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Gene Review

TIMP4  -  TIMP metallopeptidase inhibitor 4

Homo sapiens

Synonyms: Metalloproteinase inhibitor 4, TIMP-4, Tissue inhibitor of metalloproteinases 4
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Disease relevance of TIMP4


High impact information on TIMP4

  • However, TIMP-4 protein was significantly reduced in ICM myocardium [6].
  • TIMP-2 and TIMP-4 also inhibited the activation of pro-MMP-9 by MMP-26 in vitro [1].
  • However, here we report that systemic administration of human TIMP-4 by electroporation-mediated i.m. injection of naked TIMP-4 DNA stimulates tumorigenesis of human breast cancer cells in nude mice [7].
  • Total conversion of tissue inhibitor of metalloproteinase (TIMP) for specific metalloproteinase targeting: fine-tuning TIMP-4 for optimal inhibition of tumor necrosis factor-{alpha}-converting enzyme [8].
  • Transplantation of only three residues, Pro-Phe-Gly, onto the AB-loop of N-TIMP-4 resulted in a 10-fold enhancement in binding affinity; the K(i) values of the resultant mutant were almost comparable with that of TIMP-3 [8].

Biological context of TIMP4


Anatomical context of TIMP4


Associations of TIMP4 with chemical compounds


Physical interactions of TIMP4


Co-localisations of TIMP4


Regulatory relationships of TIMP4

  • However, transfer of both the AB loop and C-terminal domain of TIMP-2 to TIMP-4 generates a mutant that can activate pro-MMP-2 and so demonstrates that both these regions of TIMP-2 are important for the activation process [19].

Other interactions of TIMP4

  • Here we report that tissue inhibitor of metalloproteinases (TIMP)-2 and TIMP-4 are potent inhibitors of MMP-26, with apparent K(i) values of 1.6 and 0.62 nM, respectively [1].
  • The inhibitory properties of TIMP-4 for matrix metalloproteinases (MMPs) were compared to those of TIMP-1 and TIMP-2 [2].
  • In contrast, while MMP-2 and TIMP-4 were localized to both stem and mature CNS cells, their levels of expression were substantially reduced in the latter [20].
  • Stromal immunoreactivity ranged from 6% for TIMP-4 to 87% for MMP-13 [21].
  • Although full-length TIMP-4 displayed negligible activity against TACE, N-TIMP-4 is a slow tight-binding inhibitor with low nanomolar binding affinity [8].

Analytical, diagnostic and therapeutic context of TIMP4

  • The expression levels of MMP-26, MMP-9, TIMP-2, and TIMP-4 proteins in DCIS were significantly higher than those in IDC, atypical intraductal hyperplasia, and normal breast epithelia adjacent to DCIS and IDC by immunohistochemistry and integrated morphometry analysis [1].
  • TIMP-4 expression was seen in RT-PCR, however, only a faint band was visible in all the tissues tested [22].
  • RESULTS: In normal human liver, messenger RNAs (mRNAs) of TIMP-1, -2, and -3, but not of TIMP-4 and none of the 10 MMPs studied, were expressed in DNA microarray [23].
  • METHODS: We administered human TIMP-4 by electroporation-mediated intramuscular injection of naked DNA using the rat adjuvant-induced arthritis (AIA) model [15].
  • Arthritis-inhibiting effects of TIMP-4 may suggest a unique application of this gene therapy method for arthritis [15].


