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Gene Review

Timp2  -  tissue inhibitor of metalloproteinase 2

Mus musculus

Synonyms: D11Bwg1104e, Metalloproteinase inhibitor 2, TIMP-2, Timp-2, Tissue inhibitor of metalloproteinases 2
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Disease relevance of Timp2


High impact information on Timp2

  • These effects require alpha 3 beta 1 integrin-mediated binding of TIMP-2 to endothelial cells [6].
  • Batimastat treatment did not affect cellular levels of MMP or TIMP-2 mRNAs [7].
  • The effect of batimastat treatment on the accumulation of mRNAs encoding specific MMPs and the tissue inhibitor of metalloproteinases-2 (TIMP-2) in cultured cells, primary tumors, and tumor regrowths was measured by RNA dot blotting and hybridization with complementary probes [7].
  • In other experiments, TIMP-2 was added to the transmigration studies and was shown to reduce T cell transmigration.(ABSTRACT TRUNCATED AT 400 WORDS)[8]
  • Validating these findings by real-time quantitative PCR and layered protein scanning, we identified up-regulation of mitogen-activated protein kinase phosphatase 1 as an effector of the antiangiogenic function of TIMP-2 [9].

Chemical compound and disease context of Timp2


Biological context of Timp2


Anatomical context of Timp2


Associations of Timp2 with chemical compounds

  • Calvariae cultured for as little as 3 h with monensin revealed intracellular staining for MMPs and TIMP-2 in mesenchymal tissues, as well as in cells lining the bone plates [20].
  • The profound and durable increase in TIMP-1 and TIMP-2 proteins suggests an important regulatory role for these antiproteases in the inflammatory and fibrotic responses to bleomycin-induced lung injury [21].
  • In addition, UB branching was inhibited in isolated UB culture (Qiao J, Sakurai H, and Nigam SK. Proc Natl Acad Sci USA 96: 7330-7335, 1999) by TIMP-2 and ilomastat, suggesting a direct role for MMPs in UB branching [22].
  • Treatment of mice with L-NAME had slight effect on the expression of TIMP-1 mRNA on day 5 of pregnancy, and no effect on TIMP-2 mRNA expression during peri-implantation [23].
  • In COS-1 cells, plasma membrane-associated PC5A can be displaced by heparin, suramin, or heparinases I and III and by competition with excess exogenous TIMP-2 [24].

Other interactions of Timp2

  • Mmp14 and the gene for tissue inhibitor of metalloproteinases-2 (Timp2) show a temporally and spatially co-regulated expression during mouse development [12].
  • Similar results were obtained using mouse lungs of different developmental stages, with the addition that in mouse lung, TIMP-2 and TIMP-3 were upregulated as lung development progressed [2].
  • MT3-MMP requires TIMP-2 to accomplish full pro-MMP-2 activation and this process is enhanced in marimastatpretreated cells, consistent with regulation of active enzyme turnover by synthetic MMP inhibitors [25].
  • In conclusion, NO produced by C3-L5 cells promoted tumor-cell invasiveness by altering the balance between MMP-2 and its inhibitors TIMP-2 and 3 [26].
  • We report a dose-dependent increase in secretion of both MMP-2 and tissue inhibitor of metalloproteinases-2 (TIMP-2) in response to vitronectin [27].

