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FLASH GENE
Symbol TMPRSS6 contributors: mct/npt - updated : 15-12-2015
HGNC name transmembrane protease, serine 6
HGNC id 16517
Corresponding disease
IRIDA iron-refractory iron deficiency anemia
Location 22q12.3      Physical location : 37.461.478 - 37.499.693
Synonym name
  • matriptase-2
  • membrane-bound mosaic serine proteinase matriptase-2
  • type II transmembrane serine protease 6
  • Synonym symbol(s) FLJ30744, MT2
    EC.number 3.4.21.-
    DNA
    TYPE functioning gene
    STRUCTURE 45.20 kb     18 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    Binding site   HRE
    text structure
  • a functional hypoxia-responsive element (HRE), and action of HIF1A on TMPRSS6 promoter activity reveals a new regulative element for the suppression of hepcidin synthesis
  • MAPPING cloned Y linked N status provisional
    Physical map
    TXN2 22q13.1 thioredoxin 2 FLJ23322 22q13.1 hypothetical protein FLJ23322 EIF3S7 22q13.1 eukaryotic translation initiation factor 3, subunit 7 zeta, 66/67kDa CACNG2 22q13.1 calcium channel, voltage-dependent, gamma subunit 2 RABL4 22q13.1 RAB, member of RAS oncogene family-like 4 PVALB 22q13.1 parvalbumin NCF4 22q13.1 neutrophil cytosolic factor 4, 40kDa CSF2RB 22q13.1 colony stimulating factor 2 receptor, beta, low-affinity (granulocyte-macrophage) CSF2RB2 22q13.1 colony stimulating factor 2 receptor, beta, 2 MGC35206 22q13.1 hypothetical protein MGC35206 TST 22q13.1 thiosulfate sulfurtransferase (rhodanese) MPST 22q13.1 mercaptopyruvate sulfurtransferase FLJ12242 22q13.1 hypothetical protein FLJ12242 TMPRSS6 22q13.1 transmembrane serine protease 6 IL2RB 22q13.1 interleukin 2 receptor, beta C1QTNF6 22q13.1 C1q and tumor necrosis factor related protein 6 SSTR3 22q13.1 somatostatin receptor 3 RAC2 22q13.1 ras-related C3 botulinum toxin substrate 2 (rho family, small GTP binding protein Rac2) PSCD4 22q13.1 pleckstrin homology, Sec7 and coiled-coil domains 4 KIAA1904 22q13.1 KIAA1904 protein MFNG 22q13.1 manic fringe homolog (Drosophila) CARD10 22q13 caspase recruitment domain family, member 10 CDC42EP1 22q13.1 CDC42 effector protein (Rho GTPase binding) 1 LGALS2 22q13.1 lectin, galactoside-binding, soluble, 2 (galectin 2) GGA1 22q13.31 golgi associated, gamma adaptin ear containing, ARF binding protein 1 SH3BP1 22q13.1 SH3-domain binding protein 1 PLP
    RNA
    TRANSCRIPTS type messenger
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    18 - 3140 - 802 - 2006 16533768
    18 - 3212 - 811 - 2006 16533768
    19 - 3196 - 824 - 2006 16533768
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Digestiveliver   predominantly Homo sapiens
    Endocrineadrenal gland    
     thyroid   highly
    Reproductivemale systemtestis   
    Respiratoryrespiratory tracttrachea   
    Visualeyeretina    Homo sapiens
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Digestivehepatocyte Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period fetal
    Text liver
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • a short cytoplasmic domain, with key AAs within its cytoplasmic tail that are important in sequestering the enzyme within the cell , necessary for its regulation
  • a scavenger receptor cysteine-rich (SRCR) domain, and a serine protease domain
  • a type II transmembrane sequence
  • a central region with several modular structural domains including two CUB (complement factor C1s/C1r, urchin embryonic growth factor, bone morphogenetic protein) domains and three low density lipoprotein receptor tandem repeats
  • a C-terminal catalytic domain
  • HOMOLOGY
    Homologene
    FAMILY
  • peptidase S1 family
  • type II transmembrane serine proteases (TTSP)
  • CATEGORY enzyme
    SUBCELLULAR LOCALIZATION     plasma membrane
        intracellular
    intracellular,cytoplasm,organelle,membrane
    intracellular,cytoplasm,organelle,endoplasmic reticulum
    intracellular,cytoplasm,organelle,endosome
    intracellular,cytoplasm,organelle,lysosome
    text
  • endocytosed TMPRSS6 next transited in early endosomes and then to lysosomes
  • basic FUNCTION
  • may be involved in proteolysis and peptidolysis
  • may be playing a specialized role in matrix remodeling processes taking place in this tissue during development or in adult tissues
  • putative role of matriptase-2/TMPRSS6 in iron homeostasis
  • may be involved in matrix remodeling processes in the liver
