Affinage

TMPRSS6

Transmembrane protease serine 6 · UniProt Q8IU80

Length
811 aa
Mass
90.0 kDa
Annotated
2026-04-28
100 papers in source corpus 15 papers cited in narrative 15 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

TMPRSS6 (matriptase-2) is a hepatocyte-expressed type II transmembrane serine protease that functions as the principal negative regulator of hepcidin, the master hormone controlling systemic iron homeostasis. TMPRSS6 undergoes autocatalytic self-activation requiring an intact SEA domain, then cleaves membrane hemojuvelin (HJV) at Arg121 and Arg326, thereby disrupting BMP-SMAD signaling and suppressing hepcidin (HAMP) transcription (PMID:18976966, PMID:25156943, PMID:25704252). The protease cycles through the plasma membrane via clathrin/AP-2- and dynamin-dependent endocytosis to lysosomes; blocking internalization prolongs surface residence and enhances HJV cleavage (PMID:21724843). Its expression is induced by BMP6/iron through SMAD/ID1 as a negative-feedback loop and by STAT5, while inflammation suppresses TMPRSS6 via reduced STAT5 phosphorylation; loss-of-function mutations cause iron-refractory iron-deficiency anemia (IRIDA) in humans (PMID:21622652, PMID:24376517, PMID:18603562).

Mechanistic history

Synthesis pass · year-by-year structured walk · 11 steps
  1. 2008 High

    Identification of TMPRSS6 as the critical sensor of iron deficiency that suppresses hepcidin transcription resolved how the body permits dietary iron absorption under low-iron conditions; loss of function causes microcytic anemia from unchecked hepcidin production.

    Evidence Forward genetic screen in ENU-mutagenized mice (mask phenotype), overexpression and promoter assays

    PMID:18451267

    Open questions at the time
    • Molecular substrate of TMPRSS6 not yet identified at this stage
    • Mechanism of hepcidin promoter suppression unknown
  2. 2008 High

    Demonstration that TMPRSS6 cleaves membrane hemojuvelin via its serine protease domain identified the direct substrate linking the protease to BMP-SMAD-hepcidin signaling, and showed that IRIDA mutations impair this cleavage.

    Evidence Cell-based HJV cleavage assay with domain-deletion and patient (R774C) mutants, zebrafish overexpression

    PMID:18603562 PMID:18976966

    Open questions at the time
    • Specific cleavage sites on HJV not mapped
    • In vivo confirmation of HJV as the sole relevant substrate not established
  3. 2010 High

    Genetic epistasis placing TMPRSS6 downstream of HJV in the BMP-SMAD pathway clarified that the protease acts by eliminating a required BMP co-receptor rather than signaling independently.

    Evidence Double-knockout mice (Tmprss6−/−/Hjv−/−) with hepatic gene expression profiling

    PMID:20200349

    Open questions at the time
    • Whether TMPRSS6 cleaves additional BMP pathway components not resolved
    • Contribution of soluble HJV fragments to residual signaling unclear
  4. 2010 High

    Discovery that the SEA-domain IRIDA mutation Y141C abolishes autocatalytic activation while preserving HJV binding established that self-activation is a prerequisite for substrate cleavage and a distinct mechanistic step.

    Evidence Patient mutant characterization with subcellular localization, HJV binding, and hepcidin mRNA assays in transfected cells

    PMID:20704562

    Open questions at the time
    • Structural basis of autocatalytic cleavage not determined
    • Whether additional cofactors assist activation unknown
  5. 2011 High

    Elucidation of constitutive clathrin/AP-2/dynamin-dependent endocytosis of TMPRSS6 showed that intracellular trafficking limits cell-surface lifetime of the protease and thereby tunes the magnitude of HJV cleavage and hepcidin suppression.

    Evidence Surface labeling, colocalization with clathrin/AP-2 markers, dynamin inhibition, cytoplasmic domain mutagenesis, hepcidin promoter assays in hepatic cells

    PMID:21724843

    Open questions at the time
    • Specific internalization motif(s) in cytoplasmic tail not fully mapped
    • Whether endosomal TMPRSS6 retains catalytic activity not tested
  6. 2011 High

    BMP6/iron-driven upregulation of TMPRSS6 via SMAD/ID1 revealed a negative-feedback loop: the same signal that induces hepcidin also amplifies its suppressor, explaining how hepcidin is fine-tuned rather than simply switched on.

