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TIMP2 (TIMP metallopeptidase inhibitor 2)

Identity

Other namesCSC-21K
TIMP-2
HGNC (Hugo) TIMP2
LocusID (NCBI) 7077
Location 17q25.3
Location_base_pair Starts at 76849059 and ends at 76921472 bp from pter ( according to hg19-Feb_2009)  [Mapping]
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 (Hugo)TIMP2   11821
    Cards
    AtlasTIMP2ID42572ch17q25
    Entrez_Gene (NCBI)TIMP2  7077  TIMP metallopeptidase inhibitor 2
    GeneCards (Weizmann)TIMP2
    Ensembl (Hinxton)ENSG00000035862 [Gene_View]  chr17:76849059-76921472 [Contig_View]  TIMP2 [Vega]
    ICGC DataPortalENSG00000035862
    cBioPortalTIMP2
    AceView (NCBI)TIMP2
    Genatlas (Paris)TIMP2
    WikiGenes7077
    SOURCE (Princeton)NM_003255
    Genomic and cartography
    GoldenPath (UCSC)TIMP2  -  17q25.3   chr17:76849059-76921472 -  17q25   [Description]    (hg19-Feb_2009)
    EnsemblTIMP2 - 17q25 [CytoView]
    Mapping of homologs : NCBITIMP2 [Mapview]
    OMIM188825   
    Gene and transcription
    Genbank (Entrez)AK294290 AL110197 AL713764 BC010410 BC039613
    RefSeq transcript (Entrez)NM_003255
    RefSeq genomic (Entrez)AC_000149 NC_000017 NC_018928 NT_010783 NW_001838455 NW_004929407
    Consensus coding sequences : CCDS (NCBI)TIMP2
    Cluster EST : UnigeneHs.633514 [ NCBI ]
    CGAP (NCI)Hs.633514
    Alternative Splicing : Fast-db (Paris)GSHG0013781
    Alternative Splicing GalleryENSG00000035862
    Gene ExpressionTIMP2 [ NCBI-GEO ]     TIMP2 [ SEEK ]   TIMP2 [ MEM ]
    Protein : pattern, domain, 3D structure
    UniProt/SwissProtP16035 (Uniprot)
    NextProtP16035  [Medical]
    With graphics : InterProP16035
    Splice isoforms : SwissVarP16035 (Swissvar)
    Domaine pattern : Prosite (Expaxy)NTR (PS50189)    TIMP (PS00288)   
    Domains : Interpro (EBI)Netrin_domain [organisation]   Prot_inh_TIMP [organisation]   TIMP-like_OB-fold [organisation]   TIMP2 [organisation]   TIMP_C_dom [organisation]  
    Related proteins : CluSTrP16035
    Domain families : Pfam (Sanger)TIMP (PF00965)   
    Domain families : Pfam (NCBI)pfam00965   
    Domain families : Smart (EMBL)NTR (SM00206)  
    DMDM Disease mutations7077
    Blocks (Seattle)P16035
    PDB (SRS)1BR9    1GXD    2TMP    4ILW   
    PDB (PDBSum)1BR9    1GXD    2TMP    4ILW   
    PDB (IMB)1BR9    1GXD    2TMP    4ILW   
    PDB (RSDB)1BR9    1GXD    2TMP    4ILW   
    Human Protein AtlasENSG00000035862 [gene] [tissue] [antibody] [cell] [cancer]
    Peptide AtlasP16035
    HPRD01784
    IPIIPI00027166   IPI00917285   IPI00065464   
    Protein Interaction databases
    DIP (DOE-UCLA)P16035
    IntAct (EBI)P16035
    FunCoupENSG00000035862
    BioGRIDTIMP2
    InParanoidP16035
    Interologous Interaction database P16035
    IntegromeDBTIMP2
    STRING (EMBL)TIMP2
    Ontologies - Pathways
    Ontology : AmiGOintegrin binding  protein binding  extracellular region  basement membrane  extracellular space  central nervous system development  aging  enzyme activator activity  metalloendopeptidase inhibitor activity  negative regulation of cell proliferation  cell surface  negative regulation of endopeptidase activity  negative regulation of endopeptidase activity  extracellular matrix disassembly  extracellular matrix organization  growth cone  motile cilium  regulation of Rap protein signal transduction  response to cytokine  response to drug  neuronal cell body  positive regulation of MAPK cascade  positive regulation of neuron differentiation  positive regulation of adenylate cyclase activity  negative regulation of proteolysis  negative regulation of mitotic cell cycle  negative regulation of Ras protein signal transduction  metal ion binding  extracellular vesicular exosome  cellular response to organic substance  
