TIMP1

TIMP1 is an inhibitory molecule that regulates matrix metalloproteinases (MMPs) and disintegrin-metalloproteinases (ADAMs and ADAMTSs) through binding of the TIMP1 N-terminal domain to the metalloproteinase active site.{{cite journal | vauthors = Brew K, Nagase H | title = The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity | journal = Biochimica et Biophysica Acta (BBA) - Molecular Cell Research | volume = 1803 | issue = 1 | pages = 55–71 | date = January 2010 | pmid = 20080133 | pmc = 2853873 | doi = 10.1016/j.bbamcr.2010.01.003 }} It has also been suggested that the C-terminal domain of TIMP1 can bind to the inactive precursors pro-MMP-2 and pro-MMP-9.{{Cite journal | vauthors = Olson MW, Gervasi DC, Mobashery S, Fridman R | title = Kinetic Analysis of the Binding of Human Matrix Metalloproteinase-2 and -9 to Tissue Inhibitor of Metalloproteinase (TIMP)-1 and TIMP-2* | journal = The Journal of Biological Chemistry | volume = 272 | issue = 47 | pages = 29975–29983 | date = 1997-11-21 | pmid = 9368077 | doi = 10.1074/jbc.272.47.29975 | doi-access = free | issn = 0021-9258 }} In regulating MMPs, TIMP1 plays a crucial role in extracellular matrix (ECM) composition, wound healing,{{cite journal | vauthors = Brew K, Dinakarpandian D, Nagase H | title = Tissue inhibitors of metalloproteinases: evolution, structure and function | journal = Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology | volume = 1477 | issue = 1–2 | pages = 267–283 | date = March 2000 | pmid = 10708863 | doi = 10.1016/S0167-4838(99)00279-4 }} and pregnancy.{{cite journal | vauthors = Graham CH, Lala PK | title = Mechanism of control of trophoblast invasion in situ | journal = Journal of Cellular Physiology | volume = 148 | issue = 2 | pages = 228–234 | date = August 1991 | pmid = 1652588 | doi = 10.1002/jcp.1041480207 | s2cid = 3145982 }}{{cite journal | vauthors = Nothnick WB, Soloway P, Curry TE | title = Assessment of the role of tissue inhibitor of metalloproteinase-1 (TIMP-1) during the periovulatory period in female mice lacking a functional TIMP-1 gene | journal = Biology of Reproduction | volume = 56 | issue = 5 | pages = 1181–1188 | date = May 1997 | pmid = 9160717 | doi = 10.1095/biolreprod56.5.1181 | doi-access = free }}{{cite journal | vauthors = Nothnick WB | title = Disruption of the tissue inhibitor of metalloproteinase-1 gene results in altered reproductive cyclicity and uterine morphology in reproductive-age female mice | journal = Biology of Reproduction | volume = 63 | issue = 3 | pages = 905–912 | date = September 2000 | pmid = 10952938 | doi = 10.1095/biolreprod63.3.905 | doi-access = free }}

