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Symbol TIMP3 contributors: mct - updated : 26-03-2020
HGNC name TIMP metallopeptidase inhibitor 3
HGNC id 11822
Corresponding disease
SFD pseudoinflammatory fundus dystrophy of Sorsby
Location 22q12.3      Physical location : 33.196.801 - 33.259.027
Synonym name
  • K222 expressed in degenerative retinas
  • TIMP metallopeptidase inhibitor 3 (Sorsby fundus dystrophy, pseudoinflammatory)
  • tissue inhibitor of metalloproteinase 3
  • MIG-5 protein
  • Synonym symbol(s) HSMRK222, K222, K222TA2, TIMP-3
    TYPE functioning gene
    SPECIAL FEATURE gene in gene
    text embedded in intron V of SYN3
    STRUCTURE 62.23 kb     5 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   transcription factor
    text structure
  • promoter contain several Sp1 sites
  • MAPPING cloned Y linked N status confirmed
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    5 - 5496 - 211 - 2007 1720214
  • a 23 aa signal peptide of 2.5 kda
  • a 188 aa mature peptide of 21.7 kda
    Type ubiquitous
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver     Homo sapiens
    Endocrineadrenal gland   moderately
    Hearing/Equilibriumear   highly
    Nervousnerve   highly
    Reproductivefemale systemplacenta  highly
    Respiratorylung   highly
    Visualeye   highly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  moderately
    Epithelialbarrier/liningretinal pigment epithelium (RPE)  
    cell lineage
    cell lines
    at STAGE
  • one NTR domain
  • secondary structure twelve cysteine residues that form six disulfide bridges
    conjugated MetalloP
    interspecies homolog to rattus Timp3 (95.3 pc)
    homolog to murine Timp3 (96.2 pc)
  • protease inhibitor I35 (TIMP) family
  • CATEGORY regulatory
  • proteinaceous extracellular matrix
  • present at the blood-brain-barrier endothelium
  • basic FUNCTION
  • inhibiting VEGF mediated angiogenesis by blockage of the binding of VEGF and VEGFR2
  • inhibiting more efficiently TACE, ADAM-10, ADAM-12, and aggrecanases than all the MMPs
  • having a proapoptotic activity
  • reducing tumor growth when it's overexpressed
  • inactivating irreversibly metalloproteinases (such as collagenases) by complexing with them (MMP1, MMP2, MMP3, MMP7, MMP9, MMP13, MMP14, MMP15)
  • may form part of a tissue- specific acute response to remodeling stimuli
  • candidate tumor suppressor gene in the biliary tree
  • protein accumulation is found to be an age-dependent phenomenon
  • involved in the regulation of the essential early inductors of adipogenesis, KLF4, EGR2, and CEBPB
  • endogenous regulator of metalloproteinases, stimulating hematopoietic stem cells (HSC) proliferation by recruiting quiescent HSCs into the cell cycle
  • may act as a molecular cue in response to myelosuppression for recruiting dormant HSCs into active cell cycle and may be clinically useful for facilitating hematopoietic recovery after chemotherapy
  • differentially impacts apoptosis and inflammatory cell influx, based on involvement of TNF, during the process of mammary involution
  • the regulatory function of TIMP3 is critical in preventing adverse vascular remodeling and abdominal aortic aneurysm
  • functions to moderate the differentiation of macrophages into proinflammatory (M1) cells
  • TIMP2 and TIMP3 play fundamental and differential roles in mediating pathological remodelling, independent from their MMP-inhibitory function
  • stromal protein that inhibits the activity of various proteases and receptors
  • may induce apoptosis in Endothelial cells by triggering a caspase-independent cell death pathway and targeting a PTK2-dependent survival pathway
  • TIMP3-mediated neuroprotection is critically dependent on activation of the AKT1-MTOR pathway
  • has direct neuroprotective effects that can mitigate the deleterious effects associated with traumatic brain injury (TBI), an area with few if any therapeutic options
  • TIMP3 acts as a tumor suppressor gene by inhibiting the growth, angiogenesis, migration, and invasion of cancer cells
  • is likely a key protective molecule against iron-mediated pathology, and plays a key protective role against iron-mediated pathology
  • expression of TIMP3 in NP (nucleus pulposus) may have a key role in the development of discogenic pain
