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Gene Review

TIMP2  -  TIMP metallopeptidase inhibitor 2

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Disease relevance of TIMP2


Psychiatry related information on TIMP2


High impact information on TIMP2


Biological context of TIMP2


Anatomical context of TIMP2

  • The treatment of BESCs with 12-O-tetradecanoylphorbol 13-acetate resulted in a significant increase in the level of TIMP-1 but a significant decrease in the level of TIMP-2 in the stromal cells [15].
  • These results suggest that the expression of MMPs and TIMPs is differentially regulated by cytokines and growth factors and that the production of TIMP-1 and TIMP-2 may not be accompanied by changes in their mRNA expression in bovine endometrium and trophoblasts [15].
  • Immunohistochemical analysis of ulcer biopsies for MMP-2, -9, and TIMP-2 expression showed a reduction in the number of MMP-2-positive dermal fibroblasts in the mitogenic bovine whey extract-treated ulcers compared with pretreatment biopsies (p<0.05) that persisted over the course of the study [1].
  • The localization of proteins for MMP-1, MMP-14, and TIMP-2 showed a similar trend with strong staining intensity in cytoplasm of mammary duct and alveolar epithelial cells during pubertal mammogenesis and late involution [16].
  • Pretreatment with vitamin E (1 mM) and TIMP-2 (50 microg/ml) reversed the effect produced by H2O2 (1 mM) on Na+ dependent Ca2+ uptake in the microsomes [17].

Associations of TIMP2 with chemical compounds

  • The induction of TIMP-2 by ACTH required transcription, was mimicked by 8-bromo cyclic 3'-5' adenosine monophosphate, but was not observed in response to angiotensin II, IGF-1, fibroblast growth factor-2, transforming growth factor-beta1, or cortisol treatments [18].
  • Matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitor-2 of matrix metalloproteinases (TIMP-2) in the placenta and interplacental uterine wall in normal cows and in cattle with retention of fetal membranes [12].
  • Additionally, O2*- -induced inhibition of Na+-dependent Ca2+ uptake was reversed by SOD and TIMP-2 (50 microg ml(-1)) [19].
  • The 72 kDa protease activity was found to be inhibited by EGTA and the tissue inhibitor of metalloprotease-2 (TIMP-2) [20].
  • Heparin sepharose purified preparation of 72 kDa progelatinase is composed of two distinct population of zymogens: a 72 kDa progelatinase tightly complexed with TIMP-2 (an ambient tissue inhibitor of metalloprotease in the smooth muscle plasma membrane), and a native 72 kDa progelatinase free of any detectable TIMP-2 [21].

Physical interactions of TIMP2

  • Heparin-sepharose (100 mM NaCl eluate)-purified preparation contained the MMP-2/TIMP-2 complex [22].

Regulatory relationships of TIMP2

  • These results demonstrate that cellular outgrowth from bovine ICM is supported by fibronectin and is stimulated by TIMP-2 [23].

Other interactions of TIMP2

  • In contrast, a transient increase in the number of MMP-9- and TIMP-2-positive cells was observed in mitogenic bovine whey extract treated ulcer biopsies compared with pretreatment levels (p<0.05) [1].
  • The oxidant triggered protease activity and the Ca2+ATPase activity were found to be prevented by the antioxidant vitamin E, and also by the Ca2+ dependent matrix metalloprotease inhibitors: EGTA and TIMP-2 [20].
  • Conversely, the 140 kDa fragment blocked MMP-2 and -9 stimulation and doubled TIMP-2 expression, leading to inhibition of endothelial chemoinvasion induced by fibroblast growth factor-2 (FGF-2) [14].
  • Ovine large luteal cells may be the primary type of cell responsible for controlling the extent of remodelling of luteal ECM since they produce TIMP-1, TIMP-2 and plasminogen activator inhibitor 1 [24].
  • RNAase dimer, PDC-109 and metalloproteinase inhibitor (TIMP-2) were identified [25].

