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FLASH GENE
Symbol TMPRSS6 contributors: mct/npt - updated : 15-12-2015
HGNC name transmembrane protease, serine 6
HGNC id 16517
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
  • antithrombin III has robust inhibitory properties toward ST14, TMPRSS6, HPN and TMPRSS11E, whereas plasminogen activator inhibitor-1 and alpha(2)-antiplasmin inhibited TMPRSS6, HPN and TMPRSS11E, and to a much lesser extent ST14
  • 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