TIMP2 (TIMP metallopeptidase inhibitor 2)

Identity

Other names	CSC-21K
	TIMP-2
HGNC	TIMP2
Location	17q25.3

Note	The various human TIMP genes are localized on different chromosomes. TIMP2 contains nested DDC8 gene, whereas the other TIMPs genes are nested in synapsins genes.

DNA/RNA

Note	Comparison of the cDNA sequences of human TIMP2 with human TIMP1 shows little homology considering that seen at the amino acid level. This result implies that these genes diverged early in the evolution of this gene family.
	The translated parts of exons 1-5 are shown by black boxes. The introns are shown by lines. The 5' UTR and the 3' UTR regions are shown by white boxes.
Description	The TIMP2 gene contains five exons and spans 72,413 bases (start 74,360,654 bp to end 74,433,067 from 17pter) oriented at the minus strand. The exons are separated by four introns of 54.8, 2.7, 9.1, and 1.7 kb.
Transcription	Two transcripts of 1.2 and 3.8 kb are reported. Their difference in size is the result of the use of different polyadenylation signals within the 3'-end of the gene. There is no evidence of alternatively spliced products.
Pseudogene	TIMP4, TIMP3, TIMP1.

Protein

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.
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.

Implicated in

Entity	Cancer
Note	TIMP2 possesses a complicated role in cancer through its ability to regulate MT1-MMP activity and to inhibit MMPs, especially MMP-2. Its function as inhibitor of angiogenesis; which is independent to the previous, suggests a negative role in cancer. In addition, allelic deletion at 17q23-25 is found in approximately one-third of breast cancer patients and it has been proposed that TIMP2 may act as metastasis suppressor gene.

External links

	Nomenclature
HGNC	TIMP2   11821
Entrez_Gene	TIMP2  7077  TIMP metallopeptidase inhibitor 2
	Cards
Atlas	TIMP2ID42572ch17q25
GeneCards	TIMP2
Ensembl	TIMP2 [Search_View]   ENSG00000035862 [Gene_View]
Genatlas	TIMP2
GeneLynx	TIMP2
eGenome	TIMP2
euGene	7077
	Genomic and cartography
GoldenPath	TIMP2  -  17q25.3   chr17:74360654-74433067 -  17q25   [Description]    (hg18-Mar_2006)
Ensembl	TIMP2 - 17q25 [CytoView]
NCBI	Mapview
OMIM	Disease map [OMIM]
HomoloGene	TIMP2
	Gene and transcription
Genbank	AK057217 [ ENTREZ ]
Genbank	AL110197 [ ENTREZ ]
Genbank	AL713764 [ ENTREZ ]
Genbank	BC010410 [ ENTREZ ]
Genbank	BC039613 [ ENTREZ ]
RefSeq	NM_003255 [ SRS ]    NM_003255 [ ENTREZ ]
RefSeq	AC_000060 [ SRS ]    AC_000060 [ ENTREZ ]
RefSeq	AC_000149 [ SRS ]    AC_000149 [ ENTREZ ]
RefSeq	NC_000017 [ SRS ]    NC_000017 [ ENTREZ ]
RefSeq	NT_010641 [ SRS ]    NT_010641 [ ENTREZ ]
RefSeq	NW_001838455 [ SRS ]    NW_001838455 [ ENTREZ ]
RefSeq	NW_926918 [ SRS ]    NW_926918 [ ENTREZ ]
AceView	TIMP2 AceView - NCBI
Unigene	Hs.633514 [ SRS ]    Hs.633514 [ NCBI ]     HS633514 [ spliceNest ]
Fast-db	15334 (alternative variants)
	Protein : pattern, domain, 3D structure
SwissProt	P16035 [ SRS]    P16035 [ EXPASY ]     P16035 [ INTERPRO ]     P16035 [ UNIPROT ]
Prosite	PS50189 NTR [ SRS ]    PS50189 NTR [ Expasy ]
Prosite	PS00288 TIMP [ SRS ]    PS00288 TIMP [ Expasy ]
Interpro	IPR001134 Netrin_C [ SRS ]    IPR001134 Netrin_C [ EBI ]
Interpro	IPR001820 Prot_inh_TIMP [ SRS ]    IPR001820 Prot_inh_TIMP [ EBI ]
Interpro	IPR015613 TIMP2 [ SRS ]    IPR015613 TIMP2 [ EBI ]
CluSTr	P16035
Pfam	PF00965 TIMP [ SRS ]    PF00965 TIMP [ Sanger ]    pfam00965 [ NCBI-CDD ]
Smart	SM00206 NTR [EMBL]
Blocks	P16035
PDB	1BR9 [ SRS ]    1BR9 [ PdbSum ],   1BR9 [ IMB ]   1BR9 [ RSDB ]
PDB	1GXD [ SRS ]    1GXD [ PdbSum ],   1GXD [ IMB ]   1GXD [ RSDB ]
PDB	2TMP [ SRS ]    2TMP [ PdbSum ],   2TMP [ IMB ]   2TMP [ RSDB ]
HPRD	01784
	Protein Interaction databases
DIP	P16035
IntAct	P16035
	Polymorphism : SNP, mutations, diseases
OMIM	188825    [ map ]
GENECLINICS	188825
SNP	TIMP2 [dbSNP-NCBI]
SNP	NM_003255 [SNP-NCI]
SNP	TIMP2 [GeneSNPs - Utah]  TIMP2] [HGBASE - SRS]
HAPMAP	TIMP2 [HAPMAP]
COSMIC	TIMP2 [Somatic mutation (COSMIC-CGP-Sanger)]
HGMD	TIMP2
	General knowledge
Family Browser	TIMP2 [UCSC Family Browser]
SOURCE	NM_003255
SMD	Hs.633514
SAGE	Hs.633514
GO	enzyme inhibitor activity [Amigo]  enzyme inhibitor activity
GO	integrin binding [Amigo]  integrin binding
GO	protein binding [Amigo]  protein binding
GO	extracellular region [Amigo]  extracellular region
GO	basement membrane [Amigo]  basement membrane
GO	enzyme activator activity [Amigo]  enzyme activator activity
GO	metalloendopeptidase inhibitor activity [Amigo]  metalloendopeptidase inhibitor activity
GO	negative regulation of cell proliferation [Amigo]  negative regulation of cell proliferation
GO	cell surface [Amigo]  cell surface
GO	regulation of cAMP metabolic process [Amigo]  regulation of cAMP metabolic process
GO	regulation of MAPKKK cascade [Amigo]  regulation of MAPKKK cascade
GO	regulation of neuron differentiation [Amigo]  regulation of neuron differentiation
BIOCARTA	Inhibition of Matrix Metalloproteinases    [Genes]
PubGene	TIMP2
TreeFam	TIMP2
CTD	7077 [Comparative ToxicoGenomics Database]
	Other databases
	Probes
Probe	TIMP2 Related clones (RZPD - Berlin)
	PubMed
PubMed	147 Pubmed reference(s) in LocusLink

