TIMP2 (TIMP metallopeptidase inhibitor 2)

2008-04-01   Demitrios H Vynios 

Laboratory of Biochemistry, Department of Chemistry, School of Natural Sciences, University of Patras, 265 00 Patras, Greece





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.
Atlas Image
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.


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.


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.





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.
Atlas Image


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.




Secreted protein, as well as cell surface bound.


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 name
    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.


    Pubmed IDLast YearTitleAuthors
    107088632000Tissue inhibitors of metalloproteinases: evolution, structure and function.Brew K et al
    91190361997Membrane-type-2 matrix metalloproteinase can initiate the processing of progelatinase A and is regulated by the tissue inhibitors of metalloproteinases.Butler GS et al
    77689481995Tissue inhibitor of metalloproteinase-2 stimulates fibroblast proliferation via a cAMP-dependent mechanism.Corcoran ML et al
    146894432004The TIMPs tango with MMPs and more in the central nervous system.Crocker SJ et al
    14279081992The gene for tissue inhibitor of metalloproteinases-2 is localized on human chromosome arm 17q25.De Clerck Y et al
    39035171985Sequence of human tissue inhibitor of metalloproteinases and its identity to erythroid-potentiating activity.Docherty AJ et al
    25543041989Human 72-kilodalton type IV collagenase forms a complex with a tissue inhibitor of metalloproteases designated TIMP-2.Goldberg GI et al
    88103211996Structure and characterization of the human tissue inhibitor of metalloproteinases-2 gene.Hammani K et al
    78441571994Cell growth-promoting activity of tissue inhibitor of metalloproteinases-2 (TIMP-2).Hayakawa T et al
    169850042007Potential regulatory relationship between the nested gene DDC8 and its host gene tissue inhibitor of metalloproteinase-2.Jaworski DM et al
    150362592004TIMPs as multifacial proteins.Lambert E et al
    176788912008Tissue inhibitor of metalloproteinase-2 (TIMP-2) regulates myogenesis and beta1 integrin expression in vitro.Lluri G et al
    120322972002Structural insight into the complex formation of latent matrix metalloproteinase 2 with tissue inhibitor of metalloproteinase 2.Morgunova E et al
    180581952008The tumor microenvironment: regulation by MMP-independent effects of tissue inhibitor of metalloproteinases-2.Stetler-Stevenson WG et al
    79183911994Solution structure of the active domain of tissue inhibitor of metalloproteinases-2. A new member of the OB fold protein family.Williamson RA et al

    Other Information

    Locus ID:

    NCBI: 7077
    MIM: 188825
    HGNC: 11821
    Ensembl: ENSG00000035862


    dbSNP: 7077
    ClinVar: 7077
    TCGA: ENSG00000035862


    Gene IDTranscript IDUniprot

    Expression (GTEx)



    PathwaySourceExternal ID
    Immune SystemREACTOMER-HSA-168256
    Innate Immune SystemREACTOMER-HSA-168249
    Extracellular matrix organizationREACTOMER-HSA-1474244
    Degradation of the extracellular matrixREACTOMER-HSA-1474228
    Activation of Matrix MetalloproteinasesREACTOMER-HSA-1592389
    Neutrophil degranulationREACTOMER-HSA-6798695

    Protein levels (Protein atlas)

    Not detected


    Pubmed IDYearTitleCitations
    233886122013Discovery and validation of cell cycle arrest biomarkers in human acute kidney injury.267
    128879192003TIMP-2 mediated inhibition of angiogenesis: an MMP-independent mechanism.150
    170309882006Coregulation of vascular tube stabilization by endothelial cell TIMP-2 and pericyte TIMP-3.118
    246757172014Urinary TIMP-2 and IGFBP7 as early biomarkers of acute kidney injury and renal recovery following cardiac surgery.88
    199131212009Gene-centric association signals for lipids and apolipoproteins identified via the HumanCVD BeadChip.85
    222624092012In hepatocellular carcinoma miR-519d is up-regulated by p53 and DNA hypomethylation and targets CDKN1A/p21, PTEN, AKT3 and TIMP2.78
    161032402005Increased cardiac expression of tissue inhibitor of metalloproteinase-1 and tissue inhibitor of metalloproteinase-2 is related to cardiac fibrosis and dysfunction in the chronic pressure-overloaded human heart.68
    225321312012The role of matrix metalloproteinases (MMPs) and their inhibitors (TIMPs) in the development of esophageal cancer.60
    271912652016Long noncoding RNA DANCR promotes invasion of prostate cancer through epigenetically silencing expression of TIMP2/3.55
    222723432012The role of EZH2 in the regulation of the activity of matrix metalloproteinases in prostate cancer cells.51


    Demitrios H Vynios

    TIMP2 (TIMP metallopeptidase inhibitor 2)

    Atlas Genet Cytogenet Oncol Haematol. 2008-04-01

    Online version: http://atlasgeneticsoncology.org/gene/42572/timp2