TIMP2

TIMP metallopeptidase inhibitor 2
PDB rendering based on 1bqq.
Available structures PDB Ortholog search: PDBe, RCSB List of PDB id codes 1BR9​, 1GXD​, 2TMP​, 4ILW​
Identifiers
Symbols	TIMP2 ; CSC-21K; DDC8
External IDs	OMIM: 188825 MGI: 98753 HomoloGene: 2444 GeneCards: TIMP2 Gene
Gene ontology Molecular function • protease binding • integrin binding • protein binding • enzyme activator activity • metalloendopeptidase inhibitor activity • metal ion binding Cellular component • extracellular region • proteinaceous extracellular matrix • basement membrane • extracellular space • cell surface • growth cone • neuronal cell body • extracellular exosome Biological process • central nervous system development • aging • negative regulation of cell proliferation • response to hormone • negative regulation of endopeptidase activity • extracellular matrix disassembly • extracellular matrix organization • regulation of Rap protein signal transduction • response to cytokine • response to drug • positive regulation of MAPK cascade • positive regulation of neuron differentiation • positive regulation of adenylate cyclase activity • negative regulation of mitotic cell cycle • negative regulation of Ras protein signal transduction • negative regulation of metalloenzyme activity • negative regulation of membrane protein ectodomain proteolysis • cellular response to organic substance Sources: Amigo / QuickGO
RNA expression pattern
More reference expression data
Orthologs
Species	Human	Mouse
Entrez	7077	21858
Ensembl	ENSG00000035862	ENSMUSG00000017466
UniProt	P16035	B1AQJ3
RefSeq (mRNA)	NM_003255	NM_011594
RefSeq (protein)	NP_003246	NP_035724
Location (UCSC)	Chr 17: 78.85 – 78.93 Mb	Chr 11: 118.3 – 118.36 Mb
PubMed search

TIMP metallopeptidase inhibitor 2, a tissue inhibitor of metalloproteinases, also known as TIMP2, is a human gene, thought to be a metastasis suppressor.

Function

This gene is a member of the TIMP gene family. 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 an inhibitory role against metalloproteinases, 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.^[1] TIMP-2 functions as both an MMP inhibitor and an activator. TIMPs inhibit all active MMPs, but different TIMPs inhibit different MMPs better than other TIMPs. For example, TIMP-1 inhibits MMP-7, MMP-9, MMP-1 and MMP-3 better than TIMP-2, and TIMP-2 inhibits MMP-2 more effectively than other TIMPs.^[2]

In melanocytic cells TIMP2 gene expression may be regulated by MITF.^[3]

Interactions

TIMP2 has been shown to interact with:

• MMP14^[4] and
• MMP2.^[5][6][7][8]

See also

• TIMP1, TIMP3, TIMP4

References

1. "Entrez Gene: TIMP2 TIMP metallopeptidase inhibitor 2".
2. Bourboulia D, Stetler-Stevenson WG (Jun 2010). "Matrix metalloproteinases (MMPs) and tissue inhibitors of metalloproteinases (TIMPs): Positive and negative regulators in tumor cell adhesion". Seminars in Cancer Biology 20 (3): 161–8. doi:10.1016/j.semcancer.2010.05.002. PMC 2941566. PMID 20470890.
3. Hoek KS, Schlegel NC, Eichhoff OM, Widmer DS, Praetorius C, Einarsson SO, Valgeirsdottir S, Bergsteinsdottir K, Schepsky A, Dummer R, Steingrimsson E (2008). "Novel MITF targets identified using a two-step DNA microarray strategy". Pigment Cell Melanoma Res. 21 (6): 665–76. doi:10.1111/j.1755-148X.2008.00505.x. PMID 19067971.
4. Zucker S, Drews M, Conner C, Foda HD, DeClerck YA, Langley KE, Bahou WF, Docherty AJ, Cao J (January 1998). "Tissue inhibitor of metalloproteinase-2 (TIMP-2) binds to the catalytic domain of the cell surface receptor, membrane type 1-matrix metalloproteinase 1 (MT1-MMP)". J. Biol. Chem. 273 (2): 1216–22. doi:10.1074/jbc.273.2.1216. PMID 9422789.
5. Morgunova E, Tuuttila A, Bergmann U, Tryggvason K (May 2002). "Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2". Proc. Natl. Acad. Sci. U.S.A. 99 (11): 7414–9. doi:10.1073/pnas.102185399. PMC 124245. PMID 12032297.
6. Overall CM, Tam E, McQuibban GA, Morrison C, Wallon UM, Bigg HF, King AE, Roberts CR (December 2000). "Domain interactions in the gelatinase A.TIMP-2.MT1-MMP activation complex. The ectodomain of the 44-kDa form of membrane type-1 matrix metalloproteinase does not modulate gelatinase A activation". J. Biol. Chem. 275 (50): 39497–506. doi:10.1074/jbc.M005932200. PMID 10991943.
7. Bigg HF, Shi YE, Liu YE, Steffensen B, Overall CM (June 1997). "Specific, high affinity binding of tissue inhibitor of metalloproteinases-4 (TIMP-4) to the COOH-terminal hemopexin-like domain of human gelatinase A. TIMP-4 binds progelatinase A and the COOH-terminal domain in a similar manner to TIMP-2". J. Biol. Chem. 272 (24): 15496–500. doi:10.1074/jbc.272.24.15496. PMID 9182583.
8. Kai HS, Butler GS, Morrison CJ, King AE, Pelman GR, Overall CM (December 2002). "Utilization of a novel recombinant myoglobin fusion protein expression system to characterize the tissue inhibitor of metalloproteinase (TIMP)-4 and TIMP-2 C-terminal domain and tails by mutagenesis. The importance of acidic residues in binding the MMP-2 hemopexin C-domain". J. Biol. Chem. 277 (50): 48696–707. doi:10.1074/jbc.M209177200. PMID 12374789.

Further reading

• Liotta LA, Stetler-Stevenson W, Steeg PS (1991). "Metastasis suppressor genes.". Important Adv. Oncol.: 85–100. PMID 1869284.
• Stetler-Stevenson WG, Seo DW (2005). "TIMP-2: an endogenous inhibitor of angiogenesis.". Trends in molecular medicine 11 (3): 97–103. doi:10.1016/j.molmed.2005.01.007. PMID 15760767.

External links

• The MEROPS online database for peptidases and their inhibitors: I35.002