TIMP1

Last updated
TIMP1
Protein TIMP1 PDB 1d2b.png
Available structures
PDB Ortholog search: PDBe RCSB
Identifiers
Aliases TIMP1 , CLGI, EPA, EPO, HCI, TIMP, TIMP-1, TIMP metallopeptidase inhibitor 1
External IDs OMIM: 305370 MGI: 98752 HomoloGene: 36321 GeneCards: TIMP1
Orthologs
SpeciesHumanMouse
Entrez

7076

21857

Ensembl

ENSG00000102265

ENSMUSG00000001131

UniProt

P01033
Q6FGX5

P12032

RefSeq (mRNA)

NM_003254

NM_001044384
NM_001294280
NM_011593

RefSeq (protein)

NP_003245
NP_003245.1

NP_001037849
NP_001281209
NP_035723

Location (UCSC) Chr X: 47.58 – 47.59 Mb Chr X: 20.74 – 20.74 Mb
PubMed search [3] [4]
Wikidata
View/Edit Human View/Edit Mouse

TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a glycoprotein with a molecular weight of 28 kDa. [5] TIMP1 is expressed from several tissues of organisms.

Contents

This protein is a member of the TIMP family. The glycoprotein is a natural inhibitor of the matrix metalloproteinases (MMPs), a group of peptidases involved in degradation of the extracellular matrix. In addition to its inhibitory role against most of the known MMPs, the encoded protein is able to promote cell proliferation in a wide range of cell types, and may also have an anti-apoptotic function.

Function

TIMP1 is an inhibitory molecule that regulates matrix metalloproteinases (MMPs), and disintegrin-metalloproteinases (ADAMs and ADAMTSs). [6] In regulating MMPs, TIMP1 plays a crucial role in extracellular matrix (ECM) composition, wound healing, [7] and pregnancy. [8] [9] [10]

The dysregulated activity of TIMP1 has been implicated in cancer. [11] In pregnancy, TIMP1 plays a regulatory role in the process of implantation, particularly the cytotrophoblast invasion of the uterine endometrium. [12] Additionally, it plays a role in regulating the transcriptional profile of fetal and placental tissues associated with the early stages of pregnancy. [13] 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. [14] [15] [16]

Other names

Regulation of TIMP expression

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. [17]

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. [18]

Increased expression of TIMP1 has been found to be associated with worse prognosis of various tumors, such as laryngeal carcinoma [19] or melanoma. [20]

See also

Related Research Articles

Matrix metalloproteinases (MMPs), also known as matrix metallopeptidases or matrixins, are metalloproteinases that are calcium-dependent zinc-containing endopeptidases; other family members are adamalysins, serralysins, and astacins. The MMPs belong to a larger family of proteases known as the metzincin superfamily.

Tissue inhibitors of metalloproteinases (TIMPs) are specific endogenous protease inhibitors to the matrix metalloproteinases. There are four TIMPs; TIMP1, TIMP2, TIMP3 and TIMP4. TIMP3 has been observed progressively downregulated in Human papillomavirus-positive neoplastic keratinocytes derived from uterine cervical preneoplastic lesions at different levels of malignancy. For this reason, TIMP3 is likely to be associated with tumorigenesis and may be a potential prognostic marker for uterine cervical preneoplastic lesions progression.

MMP9 Protein-coding gene in the species Homo sapiens

Matrix metallopeptidase 9 (MMP-9), also known as 92 kDa type IV collagenase, 92 kDa gelatinase or gelatinase B (GELB), is a matrixin, a class of enzymes that belong to the zinc-metalloproteinases family involved in the degradation of the extracellular matrix. In humans the MMP9 gene encodes for a signal peptide, a propeptide, a catalytic domain with inserted three repeats of fibronectin type II domain followed by a C-terminal hemopexin-like domain.

MMP2

72 kDa type IV collagenase also known as matrix metalloproteinase-2 (MMP-2) and gelatinase A is an enzyme that in humans is encoded by the MMP2 gene. The MMP2 gene is located on chromosome 16 at position 12.2.

MMP14

Matrix metalloproteinase-14 is an enzyme that in humans is encoded by the MMP14 gene.

Interstitial collagenase, also known as fibroblast collagenase, and matrix metalloproteinase-1(MMP-1) is an enzyme that in humans is encoded by the MMP1 gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. MMP-1 was the first vertebrate collagenase both purified to homogeneity as a protein, and cloned as a cDNA. MMP-1 has an estimated molecular weight of 54 kDa.

MMP3

Stromelysin-1 also known as matrix metalloproteinase-3 (MMP-3) is an enzyme that in humans is encoded by the MMP3 gene. The MMP3 gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. MMP-3 has an estimated molecular weight of 54 kDa.