Analytical, diagnostic and therapeutic context of TIMP2


  1. Mitogenic bovine whey extract modulates matrix metalloproteinase-2, -9, and tissue inhibitor of matrix metalloproteinase-2 levels in chronic leg ulcers. Varelias, A., Cowin, A.J., Adams, D., Harries, R.H., Cooter, R.D., Belford, D.A., Fitridge, R.A., Rayner, T.E. Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society. (2006) [Pubmed]
  2. Role of MMP-2 in PKCdelta-mediated inhibition of Na+ dependent Ca2+ uptake in microsomes of pulmonary smooth muscle: involvement of a pertussis toxin sensitive protein. Chakraborti, S., Mandal, A., Das, S., Chakraborti, T. Mol. Cell. Biochem. (2005) [Pubmed]
  3. Tissue inhibitor of metalloproteinase-2 (TIMP-2) mRNA is constitutively expressed in bovine, human normal, and osteoarthritic articular chondrocytes. Zafarullah, M., Su, S., Martel-Pelletier, J., DiBattista, J.A., Costello, B.G., Stetler-Stevenson, W.G., Pelletier, J.P. J. Cell. Biochem. (1996) [Pubmed]
  4. Insulin stimulates secretion of a collagenase inhibitor by Swarm rat chondrosarcoma chondrocytes. Harper, J., Harper, E. Biochem. Biophys. Res. Commun. (1987) [Pubmed]
  5. Morphology of osteoclasts in resorbing fetal rat bone explants: effects of PTH and AIF in vitro. Wezeman, F.H., Kuettner, K.E., Horton, J.E. Anat. Rec. (1979) [Pubmed]
  6. Retinoids modulate endothelial cell production of matrix-degrading proteases and tissue inhibitors of metalloproteinases (TIMP). Braunhut, S.J., Moses, M.A. J. Biol. Chem. (1994) [Pubmed]
  7. Crystal structure of the complex formed by the membrane type 1-matrix metalloproteinase with the tissue inhibitor of metalloproteinases-2, the soluble progelatinase A receptor. Fernandez-Catalan, C., Bode, W., Huber, R., Turk, D., Calvete, J.J., Lichte, A., Tschesche, H., Maskos, K. EMBO J. (1998) [Pubmed]
  8. The role of interstitial collagens in cleft formation of mouse embryonic submandibular gland during initial branching. Fukuda, Y., Masuda, Y., Kishi, J., Hashimoto, Y., Hayakawa, T., Nogawa, H., Nakanishi, Y. Development (1988) [Pubmed]
  9. Effect of hypoxia and reoxygenation on gene expression and response to interleukin-1 in cultured articular chondrocytes. Martin, G., Andriamanalijaona, R., Grässel, S., Dreier, R., Mathy-Hartert, M., Bogdanowicz, P., Boumédiene, K., Henrotin, Y., Bruckner, P., Pujol, J.P. Arthritis Rheum. (2004) [Pubmed]
  10. Purification and partial amino acid sequence of a bovine cartilage-derived collagenase inhibitor. Murray, J.B., Allison, K., Sudhalter, J., Langer, R. J. Biol. Chem. (1986) [Pubmed]
  11. Expression of messenger ribonucleic acid encoding tissue inhibitor of metalloproteinases-2 within ovine follicles and corpora lutea. Smith, G.W., McCrone, S., Petersen, S.L., Smith, M.F. Endocrinology (1995) [Pubmed]
  12. Matrix metalloproteinases (MMP-2 and MMP-9) and tissue inhibitor-2 of matrix metalloproteinases (TIMP-2) in the placenta and interplacental uterine wall in normal cows and in cattle with retention of fetal membranes. Walter, I., Boos, A. Placenta (2001) [Pubmed]
  13. Identification of matrix metalloproteinases and metalloproteinase inhibitors in bovine corpora lutea and their variation during the estrous cycle. Goldberg, M.J., Moses, M.A., Tsang, P.C. J. Anim. Sci. (1996) [Pubmed]
  14. ERK1-2 and p38 MAPK regulate MMP/TIMP balance and function in response to thrombospondin-1 fragments in the microvascular endothelium. Donnini, S., Morbidelli, L., Taraboletti, G., Ziche, M. Life Sci. (2004) [Pubmed]