    Evidence BMP6 treatment in vitro, anti-BMP6 antibody injection in mice, TMPRSS6 mRNA/protein/activity assays, promoter analysis

    PMID:21622652

    Open questions at the time
    • Quantitative contribution of feedback loop to steady-state hepcidin levels in vivo not modeled
    • Whether other BMP ligands contribute similarly unclear
  7. 2012 High

    Deletion of Tmprss6 in β-thalassemia mice showed that the protease is required for pathological hepcidin suppression by the expanded erythroid compartment, establishing TMPRSS6 as a therapeutic target for iron-loading anemias.

    Evidence Double mutant mice (Tmprss6−/−/Hbbth3/+), hematological, iron, and hepcidin analysis

    PMID:22490684

    Open questions at the time
    • Nature of the erythroid signal that acts through TMPRSS6 not identified
    • Degree of hepcidin restoration needed for therapeutic benefit not quantified
  8. 2013 High

    Identification of STAT5 as a direct positive transcriptional regulator of TMPRSS6, suppressed during inflammation via reduced STAT5 phosphorylation, explained how inflammatory signals elevate hepcidin partly by removing the TMPRSS6 brake.

    Evidence IL-6 treatment of hepatoma cells, LPS injection in mice, STAT5 ChIP on Tmprss6 promoter, phosphorylation analysis

    PMID:24376517

    Open questions at the time
    • Relative contribution of TMPRSS6 down-regulation versus direct IL-6/STAT3-driven hepcidin induction during inflammation not dissected
    • Growth hormone/STAT5 axis regulation of TMPRSS6 in vivo not independently confirmed
  9. 2014 High

    Systematic functional analysis of IRIDA mutations showed that missense variants impair either autocatalytic activation or HJV cleavage or both, and that genotype severity correlates with phenotype, solidifying the structure-function framework for clinical genetics.

    Evidence In vitro expression of multiple patient mutants, autocatalytic activation, HJV cleavage, and hepcidin promoter reporter assays, genotype-phenotype correlation

    PMID:25156943

    Open questions at the time
    • Crystal structure of TMPRSS6 protease domain not available to map mutation effects structurally
    • Residual activity thresholds for clinical disease not defined
  10. 2015 High

    Mapping HJV cleavage to Arg121 and Arg326 defined the precise sites through which TMPRSS6 inactivates the BMP co-receptor, providing the first substrate-level resolution.

    Evidence Systematic arginine-to-alanine mutagenesis of HJV, fragment analysis in conditioned media, molecular dynamics simulation

    PMID:25704252

    Open questions at the time
    • Whether these are the only physiologically relevant cleavage sites in vivo not confirmed
    • Kinetic parameters of cleavage not measured
  11. 2019 High

    Small-molecule inhibitors of TMPRSS6 recapitulated loss-of-function effects—blocking HJV cleavage and raising hepcidin—in human primary hepatocytes, providing pharmacological proof of concept for targeting the protease.

    Evidence Peptidomimetic and non-peptidic inhibitor treatment of HepG2 cells and human primary hepatocytes, HJV cleavage and hepcidin assays

    PMID:31543462

    Open questions at the time
    • In vivo efficacy and selectivity of inhibitors not demonstrated
    • Off-target effects on other TTSP family members not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • A high-resolution crystal structure of TMPRSS6, the complete repertoire of physiological substrates beyond HJV, and the identity of the erythroid signal that acts through TMPRSS6 in ineffective erythropoiesis remain to be established.
  • No crystal or cryo-EM structure of TMPRSS6
  • Whether substrates other than HJV contribute to hepcidin regulation is unresolved
  • Identity of erythroid factor that requires TMPRSS6 for hepcidin suppression is unknown

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 5
Localization
GO:0005886 plasma membrane 3 GO:0005764 lysosome 1 GO:0005768 endosome 1
Pathway
R-HSA-162582 Signal Transduction 3 R-HSA-382551 Transport of small molecules 3
Partners
HFE2ID1SMAD4STAT5A

