HGNC Approved Gene Symbol: TIMP2
Cytogenetic location: 17q25.3 Genomic coordinates (GRCh38): 17:78,852,977-78,925,387 (from NCBI)
Stetler-Stevenson et al. (1989) found that a 21-kD protein, which is secreted by human melanoma cells and binds to type IV collagenase proenzyme secreted by the same cells, has an amino acid sequence with many similarities to human tissue inhibitor of metalloproteinase (TIMP1; 305370). For example, the positions of the 12 cysteines and 3 of the 4 tryptophan residues were conserved. Individual members of the TIMP gene family may possess selective affinities for different members of the matrix metalloproteinase family.
Stetler-Stevenson et al. (1989) demonstrated that addition of purified TIMP2 to activated type IV procollagenase resulted in inhibition of the collagenolytic activity in a stoichiometric fashion.
Noda et al. (2003) studied matrix metalloproteinases (MMPs) and their activation in association with the pathogenesis of proliferative diabetic retinopathy (PDR; see 188825). They demonstrated that pro-MMP2 (120360) was efficiently activated in the fibrovascular tissues of PDR, probably through interaction with MT1-MMP (MMP14; 600754) and TIMP2. The results suggested that MMP2 and MT1-MMP may be involved in the formation of the fibrovascular tissues.
Seo et al. (2003) demonstrated that TIMP2 abrogated angiogenic factor-induced endothelial cell proliferation in vitro and angiogenesis in vivo independent of MMP inhibition. These effects required alpha-3 (605025)/beta-1 (135630) integrin-mediated binding of TIMP2 to endothelial cells. Furthermore, TIMP2 induced a decrease in total protein tyrosine phosphatase (PTP) activity associated with beta-1 integrin subunits as well as dissociation of the phosphatase SHP1 (176883) from beta-1. TIMP2 treatment also resulted in a concomitant increase in PTP activity associated with tyrosine kinase receptors FGFR1 (136350) and KDR (191306).
Castellano et al. (2017) showed that human cord plasma treatment revitalizes the hippocampus and improves cognitive function in aged mice. TIMP2, a blood-borne factor enriched in human cord plasma, young mouse plasma, and young mouse hippocampi, appeared in the brain after systemic administration and increased synaptic plasticity and hippocampal-dependent cognition in aged mice. Depletion experiments in aged mice revealed TIMP2 to be necessary for the cognitive benefits conferred by cord plasma. Castellano et al. (2017) found that systemic pools of TIMP2 are necessary for spatial memory in young mice, while treatment of brain slices with TIMP2 antibody prevents long-term potentiation, arguing for theretofore unknown roles for TIMP2 in normal hippocampal function.
Hammani et al. (1996) characterized the genomic features of the TIMP2 gene. The gene is encoded by 5 exons spanning 83 kb of genomic DNA. The intron-exon splicing sites are conserved among TIMP1, TIMP2, and TIMP3 (188826). The 5-prime end of the gene contains several regulatory elements, including Sp1-, AP2-, AP1-, and PEA3-binding sites. However, Hammani et al. (1996) found that the AP1 site was not responsive to 12-O-tetradecanoylphorbol-13-acetate (TPA) treatment. The authors stated that TIMP2, unlike TIMP1 and TIMP3, is not upregulated by TPA or TGF-beta. Analysis of the 3-prime end of the gene revealed that the 2 mRNAs for TIMP2 (1.2 and 3.8 kb) differ by the selection of their polyadenylation signal sites, but selection of these sites does not affect RNA stability. Hammani et al. (1996) stated that TIMP2 gene has several features of a housekeeping gene and is likely to play a role significantly different from that of TIMP1 or TIMP3. See also TIMP4 (601915).
By linkage analysis, Stetler-Stevenson et al. (1992) mapped the Timp2 gene to mouse chromosome 11. Based on the known homology with human chromosome 17, they suggested that the human homolog will be found to map to the region 17q22-q25. This prediction was validated by De Clerck et al. (1992) who assigned the TIMP2 gene to chromosome 17 by analysis of somatic cell hybrids and regionalized it to 17q25 by fluorescence in situ hybridization. TIMPs have been shown to block tumor cell invasion both in vitro and in vivo, suggesting that they act as 'metastasis suppressor genes.' Allelic deletion at 17q23-q25 is found in approximately one-third of breast cancer patients.
Castellano, J. M., Mosher, K. I., Abbey, R. J., McBride, A. A., James, M. L., Berdnik, D., Shen, J. C., Zou, B., Xie, X. S., Tingle, M., Hinkson, I. V., Angst, M. S., Wyss-Coray, T. Human umbilical cord plasma proteins revitalize hippocampal function in aged mice. Nature 544: 488-492, 2017. [PubMed: 28424512] [Full Text: https://doi.org/10.1038/nature22067]
De Clerck, Y., Szpirer, C., Aly, M. S., Cassiman, J.-J., Eeckhout, Y., Rousseau, G. The gene for tissue inhibitor of metalloproteinases-2 is localized on human chromosome arm 17q25. Genomics 14: 782-784, 1992. [PubMed: 1427908] [Full Text: https://doi.org/10.1016/s0888-7543(05)80186-7]
Hammani, K., Blakis, A., Morsette, D., Bowcock, A. M., Schmutte, C., Henriet, P., DeClerck, Y. A. Structure and characterization of the human tissue inhibitor of metalloproteinases-2 gene. J. Biol. Chem. 271: 25498-25505, 1996. [PubMed: 8810321] [Full Text: https://doi.org/10.1074/jbc.271.41.25498]
Noda, K., Ishida, S., Inoue, M., Obata, K., Oguchi, Y., Okada, Y., Ikeda, E. Production and activation of matrix metalloproteinase-2 in proliferative diabetic retinopathy. Invest. Ophthal. Vis. Sci. 44: 2163-2170, 2003. [PubMed: 12714657] [Full Text: https://doi.org/10.1167/iovs.02-0662]
Seo, D.-W., Li, H., Guedez, L., Wingfield, P. T., Diaz, T., Salloum, R., Wei, B., Stetler-Stevenson, W. G. TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism. Cell 114: 171-180, 2003. [PubMed: 12887919] [Full Text: https://doi.org/10.1016/s0092-8674(03)00551-8]
Stetler-Stevenson, W. G., Krutzsch, H. C., Liotta, L. A. Tissue inhibitor of metalloproteinase (TIMP-2): a new member of the metalloproteinase inhibitor family. J. Biol. Chem. 264: 17374-17378, 1989. [PubMed: 2793861]
Stetler-Stevenson, W. G., Liotta, L. A., Seldin, M. F. Linkage analysis demonstrates that the Timp-2 locus is on mouse chromosome 11. Genomics 14: 828-829, 1992. [PubMed: 1427919] [Full Text: https://doi.org/10.1016/s0888-7543(05)80205-8]