima, L., Rondeau, E., Sraer, J.D., Nguyen, G. Kidney Int. (1998) [Pubmed]
  20. Tissue inhibitor of metalloproteinase-3 is up-regulated by transforming growth factor-beta1 in vitro and expressed in fibroblastic foci in vivo in idiopathic pulmonary fibrosis. García-Alvarez, J., Ramirez, R., Checa, M., Nuttall, R.K., Sampieri, C.L., Edwards, D.R., Selman, M., Pardo, A. Exp. Lung Res. (2006) [Pubmed]
  21. Corneal neovascularization suppressed by TIMP2 released from human amniotic membranes. Ma, X., Li, J. Yan ke xue bao = Eye science / "Yan ke xue bao" bian ji bu (2005) [Pubmed]
  22. Role of plasminogen activator and of 92-KDa type IV collagenase in glioblastoma invasion using an in vitro matrigel model. Rao, J.S., Steck, P.A., Tofilon, P., Boyd, D., Ali-Osman, F., Stetler-Stevenson, W.G., Liotta, L.A., Sawaya, R. J. Neurooncol. (1994) [Pubmed]
  23. Effect of calcineurin inhibitors on extracellular matrix turnover in isolated human glomeruli. Esposito, C., Foschi, A., Parrilla, B., Cornacchia, F., Fasoli, G., Plati, A.R., De Mauri, A., Mazzullo, T., Scudellaro, R., Dal Canton, A. Transplant. Proc. (2004) [Pubmed]
  24. Endothelial tubulogenesis within fibrin gels specifically requires the activity of membrane-type-matrix metalloproteinases (MT-MMPs). Lafleur, M.A., Handsley, M.M., Knäuper, V., Murphy, G., Edwards, D.R. J. Cell. Sci. (2002) [Pubmed]
  25. The effect of luteal "rescue" on the expression and localization of matrix metalloproteinases and their tissue inhibitors in the human corpus luteum. Duncan, W.C., McNeilly, A.S., Illingworth, P.J. J. Clin. Endocrinol. Metab. (1998) [Pubmed]
  26. Modulation of neutral protease expression in human mesangial cells by hyperglycaemic culture. Abdel Wahab, N., Mason, R.M. Biochem. J. (1996) [Pubmed]
  27. Epigenetic inactivation of the tissue inhibitor of metalloproteinase-2 (TIMP-2) gene in human prostate tumors. Pulukuri, S.M., Patibandla, S., Patel, J., Estes, N., Rao, J.S. Oncogene (2007) [Pubmed]
  28. 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]
  29. Mechanisms for pro matrix metalloproteinase activation. Murphy, G., Stanton, H., Cowell, S., Butler, G., Knäuper, V., Atkinson, S., Gavrilovic, J. APMIS (1999) [Pubmed]
  30. Activation of progelatinase A and progelatinase A/TIMP-2 complex by membrane type 2-matrix metalloproteinase. Kolkenbrock, H., Hecker-Kia, A., Orgel, D., Ulbrich, N., Will, H. Biol. Chem. (1997) [Pubmed]
  31. Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2. Goldberg, G.I., Marmer, B.L., Grant, G.A., Eisen, A.Z., Wilhelm, S., He, C.S. Proc. Natl. Acad. Sci. U.S.A. (1989) [Pubmed]
  32. TIMP-2 is released as an intact molecule following binding to MT1-MMP on the cell surface. Zucker, S., Hymowitz, M., Conner, C., DeClerck, Y., Cao, J. Exp. Cell Res. (2004) [Pubmed]
  33. 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]
  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. 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]
  36. Expression of matrix metalloproteinases and endogenous inhibitors within ascending aortic aneurysms of patients with Marfan syndrome. Ikonomidis, J.S., Jones, J.A., Barbour, J.R., Stroud, R.E., Clark, L.L., Kaplan, B.S., Zeeshan, A., Bavaria, J.E., Gorman, J.H., Spinale, F.G., Gorman, R.C. Circulation (2006) [Pubmed]
  37. Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. Stetler-Stevenson, W.G., Brown, P.D., Onisto, M., Levy, A.T., Liotta, L.A. J. Biol. Chem. (1990) [Pubmed]
  38. Demonstration in vivo that stromelysin-3 functions through its proteolytic activity. Noël, A., Boulay, A., Kebers, F., Kannan, R., Hajitou, A., Calberg-Bacq, C.M., Basset, P., Rio, M.C., Foidart, J.M. Oncogene (2000) [Pubmed]
  39. Increased matrix metalloproteinase activity and selective upregulation in LV myocardium from patients with end-stage dilated cardiomyopathy. Thomas, C.V., Coker, M.L., Zellner, J.L., Handy, J.R., Crumbley, A.J., Spinale, F.G. Circulation (1998) [Pubmed]
  40. Evidence for altered balance between matrix metalloproteinases and their inhibitors in human aortic diseases. Knox, J.B., Sukhova, G.K., Whittemore, A.D., Libby, P. Circulation (1997) [Pubmed]
  41. 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]
  42. Expression and prognostic significance of metalloproteinases and their tissue inhibitors in patients with small-cell lung cancer. Michael, M., Babic, B., Khokha, R., Tsao, M., Ho, J., Pintilie, M., Leco, K., Chamberlain, D., Shepherd, F.A. J. Clin. Oncol. (1999) [Pubmed]
  43. Endometase/matrilysin-2 in human breast ductal carcinoma in situ and its inhibition by tissue inhibitors of metalloproteinases-2 and -4: a putative role in the initiation of breast cancer invasion. Zhao, Y.G., Xiao, A.Z., Park, H.I., Newcomer, R.G., Yan, M., Man, Y.G., Heffelfinger, S.C., Sang, Q.X. Cancer Res. (2004) [Pubmed]
  44. Tissue and serum loss of metalloproteinase inhibitors in high grade soft tissue sarcomas. Benassi, M.S., Magagnoli, G., Ponticelli, F., Pazzaglia, L., Zanella, L., Gamberi, G., Ragazzini, P., Ferrari, C., Mercuri, M., Picci, P. Histol. Histopathol. (2003) [Pubmed]
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