The dysregulated activity of TIMP1 has been implicated in inflammation, cancer, and fibrosis.{{Cite journal | vauthors = Schoeps B, Frädrich J, Krüger A | title = Cut loose TIMP-1: an emerging cytokine in inflammation | journal = Trends in Cell Biology | volume = 33 | issue = 5 | pages = 413–426 | date = May 2023 | pmid = 36163148 | doi = 10.1016/j.tcb.2022.08.005 | issn = 0962-8924 }}{{Cite journal | vauthors = Takawale A, Zhang P, Patel VB, Wang X, Oudit G, Kassiri Z | title = Tissue Inhibitor of Matrix Metalloproteinase-1 Promotes Myocardial Fibrosis by Mediating CD63–Integrin β1 Interaction | journal = Hypertension | location = Dallas, Tex. | volume = 69 | issue = 6 | pages = 1092–1103 | date = June 2017 | pmid = 28373589 | doi = 10.1161/HYPERTENSIONAHA.117.09045 | url = https://www.ahajournals.org/doi/full/10.1161/HYPERTENSIONAHA.117.09045 }}{{cite journal | vauthors = Kim YS, Kim SH, Kang JG, Ko JH | title = Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression | journal = BMB Reports | volume = 45 | issue = 11 | pages = 623–628 | date = Nov 2012 | pmid = 23187000 | pmc = 4133808 | doi = 10.5483/BMBRep.2012.45.11.233 }} In pregnancy, TIMP1 plays a regulatory role in the process of implantation, particularly the cytotrophoblast invasion of the uterine endometrium.{{cite journal | vauthors = Graham CH, Lala PK | title = Mechanism of control of trophoblast invasion in situ | journal = Journal of Cellular Physiology | volume = 148 | issue = 2 | pages = 228–234 | date = August 1991 | pmid = 1652588 | doi = 10.1002/jcp.1041480207 | s2cid = 3145982 }} Additionally, it plays a role in regulating the transcriptional profile of fetal and placental tissues associated with the early stages of pregnancy.{{cite journal | vauthors = Vincent ZL, Mitchell MD, Ponnampalam AP | title = Regulation of TIMP-1 in Human Placenta and Fetal Membranes by lipopolysaccharide and demethylating agent 5-aza-2'-deoxycytidine | journal = Reproductive Biology and Endocrinology : RB&E | volume = 13 | pages = 136 | date = December 2015 | pmid = 26691525 | pmc = 4687108 | doi = 10.1186/s12958-015-0132-y | doi-access = free }} Studies attribute this role to a mechanism involving the chromatin structure at the TIMP1 promoter region, implicating new pharmaceutical possibilities for the therapeutic regulation of TIMP1. Accordingly, TIMP1 can be manipulated in vitro using techniques, like the TIMP1 knock-out.{{cite journal | vauthors = Gong Y, Scott E, Lu R, Xu Y, Oh WK, Yu Q | title = TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression | journal = PLOS ONE | volume = 8 | issue = 10 | pages = e77366 | date = 2013-10-15 | pmid = 24143225 | pmc = 3797040 | doi = 10.1371/journal.pone.0077366 | bibcode = 2013PLoSO...877366G | doi-access = free }}{{cite journal | vauthors = Jourquin J, Tremblay E, Bernard A, Charton G, Chaillan FA, Marchetti E, Roman FS, Soloway PD, Dive V, Yiotakis A, Khrestchatisky M, Rivera S | title = Tissue inhibitor of metalloproteinases-1 (TIMP-1) modulates neuronal death, axonal plasticity, and learning and memory | journal = The European Journal of Neuroscience | volume = 22 | issue = 10 | pages = 2569–2578 | date = November 2005 | pmid = 16307599 | doi = 10.1111/j.1460-9568.2005.04426.x | s2cid = 18499513 }}{{cite journal | vauthors = Graham CH, Lala PK | title = Mechanism of control of trophoblast invasion in situ | journal = Journal of Cellular Physiology | volume = 148 | issue = 2 | pages = 228–234 | date = August 1991 | pmid = 1652588 | doi = 10.1002/jcp.1041480207 | s2cid = 3145982 }}

While traditionally reported for its protease-inhibiting ability, the C-terminal domain of TIMP1 has been shown to bind to cell-surface receptors including the tetraspanins CD63 and CD82.{{Cite journal | vauthors = Jung KK, Liu XW, Chirco R, Fridman R, Kim HR | title = Identification of CD63 as a tissue inhibitor of metalloproteinase-1 interacting cell surface protein | journal = The EMBO Journal | volume = 25 | issue = 17 | pages = 3934–3942 | date = 2006-08-17 | pmid = 16917503 | pmc = 1560352 | doi = 10.1038/sj.emboj.7601281 | issn = 0261-4189 }} These interactions can activate downstream signaling pathways including the MAPK pathway.{{Cite journal | vauthors = Chirco R, Liu XW, Jung KK, Kim HR | title = Novel functions of TIMPs in cell signaling | journal = Cancer Metastasis Reviews | volume = 25 | issue = 1 | pages = 99–113 | date = March 2006 | pmid = 16680576 | doi = 10.1007/s10555-006-7893-x | issn = 0167-7659 }}