Analytical, diagnostic and therapeutic context of Timp2


  1. Regulation of hepatic fibrosis and extracellular matrix genes by the th response: new insight into the role of tissue inhibitors of matrix metalloproteinases. Vaillant, B., Chiaramonte, M.G., Cheever, A.W., Soloway, P.D., Wynn, T.A. J. Immunol. (2001) [Pubmed]
  2. Differential expression of matrix metalloproteinases and their inhibitors in human and mouse lung development. Ryu, J., Vicencio, A.G., Yeager, M.E., Kashgarian, M., Haddad, G.G., Eickelberg, O. Thromb. Haemost. (2005) [Pubmed]
  3. Differential regulation of MMP-9 and TIMP-2 expression in malignant melanoma developed in metallothionein/RET transgenic mice. Asai, M., Kato, M., Asai, N., Iwashita, T., Murakami, H., Kawai, K., Nakashima, I., Takahashi, M. Jpn. J. Cancer Res. (1999) [Pubmed]
  4. Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). Hayakawa, T., Yamashita, K., Ohuchi, E., Shinagawa, A. J. Cell. Sci. (1994) [Pubmed]
  5. Treatment of colorectal liver metastases by adenoviral transfer of tissue inhibitor of metalloproteinases-2 into the liver tissue. Brand, K., Baker, A.H., Perez-Cantó, A., Possling, A., Sacharjat, M., Geheeb, M., Arnold, W. Cancer Res. (2000) [Pubmed]
  6. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Seo, D.W., Li, H., Guedez, L., Wingfield, P.T., Diaz, T., Salloum, R., Wei, B.Y., Stetler-Stevenson, W.G. Cell (2003) [Pubmed]
  7. Effect of matrix metalloproteinase inhibitor batimastat on breast cancer regrowth and metastasis in athymic mice. Sledge, G.W., Qulali, M., Goulet, R., Bone, E.A., Fife, R. J. Natl. Cancer Inst. (1995) [Pubmed]
  8. The induction of 72-kD gelatinase in T cells upon adhesion to endothelial cells is VCAM-1 dependent. Romanic, A.M., Madri, J.A. J. Cell Biol. (1994) [Pubmed]
  9. Modulation of tumor-host interactions, angiogenesis, and tumor growth by tissue inhibitor of metalloproteinase 2 via a novel mechanism. Feldman, A.L., Stetler-Stevenson, W.G., Costouros, N.G., Knezevic, V., Baibakov, G., Alexander, H.R., Lorang, D., Hewitt, S.M., Seo, D.W., Miller, M.S., O'Connor, S., Libutti, S.K. Cancer Res. (2004) [Pubmed]
  10. Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression is regulated by multiple neural differentiation signals. Jaworski, D.M., Pérez-Martínez, L. J. Neurochem. (2006) [Pubmed]
  11. Purification and characterization of two collagenase inhibitors from mouse sarcoma 180 conditioned medium. Rosenthal, R.A., Moses, M.A., Shintani, Y., Megyesi, J.F., Langer, R., Folkman, J. J. Cell. Biochem. (1994) [Pubmed]
  12. The matrix metalloproteinase-14 (MMP-14) gene is structurally distinct from other MMP genes and is co-expressed with the TIMP-2 gene during mouse embryogenesis. Apte, S.S., Fukai, N., Beier, D.R., Olsen, B.R. J. Biol. Chem. (1997) [Pubmed]
  13. Gene encoding a novel murine tissue inhibitor of metalloproteinases (TIMP), TIMP-3, is expressed in developing mouse epithelia, cartilage, and muscle, and is located on mouse chromosome 10. Apte, S.S., Hayashi, K., Seldin, M.F., Mattei, M.G., Hayashi, M., Olsen, B.R. Dev. Dyn. (1994) [Pubmed]
  14. Pattern of messenger ribonucleic acid expression of tissue inhibitors of metalloproteinases (TIMPs) during testicular maturation in male mice lacking a functional TIMP-1 gene. Nothnick, W.B., Soloway, P.D., Curry, T.E. Biol. Reprod. (1998) [Pubmed]
  15. Temporal and spatial expression of tissue inhibitors of metalloproteinases during the natural ovulatory cycle of the mouse. Inderdeo, D.S., Edwards, D.R., Han, V.K., Khokha, R. Biol. Reprod. (1996) [Pubmed]
  16. Cell and agonist-specific regulation of genes for matrix metalloproteinases and their tissue inhibitors by primary glial cells. Crocker, S.J., Milner, R., Pham-Mitchell, N., Campbell, I.L. J. Neurochem. (2006) [Pubmed]
  17. Temporospatial gene expression and protein localization of matrix metalloproteinases and their inhibitors during mouse molar tooth development. Yoshiba, N., Yoshiba, K., Stoetzel, C., Perrin-Schmitt, F., Cam, Y., Ruch, J.V., Lesot, H. Dev. Dyn. (2003) [Pubmed]