    Ontology : EGO-EBIintegrin binding  protein binding  extracellular region  basement membrane  extracellular space  central nervous system development  aging  enzyme activator activity  metalloendopeptidase inhibitor activity  negative regulation of cell proliferation  cell surface  negative regulation of endopeptidase activity  negative regulation of endopeptidase activity  extracellular matrix disassembly  extracellular matrix organization  growth cone  motile cilium  regulation of Rap protein signal transduction  response to cytokine  response to drug  neuronal cell body  positive regulation of MAPK cascade  positive regulation of neuron differentiation  positive regulation of adenylate cyclase activity  negative regulation of proteolysis  negative regulation of mitotic cell cycle  negative regulation of Ras protein signal transduction  metal ion binding  extracellular vesicular exosome  cellular response to organic substance  
    Pathways : BIOCARTAInhibition of Matrix Metalloproteinases [Genes]   
    Protein Interaction DatabaseTIMP2
    Wikipedia pathwaysTIMP2
    Gene fusion - rearrangments
    Polymorphisms : SNP, mutations, diseases
    SNP Single Nucleotide Polymorphism (NCBI)TIMP2
    snp3D : Map Gene to Disease7077
    SNP (GeneSNP Utah)TIMP2
    SNP : HGBaseTIMP2
    Genetic variants : HAPMAPTIMP2
    Exome VariantTIMP2
    1000_GenomesTIMP2 
    ICGC programENSG00000035862 
    Somatic Mutations in Cancer : COSMICTIMP2 
    CONAN: Copy Number AnalysisTIMP2 
    Mutations and Diseases : HGMDTIMP2
    Genomic VariantsTIMP2  TIMP2 [DGVbeta]
    dbVarTIMP2
    ClinVarTIMP2
    Pred. of missensesPolyPhen-2  SIFT(SG)  SIFT(JCVI)  Align-GVGD  MutAssessor  Mutanalyser  
    Pred. splicesGeneSplicer  Human Splicing Finder  MaxEntScan  
    Diseases
    OMIM188825   
    MedgenTIMP2
    GENETestsTIMP2
    Disease Genetic AssociationTIMP2
    Huge Navigator TIMP2 [HugePedia]  TIMP2 [HugeCancerGEM]
    General knowledge
    Homologs : HomoloGeneTIMP2
    Homology/Alignments : Family Browser (UCSC)TIMP2
    Phylogenetic Trees/Animal Genes : TreeFamTIMP2
    Chemical/Protein Interactions : CTD7077
    Chemical/Pharm GKB GenePA36527
    Clinical trialTIMP2
    Cancer Resource (Charite)ENSG00000035862
    Other databases
    Probes
    Litterature
    PubMed306 Pubmed reference(s) in Entrez
    CoreMineTIMP2
    iHOPTIMP2
    OncoSearchTIMP2

    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.
    Goldberg GI, Marmer BL, Grant GA, Eisen AZ, Wilhelm S, He C.
    Proc Natl Acad Sci USA 1989; 86: 8207-8211.
    PMID 2554304
     
    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
     
    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
     
    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
     
    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.
    Corcoran ML, Stetler-Stevenson WG.
    J Biol Chem 1995; 270: 13453-13459.
    PMID 7768948
     
    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
     
    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.
    Brew K, Dinakarpandian D, Nagase H.
    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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    Contributor(s)

    Written04-2008Demitrios 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. 2009;13(3):229-231.
    Free online version   Free pdf version   [Bibliographic record ]
    URL : http://AtlasGeneticsOncology.org/Genes/TIMP2ID42572ch17q25.html

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    indexed on : Fri Aug 8 11:20:44 CEST 2014

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