  • negatively regulates the expression of the systemic iron regulatory hormone hepcidin and is essential for normal systemic iron homeostasis (may cleave a protein that acts in or on hepatocytes to negatively regulate hepcidin production, secretion, or clearance)
  • regulator of hepcidin synthesis and iron handling, that is crucial in hemoglobin level maintenance
  • involvement of TMPRSS6 in control of iron homeostasis and in normal erythropoiesis
  • controls iron homeostasis through its negative regulation of expression of hepcidin
  • controls iron homeostasis through its negative regulation of expression of hepcidin
  • importance of TMPRSS6 trafficking at the plasma membrane in the regulation of hepcidin expression, an event that is essential for iron homeostasis
  • TMPRSS6 cleavage of HFE2 occurs either at the cell surface or during a retrograde trafficking to the TGN/Golgi compartment in a NEO1-dependent manner
  • has the ability to suppress the angiogenic nature of HECV (human vascular endothelial cells), suggesting that it could have a potential role in prostate and breast tumour suppression through its anti-angiogenic properties
  • is the key enzyme of iron homoeostasis modulating the expression of the liver peptide hormone HAMP
  • crucial role in the regulation of iron homeostasis by inhibiting HAMP expression
  • is a critical participant in retinal iron homeostasis
  • hepatic membrane serine protease that regulates iron homeostasis
  • type II transmembrane serine protease controlling the expression of hepcidin, the key regulator of iron homeostasis
  • regulates HAMP expression by cleaving hemojuvelin (HFE2), a bone morphogenetic protein (BMP) coreceptor in the hepcidin regulatory pathway
  • CELLULAR PROCESS
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    a component
  • NEO1 likely forms a ternary complex with both TMPRSS6 and HFE2 at the plasma membrane
  • INTERACTION
    DNA
    RNA
    small molecule
    protein
  • controls iron homeostasis by repressing expression of the HAMP gene, which encodes hepcidin, the major hormonal regulator of iron metabolism
  • TMPRSS6 regulates the levels of membrane-bound HFE2 in hepatocytes by binding to and cleaving HFE2 into an inactive soluble form that is released from cells
  • NEO1 interacted with TMPRSS6 as well as with HFE2 and facilitated the cleavage of HFE2 by TMPRSS6
  • SPINT2 is an inhibitor of PRSS6 that modulates the synthesis of HAMP and provides new insights into the regulatory mechanism of iron homoeostasis
  • its inhibition via decreased STAT5 phosphorylation may be an additional mechanism by which inflammation stimulates hepcidin expression to regulate iron homeostasis and immunity
  • suppresses the expression of hepatic hepcidin, an iron regulatory hormone, by cleaving membrane HFE2 into an inactive form
  • cell & other
    REGULATION
    induced by BMP6 and iron (BMP6 and iron not only induce hepcidin expression but also induce TMPRSS6, a negative regulator of hepcidin expression)
    Other modulation of its expression could serve as a negative feedback inhibitor to avoid excessive hepcidin increases by iron to help maintain tight homeostatic balance of systemic iron levels
    in addition to shedding, internalization of TMPRSS6 can also act as a cellular mode of TMPRSS6 regulation with direct consequences on the processing of specific cell-surface substrates such as HFE2
    up-regulated under iron deprivation
    N-glycosylation is required for TMPRSS6 autoactivation and ectodomain shedding
    ASSOCIATED DISORDERS
    corresponding disease(s) IRIDA
    Susceptibility
  • to breast cancer
  • to lower hemoglobin levels
  • to variation in serum iron and transferrin saturation
  • to iron deficiency and iron-deficiency anemia
  • Variant & Polymorphism SNP
  • A allele of rs855791 associated with lower hemoglobin levels
  • SNPs associated with variation in serum iron and transferrin saturation
  • variants in TMPRSS6 are genetic risk factors for iron deficiency and iron-deficiency anemia (IDA)
  • Candidate gene
    Marker
    Therapy target
    SystemTypeDisorderPubmed
    metabolismiron 
    inhibition of the putative protease function of TMPRSS6 might be a potential treatment for disorders in which hepcidin is inappropriately low, such as primary hemochromatosis and iron loading anemias
    bloodhemoglobin 
    similarly, treatment with agonists or with the endogenous substrate of TMPRSS6 might be employed in the anemia of chronic disease, in which hepcidin is inappropriately high
    ANIMAL & CELL MODELS