Encyclopedia of Signaling Molecules

2018 Edition
| Editors: Sangdun Choi

Tissue Inhibitor of Metalloproteinase

  • Marcello G. Masciantonio
  • Sean E. GillEmail author
Reference work entry
DOI: https://doi.org/10.1007/978-3-319-67199-4_101950


Historical Background

In mammals, the tissue inhibitor of metalloproteinase (TIMP) family is comprised of four members, TIMP1-4. TIMPs are the primary inhibitors of metalloproteinases, such as the matrix metalloprotease (MMP) family, a disintegrin and metalloproteinase (ADAM) family, and the ADAMs with thrombospondin motifs (ADAMTS) family (Brew and Nagase 2010). TIMPs range in size from 22 to 28 kDA and are variably glycosylated (Murphy 2011). Further, each TIMP contains two distinct domains, an N-terminal and C-terminal domain of ∼125 and 65 amino acids, respectively, connected through six conserved disulfide bonds (Brew and Nagase 2010; Murphy 2011). Each of these domains has critical roles in controlling TIMP function and localization.

The N-terminal domain, which folds independently and is composed of three α helices and five β strands arranged in a twisted β barrel, is critical for the inhibition of...

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  1. Brew K, Nagase H. The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity. Biochim Biophys Acta. 2010;1803(1):55–71. doi:10.1016/j.bbamcr.2010.01.003.CrossRefPubMedPubMedCentralGoogle Scholar
  2. Chen P, McGuire JK, Hackman RC, Kim K-H, Black RA, Poindexter K, et al. Tissue inhibitor of metalloproteinase-1 moderates airway re-epithelialization by regulating matrilysin activity. Am J Pathol. 2008;172(5):1256–70. doi:10.2353/ajpath.2008.070891.CrossRefPubMedPubMedCentralGoogle Scholar
  3. Chirco R, Liu XW, Jung KK, Kim HRC. Novel functions of TIMPs in cell signaling. Cancer Metastasis Rev. 2006;25:99–113. doi:10.1007/s10555-006-7893-x.CrossRefPubMedPubMedCentralGoogle Scholar
  4. Del Campo SEM, Latchana N, Levine KM, Grignol VP, Fairchild ET, Jaime-Ramirez AC, et al. MiR-21 enhances melanoma invasiveness via inhibition of tissue inhibitor of metalloproteinases 3 expression: in vivo effects of MiR-21 inhibitor. PLoS One. 2015;10(1):1–19. doi:10.1371/journal.pone.0115919.CrossRefGoogle Scholar
  5. Edwards DR, Handsley MM, Pennington CJ. The ADAM metalloproteinases. Mol Asp Med. 2008;29:258–89. doi:10.1016/j.mam.2008.08.001.CrossRefGoogle Scholar
  6. Endo K, Takino T, Miyamori H, Kinsen H, Yoshizaki T, Furukawa M, et al. Cleavage of syndecan-1 by membrane type matrix metalloproteinase-1 stimulates cell migration. J Biol Chem. 2003;278(42):40764–70. doi:10.1074/jbc.M306736200.CrossRefPubMedPubMedCentralGoogle Scholar
  7. Fassina G, Ferrari N, Brigati C, Benelli R, Santi L, Noonan DM, et al. Tissue inhibitors of metalloproteases: regulation and biological activities. Clin Exp Metastasis. 2000;18:111–20. doi:10.1023/A:1006797522521.CrossRefPubMedPubMedCentralGoogle Scholar
  8. Gill SE, Pape MC, Leco KJ. Tissue inhibitor of metalloproteinases 3 regulates extracellular matrix-cell signaling during bronchiole branching morphogenesis. Dev Biol. 2006;298:540–54. doi:10.1016/j.ydbio.2006.07.004.CrossRefPubMedPubMedCentralGoogle Scholar
  9. Gill SE, Huizar I, Bench EM, Sussman SW, Wang Y, Khokha R, et al. Tissue inhibitor of metalloproteinases 3 regulates resolution of inflammation following acute lung injury. Am J Pathol. 2010;176(1):64–73. doi:10.2353/ajpath.2010.090158.CrossRefPubMedPubMedCentralGoogle Scholar