  15. Differential regulation of the expression of matrix metalloproteinases and tissue inhibitors of metalloproteinases by cytokines and growth factors in bovine endometrial stromal cells and trophoblast cell line BT-1 in vitro. Hirata, M., Sato, T., Tsumagari, M., Shimada, A., Nakano, H., Hashizume, K., Ito, A. Biol. Reprod. (2003) [Pubmed]
  16. Expression and localization of extracellular matrix-degrading proteinases and their inhibitors in the bovine mammary gland during development, function, and involution. Rabot, A., Sinowatz, F., Berisha, B., Meyer, H.H., Schams, D. J. Dairy Sci. (2007) [Pubmed]
  17. Role of MMP-2 in inhibiting Na+ dependent Ca2+ uptake by H2O2 in microsomes isolated from pulmonary smooth muscle. Mandal, A., Chakraborti, T., Choudhury, R., Ghosh, B., Ghosh, A.N., Das, S., Chakraborti, S. Mol. Cell. Biochem. (2005) [Pubmed]
  18. Tissue inhibitor of metalloproteinase-2 (TIMP-2) expression is strongly induced by ACTH in adrenocortical cells. Quirin, N., Keramidas, M., Garin, J., Chambaz, E., Feige, J.J. J. Cell. Physiol. (1999) [Pubmed]
  19. Matrix metalloproteinase-2-mediated inhibition of Na+-dependent Ca+ uptake by superoxide radicals (O2*-) in microsomes of pulmonary smooth muscle. Mandal, A., Chakraborti, T., Das, S., Ghosh, B., Ghosh, A., Chakraborti, S. IUBMB Life (2004) [Pubmed]
  20. Role of membrane-associated Ca+ dependent matrix metalloprotease-2 in the oxidant activation of Ca2+Atpase by tertiary butylhydroperoxide. Das, S., Chakraborti, T., Mandal, M., Mandal, A., Chakraborti, S. Mol. Cell. Biochem. (2002) [Pubmed]
  21. Identification, purification and characterization of matrix metalloproteinase-2 in bovine pulmonary artery smooth muscle plasma membrane. Das, S., Mandal, M., Mandal, A., Chakraborti, T., Chakraborti, S. Mol. Cell. Biochem. (2004) [Pubmed]
  22. Isolation of MMP-2 from MMP-2/TIMP-2 complex: characterization of the complex and the free enzyme in pulmonary vascular smooth muscle plasma membrane. Das, S., Mandal, M., Chakraborti, T., Mandal, A., Chakraborti, S. Biochim. Biophys. Acta (2004) [Pubmed]
  23. Evaluation of extracellular matrix proteins and tissue inhibitor of matrix metalloproteinases-2 on bovine inner cell mass outgrowth in vitro. Schilperoort-Haun, K.R., Menino, A.R. In Vitro Cell. Dev. Biol. Anim. (2002) [Pubmed]
  24. Regulation of ovarian extracellular matrix remodelling by metalloproteinases and their tissue inhibitors: effects on follicular development, ovulation and luteal function. Smith, M.F., McIntush, E.W., Ricke, W.A., Kojima, F.N., Smith, G.W. J. Reprod. Fertil. Suppl. (1999) [Pubmed]
  25. D-fructose-binding proteins in bull seminal plasma: isolation and characterization. Liberda, J., Kraus, M., Ryslavá, H., Vlasáková, M., Jonáková, V., Tichá, M. Folia Biol. (Praha) (2001) [Pubmed]
  26. Basement membrane integrity and keratinization in healthy and ulcerated bovine hoof tissue. Hendry, K.A., Knight, C.H., Galbraith, H., Wilde, C.J. J. Dairy Res. (2003) [Pubmed]
  27. Three-dimensional structure of human tissue inhibitor of metalloproteinases-2 at 2.1 A resolution. Tuuttila, A., Morgunova, E., Bergmann, U., Lindqvist, Y., Maskos, K., Fernandez-Catalan, C., Bode, W., Tryggvason, K., Schneider, G. J. Mol. Biol. (1998) [Pubmed]
  28. Identification of a heparin-binding protein in bovine seminal fluid as tissue inhibitor of metalloproteinases-2. McCauley, T.C., Zhang, H.M., Bellin, M.E., Ax, R.L. Mol. Reprod. Dev. (2001) [Pubmed]
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