  1. 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]
  2. E. coli expression of TIMP-4 and comparative kinetic studies with TIMP-1 and TIMP-2: insights into the interactions of TIMPs and matrix metalloproteinase 2 (gelatinase A). Troeberg, L., Tanaka, M., Wait, R., Shi, Y.E., Brew, K., Nagase, H. Biochemistry (2002) [Pubmed]
  3. Tissue inhibitor of metalloproteinases 4 (TIMP4) is involved in inflammatory processes of human cardiovascular pathology. Koskivirta, I., Rahkonen, O., Mäyränpää, M., Pakkanen, S., Husheem, M., Sainio, A., Hakovirta, H., Laine, J., Jokinen, E., Vuorio, E., Kovanen, P., Järveläinen, H. Histochem. Cell Biol. (2006) [Pubmed]
  4. Differential expression and localization of TIMP-1 and TIMP-4 in human gliomas. Groft, L.L., Muzik, H., Rewcastle, N.B., Johnston, R.N., Knäuper, V., Lafleur, M.A., Forsyth, P.A., Edwards, D.R. Br. J. Cancer (2001) [Pubmed]
  5. Development and characterization of a new polyclonal antibody specifically against tissue inhibitor of metalloproteinases 4 in human breast cancer. Hurst, D.R., Li, H., Xu, X., Badisa, V.L., Shi, Y.E., Sang, Q.X. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  6. Differential expression of tissue inhibitors of metalloproteinases in the failing human heart. Li, Y.Y., Feldman, A.M., Sun, Y., McTiernan, C.F. Circulation (1998) [Pubmed]
  7. Stimulation of mammary tumorigenesis by systemic tissue inhibitor of matrix metalloproteinase 4 gene delivery. Jiang, Y., Wang, M., Celiker, M.Y., Liu, Y.E., Sang, Q.X., Goldberg, I.D., Shi, Y.E. Cancer Res. (2001) [Pubmed]
  8. Total conversion of tissue inhibitor of metalloproteinase (TIMP) for specific metalloproteinase targeting: fine-tuning TIMP-4 for optimal inhibition of tumor necrosis factor-{alpha}-converting enzyme. Lee, M.H., Rapti, M., Murphy, G. J. Biol. Chem. (2005) [Pubmed]
  9. Invertebrate tissue inhibitor of metalloproteinase: structure and nested gene organization within the synapsin locus is conserved from Drosophila to human. Pohar, N., Godenschwege, T.A., Buchner, E. Genomics (1999) [Pubmed]
  10. Single nucleotide polymorphisms of tissue inhibitor of metalloproteinase genes in familial moyamoya disease. Kang, H.S., Kim, S.K., Cho, B.K., Kim, Y.Y., Hwang, Y.S., Wang, K.C. Neurosurgery (2006) [Pubmed]
  11. Differential expression of tissue inhibitors of metalloproteinases (TIMP-1, -2, -3, and -4) in normal and aberrant wound healing. Vaalamo, M., Leivo, T., Saarialho-Kere, U. Hum. Pathol. (1999) [Pubmed]
  12. TIMP-1, -2, -3, and -4 in idiopathic pulmonary fibrosis. A prevailing nondegradative lung microenvironment? Selman, M., Ruiz, V., Cabrera, S., Segura, L., Ramírez, R., Barrios, R., Pardo, A. Am. J. Physiol. Lung Cell Mol. Physiol. (2000) [Pubmed]
  13. Tissue inhibitors of metalloproteinase expression in human breast cancer: TIMP-3 is associated with adjuvant endocrine therapy success. Span, P.N., Lindberg, R.L., Manders, P., Tjan-Heijnen, V.C., Heuvel, J.J., Beex, L.V., Sweep, C.G. J. Pathol. (2004) [Pubmed]
  14. Expression of matrix metalloproteinase-26 and tissue inhibitor of matrix metalloproteinase-3 and -4 in endometrium throughout the normal menstrual cycle and alteration in users of levonorgestrel implants who experience irregular uterine bleeding. Chegini, N., Rhoton-Vlasak, A., Williams, R.S. Fertil. Steril. (2003) [Pubmed]
  15. Inhibition of adjuvant-induced arthritis by systemic tissue inhibitor of metalloproteinases 4 gene delivery. Celiker, M.Y., Ramamurthy, N., Xu, J.W., Wang, M., Jiang, Y., Greenwald, R., Shi, Y.E. Arthritis Rheum. (2002) [Pubmed]
  16. Identification, regulation and role of tissue inhibitor of metalloproteinases-4 (TIMP-4) in human platelets. Radomski, A., Jurasz, P., Sanders, E.J., Overall, C.M., Bigg, H.F., Edwards, D.R., Radomski, M.W. Br. J. Pharmacol. (2002) [Pubmed]
  17. Endometrial TIMP-4 mRNA is expressed in the stroma, while TIMP-4 protein accumulates in the epithelium and is released to the uterine fluid. Pilka, R., Noskova, V., Domanski, H., Andersson, C., Hansson, S., Casslén, B. Mol. Hum. Reprod. (2006) [Pubmed]
  18. Differential roles of TIMP-4 and TIMP-2 in pro-MMP-2 activation by MT1-MMP. Hernandez-Barrantes, S., Shimura, Y., Soloway, P.D., Sang, Q.A., Fridman, R. Biochem. Biophys. Res. Commun. (2001) [Pubmed]
  19. Characterization of the AB loop region of TIMP-2. Involvement in pro-MMP-2 activation. Rapti, M., Knaüper, V., Murphy, G., Williamson, R.A. J. Biol. Chem. (2006) [Pubmed]
  20. Expression and modulation of matrix metalloproteinase-2 and tissue inhibitors of metalloproteinases in human embryonic CNS stem cells. Frölichsthal-Schoeller, P., Vescovi, A.L., Krekoski, C.A., Murphy, G., Edwards, D.R., Forsyth, P. Neuroreport (1999) [Pubmed]
  21. Differential expression of matrix metalloproteinases and their inhibitors in non-small cell lung cancer. Thomas, P., Khokha, R., Shepherd, F.A., Feld, R., Tsao, M.S. J. Pathol. (2000) [Pubmed]
  22. Presence of four tissue inhibitors of matrix metalloproteinases (TIMP-1, -2, -3 and -4) in human fetal membranes. Fortunato, S.J., Menon, R., Lombardi, S.J. Am. J. Reprod. Immunol. (1998) [Pubmed]
  23. Evaluation of matrix metalloproteinases and their endogenous tissue inhibitors in biliary atresia-associated liver fibrosis. Hsieh, C.S., Chuang, J.H., Huang, C.C., Chou, M.H., Wu, C.L., Lee, S.Y., Chen, C.L. J. Pediatr. Surg. (2005) [Pubmed]
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