TIMP metallopeptidase inhibitor 1, also known as TIMP1, a tissue inhibitor of metalloproteinases, is a two-domain glycoprotein with a molecular weight of 28 kDa.[5] TIMP1 is expressed in several tissues of organisms.
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) through binding of the TIMP1 N-terminal domain to the metalloproteinase active site.[6] 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.[7] In regulating MMPs, TIMP1 plays a crucial role in extracellular matrix (ECM) composition, wound healing,[8] and pregnancy.[9][10][11]
The dysregulated activity of TIMP1 has been implicated in inflammation, cancer, and fibrosis.[12][13][14] In pregnancy, TIMP1 plays a regulatory role in the process of implantation, particularly the cytotrophoblast invasion of the uterine endometrium.[15] Additionally, it plays a role in regulating the transcriptional profile of fetal and placental tissues associated with the early stages of pregnancy.[16] 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.[17][18][19]
Cell-surface receptor binding
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 tetraspaninsCD63 and CD82.[20] These interactions can activate downstream signaling pathways including the MAPK pathway.[21]
Other names
Erythroid potentiating activity (EPA)
Human collagenase inhibitor (HCI)
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 humanfemales. This gene is located within intron 6 of the synapsin I gene and is transcribed in the opposite direction.[22]
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.[23]
Increased expression of TIMP1 has been found to be associated with worse prognosis of various tumors, such as laryngeal carcinoma[24] or melanoma.[25]
↑ Jourquin J, Tremblay E, Bernard A, Charton G, Chaillan FA, Marchetti E, etal. (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): 2569–2578. doi:10.1111/j.1460-9568.2005.04426.x. PMID16307599. S2CID18499513.
Hornebeck W (December 2003). "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". Pathologie-biologie. 51 (10): 569–573. doi:10.1016/j.patbio.2003.09.003. PMID14622947.
1d2b: THE MMP-INHIBITORY, N-TERMINAL DOMAIN OF HUMAN TISSUE INHIBITOR OF METALLOPROTEINASES-1 (N-TIMP-1), SOLUTION NMR, 29 STRUCTURES
1oo9: Orientation in Solution of MMP-3 Catalytic Domain and N-TIMP-1 from Residual Dipolar Couplings
1uea: MMP-3/TIMP-1 COMPLEX
2j0t: CRYSTAL STRUCTURE OF THE CATALYTIC DOMAIN OF MMP-1 IN COMPLEX WITH THE INHIBITORY DOMAIN OF TIMP-1
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