  18. 92-kDa type IV collagenase and TIMP-3, but not 72-kDa type IV collagenase or TIMP-1 or TIMP-2, are highly expressed during mouse embryo implantation. Reponen, P., Leivo, I., Sahlberg, C., Apte, S.S., Olsen, B.R., Thesleff, I., Tryggvason, K. Dev. Dyn. (1995) [Pubmed]
  19. Differential regulation of TIMP-1, -2, and -3 mRNA and protein expressions during mouse incisor development. Yoshiba, N., Yoshiba, K., Stoetzel, C., Perrin-Schmitt, F., Cam, Y., Ruch, J.V., Hosoya, A., Ozawa, H., Lesot, H. Cell Tissue Res. (2006) [Pubmed]
  20. Localisation of matrix metalloproteinases and TIMP-2 in resorbing mouse bone. Dew, G., Murphy, G., Stanton, H., Vallon, R., Angel, P., Reynolds, J.J., Hembry, R.M. Cell Tissue Res. (2000) [Pubmed]
  21. Selective induction of tissue inhibitor of metalloproteinase-1 in bleomycin-induced pulmonary fibrosis. Madtes, D.K., Elston, A.L., Kaback, L.A., Clark, J.G. Am. J. Respir. Cell Mol. Biol. (2001) [Pubmed]
  22. Matrix metalloproteinases and their inhibitors regulate in vitro ureteric bud branching morphogenesis. Pohl, M., Sakurai, H., Bush, K.T., Nigam, S.K. Am. J. Physiol. Renal Physiol. (2000) [Pubmed]
  23. Regulation of matrix metalloproteinases (MMPS) and their inhibitors (TIMPS) during mouse peri-implantation: role of nitric oxide. Zhang, X., Wang, H.M., Lin, H.Y., Liu, G.Y., Li, Q.L., Zhu, C. Placenta (2004) [Pubmed]
  24. The cysteine-rich domain of the secreted proprotein convertases PC5A and PACE4 functions as a cell surface anchor and interacts with tissue inhibitors of metalloproteinases. Nour, N., Mayer, G., Mort, J.S., Salvas, A., Mbikay, M., Morrison, C.J., Overall, C.M., Seidah, N.G. Mol. Biol. Cell (2005) [Pubmed]
  25. Differential inhibition of membrane type 3 (MT3)-matrix metalloproteinase (MMP) and MT1-MMP by tissue inhibitor of metalloproteinase (TIMP)-2 and TIMP-3 rgulates pro-MMP-2 activation. Zhao, H., Bernardo, M.M., Osenkowski, P., Sohail, A., Pei, D., Nagase, H., Kashiwagi, M., Soloway, P.D., DeClerck, Y.A., Fridman, R. J. Biol. Chem. (2004) [Pubmed]
  26. Nitric-oxide production by murine mammary adenocarcinoma cells promotes tumor-cell invasiveness. Orucevic, A., Bechberger, J., Green, A.M., Shapiro, R.A., Billiar, T.R., Lala, P.K. Int. J. Cancer (1999) [Pubmed]
  27. Intact vitronectin induces matrix metalloproteinase-2 and tissue inhibitor of metalloproteinases-2 expression and enhanced cellular invasion by melanoma cells. Bafetti, L.M., Young, T.N., Itoh, Y., Stack, M.S. J. Biol. Chem. (1998) [Pubmed]
  28. Stromelysin (MMP-3) synthesis is up-regulated in estrogen-deficient mouse osteoblasts in vivo and in vitro. Breckon, J.J., Papaioannou, S., Kon, L.W., Tumber, A., Hembry, R.M., Murphy, G., Reynolds, J.J., Meikle, M.C. J. Bone Miner. Res. (1999) [Pubmed]
  29. MT-MMP, the cell surface activator of proMMP-2 (pro-gelatinase A), is expressed with its substrate in mouse tissue during embryogenesis. Kinoh, H., Sato, H., Tsunezuka, Y., Takino, T., Kawashima, A., Okada, Y., Seiki, M. J. Cell. Sci. (1996) [Pubmed]
  30. Targeted inhibition of osteopontin expression in the mammary gland causes abnormal morphogenesis and lactation deficiency. Nemir, M., Bhattacharyya, D., Li, X., Singh, K., Mukherjee, A.B., Mukherjee, B.B. J. Biol. Chem. (2000) [Pubmed]
  31. Repetitive nonlethal oxidant injury to retinal pigment epithelium decreased extracellular matrix turnover in vitro and induced sub-RPE deposits in vivo. Marin-Castaño, M.E., Striker, G.E., Alcazar, O., Catanuto, P., Espinosa-Heidmann, D.G., Cousins, S.W. Invest. Ophthalmol. Vis. Sci. (2006) [Pubmed]
  32. Murine subtilisin-like proteinase SPC6 is expressed during embryonic implantation, somitogenesis, and skeletal formation. Rancourt, S.L., Rancourt, D.E. Dev. Genet. (1997) [Pubmed]
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