TIMP2

Tissue inhibitor of metalloproteinases 2 (TIMP2) is a gene and a corresponding protein. The gene is a member of the TIMP gene family. The protein is thought to be a metastasis suppressor.

MMP7

Matrilysin also known as matrix metalloproteinase-7 (MMP-7), pump-1 protease (PUMP-1), or uterine metalloproteinase is an enzyme in humans that is encoded by the MMP7 gene. The enzyme has also been known as matrin, putative metalloproteinase-1, matrix metalloproteinase pump 1, PUMP-1 proteinase, PUMP, metalloproteinase pump-1, putative metalloproteinase, MMP). Human MMP-7 has a molecular weight around 30 kDa.

MMP10

Stromelysin-2 also known as matrix metalloproteinase-10 (MMP-10) or transin-2 is an enzyme that in humans is encoded by the MMP10 gene.

Matrix metallopeptidase 13

Collagenase 3 is an enzyme that in humans is encoded by the MMP13 gene. It is a member of the matrix metalloproteinase (MMP) family. Like most MMPs, it is secreted as an inactive pro-form. MMP-13 has an predicted molecular weight around 54 kDa. It is activated once the pro-domain is cleaved, leaving an active enzyme composed of the catalytic domain and the hemopexin-like domain PDB: 1PEX​. Although the actual mechanism has not been described, the hemopexin domain participates in collagen degradation, the catalytic domain alone being particularly inefficient in collagen degradation. During embryonic development, MMP-13 is expressed in the skeleton as required for restructuring the collagen matrix for bone mineralization. In pathological situations it is highly overexpressed; this occurs in human carcinomas, rheumatoid arthritis and osteoarthritis.

Matrix metallopeptidase 12 Enzyme involved in breakdown of extracellular matrix, encoded for by the MMP12 gene in humans

Matrix metalloproteinase-12 (MMP-12) also known as macrophage metalloelastase (MME) or macrophage elastase (ME) is an enzyme that in humans is encoded by the MMP12 gene.

MMP19

Matrix metalloproteinase-19 (MMP-19) also known as matrix metalloproteinase RASI is an enzyme that in humans is encoded by the MMP19 gene.

TIMP4

Metalloproteinase inhibitor 4 is an enzyme that in humans is encoded by the TIMP4 gene.

MMP25

Matrix metalloproteinase-25 is an enzyme that in humans is encoded by the MMP25 gene.

MMP28

Matrix metalloproteinase 28 also known as epilysin is an enzyme that in humans is encoded by the MMP28 gene.

MMP8

Neutrophil collagenase, also known as matrix metalloproteinase-8 (MMP-8) or PMNL collagenase (MNL-CL), is a collagen cleaving enzyme which is present in the connective tissue of most mammals. In humans, the MMP-8 protein is encoded by the MMP8 gene. The gene is part of a cluster of MMP genes which localize to chromosome 11q22.3. Most MMP's are secreted as inactive proproteins which are activated when cleaved by extracellular proteinases. However, the enzyme encoded by this gene is stored in secondary granules within neutrophils and is activated by autolytic cleavage.

MMP21

Matrix metalloproteinase-21 (MMP-21) is an enzyme that in humans is encoded by the MMP21 gene.

MMP15

Matrix metalloproteinase 15 also known as MMP15 is an enzyme that in humans is encoded by the MMP15 gene.

The hemopexin family is a family of evolutionarily related proteins. Hemopexin-like repeats occur in vitronectin and some matrix metalloproteinases family (matrixins). The HX repeats of some matrixins bind tissue inhibitor of metallopeptidases (TIMPs).