• Erythroid potentiating activity (EPA)
• Human collagenase inhibitor (HCI)

Transcription of this gene is highly inducible in response to many cytokines and hormones. In addition, the expression from some but not all inactive X chromosomes suggests that this gene inactivation is polymorphic in human females. This gene is located within intron 6 of the synapsin I gene and is transcribed in the opposite direction.{{cite web | title = Entrez Gene: TIMP1 TIMP metallopeptidase inhibitor 1 | url = https://www.ncbi.nlm.nih.gov/sites/entrez?Db=gene&Cmd=ShowDetailView&TermToSearch=7076 }}

In adrenocortical cells the trophic hormone ACTH induces expression of TIMP-1 and the increase in TIMP expression is also associated with decreased collagenase activity.{{cite journal | vauthors = Reichenstein M, Reich R, LeHoux JG, Hanukoglu I | title = ACTH induces TIMP-1 expression and inhibits collagenase in adrenal cortex cells | journal = Molecular and Cellular Endocrinology | volume = 215 | issue = 1–2 | pages = 109–114 | date = February 2004 | pmid = 15026182 | doi = 10.1016/j.mce.2003.11.011 | citeseerx = 10.1.1.538.7614 | s2cid = 6836003 }}

Increased expression of TIMP1 has been found to be associated with worse prognosis of various tumors, such as laryngeal carcinoma{{cite journal | vauthors = Ma J, Wang J, Fan W, Pu X, Zhang D, Fan C, Xiong L, Zhu H, Xu N, Chen R, Liu S | title = Upregulated TIMP-1 correlates with poor prognosis of laryngeal squamous cell carcinoma | journal = International Journal of Clinical and Experimental Pathology | volume = 7 | issue = 1 | pages = 246–254 | date = Dec 2013 | pmid = 24427345 | pmc = 3885479 }} or melanoma.{{cite journal | vauthors = Tarhini AA, Lin Y, Yeku O, LaFramboise WA, Ashraf M, Sander C, Lee S, Kirkwood JM | title = A four-marker signature of TNF-RII, TGF-α, TIMP-1 and CRP is prognostic of worse survival in high-risk surgically resected melanoma | journal = Journal of Translational Medicine | volume = 12 | pages = 19 | date = January 2014 | pmid = 24457057 | pmc = 3909384 | doi = 10.1186/1479-5876-12-19 | doi-access = free }}

• TIMP2, TIMP3, TIMP4

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• {{cite journal | vauthors = Hornebeck W | title = Down-regulation of tissue inhibitor of matrix metalloprotease-1 (TIMP-1) in aged human skin contributes to matrix degradation and impaired cell growth and survival | journal = Pathologie-biologie | volume = 51 | issue = 10 | pages = 569–573 | date = December 2003 | pmid = 14622947 | doi = 10.1016/j.patbio.2003.09.003 }}
• {{cite journal | vauthors = Gardner J, Ghorpade A | title = Tissue inhibitor of metalloproteinase (TIMP)-1: the TIMPed balance of matrix metalloproteinases in the central nervous system | journal = Journal of Neuroscience Research | volume = 74 | issue = 6 | pages = 801–806 | date = December 2003 | pmid = 14648584 | pmc = 3857704 | doi = 10.1002/jnr.10835 }}

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• The MEROPS online database for peptidases and their inhibitors: [http://merops.sanger.ac.uk/cgi-bin/merops.cgi?id=I35.001 I35.001]
• {{PDBe-KB2|P01033|Metalloproteinase inhibitor 1}}

{{PDB Gallery|geneid=7076}}