  10. Jung K-K, Liu X-W, Chirco R, Fridman R, Kim H-RC. Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein. EMBO J. 2006;25:3934–42. doi:10.1038/sj.emboj.7601281.CrossRefPubMedPubMedCentralGoogle Scholar
  11. Khokha R, Murthy A, Weiss A. Metalloproteinases and their natural inhibitors in inflammation and immunity. Nat Rev Immunol. 2013;13:649–65. doi:10.1038/nri3499.CrossRefPubMedPubMedCentralGoogle Scholar
  12. Kim HI, Lee H, Kim TH, Lee J, Lee S, Lee S. Growth-stimulatory activity of TIMP-2 is mediated through c-Src activation followed by activation of FAL, PI3-kinase/AKT, and ERK1/2 independent of MMP inhibition in lung adenocarcinoma cells. Oncotarget. 2015;6(40):42905–22.PubMedPubMedCentralCrossRefGoogle Scholar
  13. Lorente L, Martín MM, Solé-Vioĺn J, Blanquer J, Labarta L, Díaz C, et al. Association of sepsis-related mortality with early increase of TIMP-1/MMP-9 ratio. PLoS One. 2014;9(4):e94318. doi:10.1371/journal.pone.0094318.CrossRefPubMedPubMedCentralGoogle Scholar
  14. Melendez-Zajgla J, Del Pozo L, Ceballos G, Maldonado V. Tissue inhibitor of metalloproteinases-4: the road less traveled. Mol Cancer. 2008;7:85. doi:10.1186/1476-4598-7-85.CrossRefPubMedPubMedCentralGoogle Scholar
  15. Murphy G. Tissue inhibitors of metalloproteinases. Genome Biol. 2011;12:233.PubMedPubMedCentralCrossRefGoogle Scholar
  16. Seo D-W, Li H, Qu C-K, Oh J, Kim Y-S, Diaz T, et al. Shp-1 mediates the antiproliferative activity of tissue inhibitor of metalloproteinase-2 in human microvascular endothelial cells. J Biol Chem. 2006;281(6):3711–21. doi:10.1074/jbc.M509932200.CrossRefPubMedPubMedCentralGoogle Scholar
  17. Stetler-Stevenson WG. Tissue inhibitors of metalloproteinases in cell signaling: metalloproteinase-independent biological activities. Sci Signal. 2008;1(27):re6. doi:10.1126/scisignal.127re6.CrossRefPubMedPubMedCentralGoogle Scholar
  18. Takawale A, Fan D, Basu R, Shen M, Parajuli N, Wang W, et al. Myocardial recovery from ischemia-reperfusion is compromised in the absence of tissue inhibitor of metalloproteinase 4. Circ Heart Fail. 2014;7(4):652–62. doi:10.1161/CIRCHEARTFAILURE.114.001113.CrossRefPubMedPubMedCentralGoogle Scholar
  19. Westhoff JH, Tönshoff B, Waldherr S, Pöschi J, Teufel U, Westhoff TH, et al. Urinary tissue inhibitor of metalloproteinase-2 (TIMP-2)- insulin-like growth factor-binding protein 7 (IGFBP7) predicts adverse outcome in pediatric acute kidney injury. PLoS One. 2015;10(11):1–16. doi:10.1371/journal.pone.0143628.CrossRefGoogle Scholar
  20. Yan A, Yang C, Chen Z, Li C, Cai L. MiR-761 promotes progression and metastasis of non-small cell lung cancer by targeting ING4 and TIMP2. Cell Physiol Biochem. 2015;37(1):55–66. doi:10.1159/000430333.CrossRefPubMedPubMedCentralGoogle Scholar

Copyright information

© Springer International Publishing AG 2018

Authors and Affiliations

  1. 1.Centre for Critical Illness ResearchLawson Health Research InstituteLondonCanada
  2. 2.Division of RespirologySchulich School of Medicine and Dentistry, Western UniversityLondonCanada
  3. 3.Department of MedicineSchulich School of Medicine and Dentistry, Western UniversityLondonCanada
  4. 4.Department of Physiology and PharmacologySchulich School of Medicine and Dentistry, Western UniversityLondonCanada