References

  1. 1 2 3 GRCh38: Ensembl release 89: ENSG00000102265 - Ensembl, May 2017
  2. 1 2 3 GRCm38: Ensembl release 89: ENSMUSG00000001131 - Ensembl, May 2017
  3. ↑ "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. ↑ "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. ↑ Nee, Larine E.; Mcmorrow, Tara; Campbell, Eric; Slattery, Craig; Ryan, Michael P. (2004-10-01). "TNF-α and IL-1β–mediated regulation of MMP-9 and TIMP-1 in renal proximal tubular cells". Kidney International. 66 (4): 1376–1386. doi:10.1111/j.1523-1755.2004.00900.x. ISSN   0085-2538. PMID   15458430.
  6. ↑ Brew K, Nagase H (January 2010). "The tissue inhibitors of metalloproteinases (TIMPs): an ancient family with structural and functional diversity". Biochimica et Biophysica Acta (BBA) - Molecular Cell Research. 1803 (1): 55–71. doi:10.1016/j.bbamcr.2010.01.003. PMC   2853873 . PMID   20080133.
  7. ↑ Brew K, Dinakarpandian D, Nagase H (March 2000). "Tissue inhibitors of metalloproteinases: evolution, structure and function". Biochimica et Biophysica Acta (BBA) - Protein Structure and Molecular Enzymology. 1477 (1–2): 267–83. doi:10.1016/S0167-4838(99)00279-4. PMID   10708863.
  8. ↑ Graham CH, Lala PK (August 1991). "Mechanism of control of trophoblast invasion in situ". Journal of Cellular Physiology. 148 (2): 228–34. doi:10.1002/jcp.1041480207. PMID   1652588. S2CID   3145982.
  9. ↑ Nothnick WB, Soloway P, Curry TE (May 1997). "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". Biology of Reproduction. 56 (5): 1181–8. doi: 10.1095/biolreprod56.5.1181 . PMID   9160717.
  10. ↑ Nothnick WB (September 2000). "Disruption of the tissue inhibitor of metalloproteinase-1 gene results in altered reproductive cyclicity and uterine morphology in reproductive-age female mice". Biology of Reproduction. 63 (3): 905–12. doi: 10.1095/biolreprod63.3.905 . PMID   10952938.
  11. ↑ Kim YS, Kim SH, Kang JG, Ko JH (2012). "Expression level and glycan dynamics determine the net effects of TIMP-1 on cancer progression". BMB Reports. 45 (11): 623–8. doi:10.5483/BMBRep.2012.45.11.233. PMC   4133808 . PMID   23187000.
  12. ↑ Graham CH, Lala PK (August 1991). "Mechanism of control of trophoblast invasion in situ". Journal of Cellular Physiology. 148 (2): 228–34. doi:10.1002/jcp.1041480207. PMID   1652588. S2CID   3145982.
  13. ↑ Vincent ZL, Mitchell MD, Ponnampalam AP (December 2015). "Regulation of TIMP-1 in Human Placenta and Fetal Membranes by lipopolysaccharide and demethylating agent 5-aza-2'-deoxycytidine". Reproductive Biology and Endocrinology. 13: 136. doi:10.1186/s12958-015-0132-y. PMC   4687108 . PMID   26691525.
  14. ↑ Gong Y, Scott E, Lu R, Xu Y, Oh WK, Yu Q (2013-10-15). "TIMP-1 promotes accumulation of cancer associated fibroblasts and cancer progression". PLOS ONE. 8 (10): e77366. Bibcode:2013PLoSO...877366G. doi: 10.1371/journal.pone.0077366 . PMC   3797040 . PMID   24143225.
  15. ↑ Jourquin J, Tremblay E, Bernard A, Charton G, Chaillan FA, Marchetti E, Roman FS, Soloway PD, Dive V, Yiotakis A, Khrestchatisky M, Rivera S (November 2005). "Tissue inhibitor of metalloproteinases-1 (TIMP-1) modulates neuronal death, axonal plasticity, and learning and memory". The European Journal of Neuroscience. 22 (10): 2569–78. doi:10.1111/j.1460-9568.2005.04426.x. PMID   16307599. S2CID   18499513.
  16. ↑ Graham CH, Lala PK (August 1991). "Mechanism of control of trophoblast invasion in situ". Journal of Cellular Physiology. 148 (2): 228–34. doi:10.1002/jcp.1041480207. PMID   1652588. S2CID   3145982.
  17. ↑ "Entrez Gene: TIMP1 TIMP metallopeptidase inhibitor 1".
  18. ↑ Reichenstein M, Reich R, LeHoux JG, Hanukoglu I (February 2004). "ACTH induces TIMP-1 expression and inhibits collagenase in adrenal cortex cells". Molecular and Cellular Endocrinology. 215 (1–2): 109–14. CiteSeerX   10.1.1.538.7614 . doi:10.1016/j.mce.2003.11.011. PMID   15026182. S2CID   6836003.
  19. ↑ Ma J, Wang J, Fan W, Pu X, Zhang D, Fan C, Xiong L, Zhu H, Xu N, Chen R, Liu S (Dec 2013). "Upregulated TIMP-1 correlates with poor prognosis of laryngeal squamous cell carcinoma". International Journal of Clinical and Experimental Pathology. 7 (1): 246–54. PMC   3885479 . PMID   24427345.
  20. ↑ Tarhini AA, Lin Y, Yeku O, LaFramboise WA, Ashraf M, Sander C, Lee S, Kirkwood JM (January 2014). "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 of Translational Medicine. 12: 19. doi:10.1186/1479-5876-12-19. PMC   3909384 . PMID   24457057.

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