| Note | The proteins encoded by this gene family are natural inhibitors of the matrix metalloproteinases, a group of peptidases involved in degradation of the extracellular matrix. In addition to this role, the encoded protein has a unique role among TIMP family members in its ability to directly suppress the proliferation of endothelial cells. As a result, the encoded protein may be critical to the maintenance of tissue homeostasis by suppressing the proliferation of quiescent tissues in response to angiogenic factors, and by inhibiting protease activity in tissues undergoing remodelling of the extracellular matrix. |
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| Description | Propeptide: Size 220 amino acids; Molecular mass 24.4 kDa.
Mature protein: Size 194 amino acids; Molecular mass 21 kDa.
It belongs to the protease inhibitor I35 (TIMP) family.
It contains 1 NTR domain. No N- glycosylation is observed. |
| Expression | Constitutive. |
| Localisation | Secreted protein, as well as cell surface bound. |
| Function | A variety of distinct functions have been described so far:
1. TIMP2 complexes with some of enzymes of metalloproteinases family and irreversibly inactivates them. It is known to act on MMP-1, MMP-2, MMP-3, MMP-7, MMP-8, MMP-9, MMP-10, MMP-13, MMP-14, MMP-15, MMP-16 and MMP-19, through its tight binding to the enzymes in a 1:1 stoichiometry with a Ki ‹ 10-9 M. The complex between human proMMP-2 and TIMP-2 is well studied and its crystal structure reveals an interaction between the hemopexin domain of proMMP-2 and the C-terminal domain of TIMP2, leaving the catalytic site of MMP-2 and the inhibitory site of TIMP2 distant and spatially isolated. The activity of TIMP2 is dependent on the presence of disulfide bonds in its structure. 2. TIMP2 is a positive regulator of MMP-14 (MT1-MMP) by promoting the availability of the enzyme at the cell surface and supporting pericellular proteolysis (after forming the trimolecular complex of MMP-14, TIMP-2 and proMMP-2). Through this activity of TIMP2 the specific activation of proMMP-2, after the interaction of TIMP2 with MT1-MMP (possibly MT2-MMP and MT3-MMP) in cell surface, is achieved. 3. Inhibition of angiogenesis, after binding to alpha3 / beta1-integrin, resulting in a decreased association of the protein tyrosine phosphatase Shp-1 with beta1-integrin subunits and increased association of Shp-1 with tyrosine kinase growth factor receptors (both VEGFR-2 and EGFR-1). 4. Inhibition of endothelial cell proliferation. This activity is localized to TIMP2 C-terminal domain, specifically to the C-terminal disulfide loop, referred to as loop 6. 5. Antiapoptotic activity. 6. TIMP2 has been found to block tumor cell invasion both in vitro and in vivo and may act as metastasis suppressor gene. |
| Homology | TIMP2 shares 40% aminoacid sequence homology with TIMP1 especially in the N-terminal domain. |
| Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity. |
| Docherty AJ, Lyons A, Smith BJ, Wright EM, Stephens PE, Harris TJ, Murphy G, Reynolds JJ. |
| Nature 1985; 318: 66-68. |
| PMID 3903517 |
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| Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2. |
| Goldberg GI, Marmer BL, Grant GA, Eisen AZ, Wilhelm S, He C. |
| Proc Natl Acad Sci USA 1989; 86: 8207-8211. |
| PMID 2554304 |
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| Tissue inhibitor of metalloproteinase (TIMP-2). A new member of the metalloproteinase inhibitor family. |
| Stetler-Stevenson WG, Krutzsch HC, Liotta LA. |
| J Biol Chem. 1989; 264: 17374-17378. |
| PMID 2793861 |
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| Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues. |
| Stetler-Stevenson WG, Brown PD, Onisto M, Levy AT, Liotta LA. |
| J Biol Chem 1990; 265: 13933-13938. |
| PMID 2380196 |
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| The gene for tissue inhibitor of metalloproteinases-2 is localized on human chromosome arm 17q25. |
| DeClerck Y, Szpirer C, Aly MS, Cassiman JJ, Eeckhout Y, Rousseau G. |
| Genomics 1992; 14: 782-784. |
| PMID 1427908 |
| |
| Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2). |
| Hayakawa T, Yamashita K, Ohuchi E, Shinagawa A. |
| J Cell Sci 1994; 107: 2373-2379. |
| PMID 7844157 |
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| Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the OB fold protein family. |
| Williamson RA, Martorell G, Carr MD, Murphy G, Docherty AJ, Freedman RB, Feeney J. |
| Biochemistry 1994; 33: 11745-11759. |
| PMID 7918391 |
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| Tissue inhibitor of metalloproteinase-2 stimulates fibroblast proliferation via a cAMP-dependent mechanism. |
| Corcoran ML, Stetler-Stevenson WG. |
| J Biol Chem 1995; 270: 13453-13459. |
| PMID 7768948 |
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| Structure and Characterization of the Human Tissue Inhibitor of Metalloproteinases-2 Gene. |
| Hammani K, Blakis A, Morsette D, Bowcock AM, Schmutte C, Henriet P, DeClerck YA. |
| J Biol Chem 1996; 271: 25498-25505. |
| PMID 8810321 |
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| Membrane type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases. |
| Butler GS, Will H, Atkinson SJ, Murphy G. |
| Eur J Biochem 1997; 244: 653657. |
| PMID 9119036 |
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| Tissue inhibitors of metalloproteinases: evolution, structure and function. |
| Brew K, Dinakarpandian D, Nagase H. |
| Biochim Biophys Acta 2000; 1477: 267-283. Review. |
| PMID 10708863 |
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| Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2. |
| Morgunova E, Tuuttila A, Bergmann U, Tryggvason K. |
| Proc Natl Acad Sci U S A 2002; 99: 7414-7419. |
| PMID 12032297 |
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| The TIMPs tango with MMPs and more in the central nervous system. |
| Crocker SJ, Pagenstecher A, Campbell IL. |
| J Neurosci Res 2004; 75: 1-11. Review. |
| PMID 14689443 |
| |
| TIMPs as multifacial proteins. |
| Lambert E, Dasse E, Haye B, Petitfrere E. |
| Crit Rev Oncol Hematol 2004; 49: 187-198. Review. |
| PMID 15036259 |
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| TIMP-2: an endogenous inhibitor of angiogenesis. |
| Stetler-Stevenson WG, Seo DW. |
| Trends Mol Med 2005; 11: 97-103. Review. |
| PMID 15760767 |
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| Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2. |
| Jaworski DM, Beem-Miller M, Lluri G, Barrantes-Reynolds R. |
| Physiol Genomics 2007; 28: 168-178. |
| PMID 16985004 |
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| Tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates myogenesis and beta1 integrin expression in vitro. |
| Lluri G, Langlois GD, Soloway PD, Jaworski DM. |
| Exp Cell Res 2008; 314: 11-24. |
| PMID 17678891 |
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| The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2. |
| Stetler-Stevenson WG. |
| Cancer Metastasis Rev 2008; 27: 57-66. Review. |
| PMID 18058195 |
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