Bibliography

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Nature 1985; 318: 66-68.

PMID 3903517

Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2.

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Proc Natl Acad Sci USA 1989; 86: 8207-8211.

PMID 2554304

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J Biol Chem. 1989; 264: 17374-17378.

PMID 2793861

Tissue inhibitor of metalloproteinases-2 (TIMP-2) mRNA expression in tumor cell lines and human tumor tissues.

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J Biol Chem 1990; 265: 13933-13938.

PMID 2380196

The gene for tissue inhibitor of metalloproteinases-2 is localized on human chromosome arm 17q25.

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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

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

Tissue inhibitor of metalloproteinase-2 stimulates fibroblast proliferation via a cAMP-dependent mechanism.

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J Biol Chem 1995; 270: 13453-13459.

PMID 7768948

Structure and Characterization of the Human Tissue Inhibitor of Metalloproteinases-2 Gene.

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J Biol Chem 1996; 271: 25498-25505.

PMID 8810321

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

Tissue inhibitors of metalloproteinases: evolution, structure and function.

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Biochim Biophys Acta 2000; 1477: 267-283. Review.

PMID 10708863

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

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

TIMP-2: an endogenous inhibitor of angiogenesis.

Stetler-Stevenson WG, Seo DW.

Trends Mol Med 2005; 11: 97-103. Review.

PMID 15760767

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

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

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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Last year publications	automatic search in PubMed

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Contributor(s)

Written	04-2008	Demitrios H Vynios
		Laboratory of Biochemistry, Department of Chemistry, School of Natural Sciences, University of Patras, 265 00 Patras, Greece

Citation

This paper should be referenced as such :

Vynios DH . TIMP2 (TIMP metallopeptidase inhibitor 2). Atlas Genet Cytogenet Oncol Haematol. April 2008 . URL : http://AtlasGeneticsOncology.org/Genes/TIMP2ID42572ch17q25.html

© Atlas of Genetics and Cytogenetics in Oncology and Haematology

indexed on : Mon Aug 11 21:18:07 2008