  • might play an important role in the pathogenesis of intervertebral disc degeneration (IDD)
  • CELLULAR PROCESS cell life, cell death/apoptosis
    signaling sensory transduction/vision
    a component
    small molecule
  • VEGF and VEGFR2
  • binding MMPs in a 1:1 stoechiometry
  • inhibiting ADAMTS5 and ADAMTS4
  • regulator of MMP2 by RPE cells
  • LRP1 is the master regulator of extracellular levels of TIMP3
  • ITGA7 binds to tissue inhibitor of metalloproteinase 3 (TIMP3) in prostate cancer cells
  • imbalance between ADAMTS4 and TIMP3 may play an important role in the pathogenesis of intervertebral disc degeneration (IDD)
  • hepatic TIMP3 can slow progression of Non-alcoholic fatty liver disease (NAFLD), and tumorigenesis, at least in part, through the regulation of ADAM17 activity
  • as a novel CLOCK-dependent diurnal gene, TIMP3 inhibits the expression of inflammatory cytokines that are up-regulated by UV irradiation in human keratinocytes
  • IL32 may increase TIMP3 expression via hypomethylation through inactivation of NFKB1 activity, and thereby reduce lung tumor growth
  • CDKN2A/TIMP3 modulation of inflammatory response and vascularization in the context of intervertebral disk degeneration (IVDD)
  • cell & other
    activated by TH
    induced by mitogenic stimulation
    Other endocytosed and degraded by a number of cell types including chondrocytes, fibroblasts, and monocytes
    corresponding disease(s) SFD
    related resource CNGA1Mutations
    Retinal Information Network
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral       loss of function
    by methylation in uterus breast, colon, brain carcinomas
    tumoral       loss of function
    in renal clear cell carcinoma with poor prognosis
    constitutional     --low  
    in heart failure
    tumoral     --low  
    in uveal melanoma with metastases
    constitutional     --over  
    increased in the renal arteries and proximal tubules of subjects with diabetic nephropathy or chronic allograft nephropathy
    constitutional     --low  
    is reduced in atherosclerotic plaques from subjects with type 2 diabetes and increased by SIRT1
    constitutional     --low  
    during preadipocyte differentiation, the Sp1-dependent decrease in TIMP3 expression is required for the successful implementation of the adipocyte differentiation program
    silenced by promoter methylation in a consistent fraction of Papillary thyroid carcinoma
    constitutional     --low  
    increases inflammation and polarizes macrophages towards a more inflammatory phenotype resulting in increased atherosclerosis
    constitutional     --over  
    TIMP3 mRNA expression increases and TIMP3 protein is in the appropriate cellular layers to regulate proteolytic remodeling as the follicle progresses toward ovulation
    induces choroidal neovascularization by moderating the polarization of macrophages in age-related macular degeneration
    Susceptibility to age-related macular degeneration
    Variant & Polymorphism SNP , other
  • SNP may contribute to individual differences in breast cancer susceptibilty and survival
  • S156C mutation results in an abnormal localization of protein and increases angiogenesis
  • association of variants with age-related macular degeneration
  • expression level of TIMP3 was significantly associated with AMD pathology
  • Candidate gene
  • plasma TIMP3 is a potential biomarker for predicting the tumor stage and T status in patients with oral squamous cell carcinoma (OSCC)
  • positive correlation between TIMP-3 promoter methylation and gastric cancer risk and indicated that TIMP-3 promoter methylation may be used as a molecular marker for gastric cancer
  • Therapy target
    cancerhead and neck 
    promoter methylation of TIMP3 (and CDH1) predicts better outcome in head and neck squamous cell carcinoma treated by radiotherapy only
    could serve as a therapeutic approach in limiting abdominal aortic aneurysm development or expansion
    TIMP3 is a new target for inhibition of progression and chemotherapeutic resistance
  • iron overload in Timp3-/- mice showed twofold higher iron accumulation in the liver compared with WT mice because of constituently lower levels of ferroportin