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FLASH GENE
Symbol TIMP3 contributors: mct - updated : 21-08-2014
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
    DNA
    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
    Physical map
    HSN44A4A 22q12.1-q12.3 hypothetical protein HSN44A4A YWHAH 22q12.2 tyrosine 3-monooxygenase/tryptophan 5-monooxygenase activation protein, eta polypeptide LOC391329 22 similar to ribosomal protein S17 SLC5A1 22q12.3 solute carrier family 5 (sodium/glucose cotransporter), member 1 ADTB1L1 22q12.3 adaptin, beta 1-like 1 ADTB1L2 22q12.3 adaptin, beta 1-like 2 LOC150297 22q12.3 hypothetical protein LOC150297 RFPL2 22q12.3 ret finger protein-like 2 SLC5A4 22q12.1-q12.3 solute carrier family 5 (low affinity glucose cotransporter), member 4 LOC391330 22 similar to immunoglobulin lambda light chain VLJ region RFPL3 22q12.2 ret finger protein-like 3 RFPL3S 22q12.3 ret finger protein-like 3 antisense HSPC117 22q12 hypothetical protein HSPC117 BPIL2 22q12.3 bactericidal/permeability-increasing protein-like 2 FBXO7 22q12-q13 F-box only protein 7 SYN3 22q12.3 synapsin III TIMP3 22q12.13 tissue inhibitor of metalloproteinase 3 (Sorsby fundus dystrophy, pseudoinflammatory) LARGE 22q12.3-q13.1 like-glycosyltransferase
    RNA
    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
  • EXPRESSION
    Type ubiquitous
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Endocrineadrenal gland   moderately
     thyroid   moderately
    Hearing/Equilibriumear   highly
    Nervousnerve   highly
    Reproductivefemale systemplacenta  highly
    Respiratorylung   highly
    Visualeye   highly
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone  moderately
    Epithelialbarrier/liningretinal pigment epithelium (RPE)  
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • one NTR domain
  • secondary structure twelve cysteine residues that form six disulfide bridges
    conjugated MetalloP
    HOMOLOGY
    interspecies homolog to rattus Timp3 (95.3 pc)
    homolog to murine Timp3 (96.2 pc)
    Homologene
    FAMILY
  • protease inhibitor I35 (TIMP) family
  • CATEGORY regulatory
    SUBCELLULAR LOCALIZATION extracellular
        intracellular
    intracellular,nucleus
    text
  • 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
  • CELLULAR PROCESS cell life, cell death/apoptosis
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling sensory transduction/vision
    a component
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • 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
  • cell & other
    REGULATION
    activated by TH
    induced by mitogenic stimulation
    hydrocortisone
    Other endocytosed and degraded by a number of cell types including chondrocytes, fibroblasts, and monocytes
    ASSOCIATED DISORDERS
    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
    tumoral        
    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
    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
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    cancerhead and neck 
    promoter methylation of TIMP3 (and CDH1) predicts better outcome in head and neck squamous cell carcinoma treated by radiotherapy only
    cardiovascular  
    could serve as a therapeutic approach in limiting abdominal aortic aneurysm development or expansion
    ANIMAL & CELL MODELS