Evidence

Reading pass · 15 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2008 TMPRSS6 (matriptase-2) is required to sense iron deficiency and suppress hepcidin (Hamp) transcription; overexpression of normal TMPRSS6 suppresses activation of the Hamp promoter, and the TMPRSS6 cytoplasmic domain mediates Hamp suppression via proximal promoter elements. Loss-of-function (splicing defect) in mice causes microcytic anemia due to high hepcidin and reduced dietary iron absorption. Chemically induced mouse mutant (mask), overexpression of TMPRSS6, promoter assays Science High 18451267
2008 TMPRSS6/matriptase-2 inhibits hepcidin activation by cleaving membrane hemojuvelin (HJV) at the plasma membrane; the serine protease domain is required for cleavage activity, the IRIDA patient mutant R774C shows decreased cleavage capacity, and the ectodomain of matriptase-2 mediates interaction with HJV. Cell-based cleavage assay, domain deletion mutants, patient mutant functional characterization, zebrafish overexpression Cell Metabolism High 18976966
2008 A truncating TMPRSS6 mutation in humans causes inappropriately elevated hepcidin levels, leading to defective iron absorption and iron-refractory iron-deficiency anemia (IRIDA), confirming the inhibitory role of TMPRSS6 on hepcidin synthesis in humans. Linkage analysis, gene sequencing, serum/urinary hepcidin measurement in patients Haematologica High 18603562
2010 TMPRSS6 down-regulates the BMP-SMAD signaling pathway to control hepcidin expression; mice deficient in both Tmprss6 and hemojuvelin (Hjv) show markedly decreased hepcidin and Id1 mRNA and develop systemic iron overload similar to Hjv-deficient mice alone, placing Tmprss6 downstream of Hjv in the BMP/Smad pathway. Genetic epistasis in double-knockout mice (Tmprss6−/−/Hjv−/−), hepatic gene expression analysis Blood High 20200349
2010 TMPRSS6 expression is upregulated by hypoxia-inducible factors (HIF-1α and HIF-2α) in hepatic cell lines; HIF-dependent up-regulation of TMPRSS6 increases membrane HJV shedding and decreases hepcidin promoter responsiveness to BMP signaling. Hypoxia treatment of hepatic cell lines, HIF pathway activation/inhibition, HJV shedding assays, hepcidin promoter reporter assay The Journal of Biological Chemistry Medium 20966077
2010 A TMPRSS6 mutation (Y141C) in the SEA domain prevents autocatalytic self-activation of the protease; the mutant localizes normally and binds HJV but cannot auto-catalytically activate itself, resulting in increased hepcidin mRNA expression. Patient mutation characterization, cell transfection, subcellular localization, HJV binding assay, hepcidin mRNA measurement The Biochemical Journal High 20704562
2011 TMPRSS6 undergoes constitutive clathrin/AP-2-dependent, dynamin-dependent endocytosis in hepatic cells; internalized TMPRSS6 transits through early endosomes to lysosomes. Mutations in the N-terminal cytoplasmic domain that block endocytosis keep TMPRSS6 at the cell surface, resulting in sustained HJV cleavage and significantly decreased hepcidin production. Cell surface labeling, co-localization with clathrin/AP-2 markers, dynamin inhibition, site-directed mutagenesis of cytoplasmic internalization signals, hepcidin promoter assay The Journal of Biological Chemistry High 21724843
2011 BMP6 and iron stimulate TMPRSS6 expression at the mRNA and protein levels via the BMP-SMAD pathway, with inhibitor of DNA binding 1 (ID1) identified as the key downstream element; TMPRSS6 upregulation by BMP6/iron increases matriptase-2 activity, HJV cleavage, and reduces hepcidin promoter responsiveness—a negative feedback loop. BMP6 treatment in vitro, neutralizing antibody injection in mice, TMPRSS6 mRNA/protein/activity assays, chromatin and promoter analysis Blood High 21622652
2011 The TMPRSS6 SNP rs855791 (V736A) is a functional variant: the 736A isoform inhibits hepcidin more efficiently than 736V in vitro and is associated with lower hepcidin levels and higher iron parameters in a genotyped population. In vitro overexpression of TMPRSS6 V736A vs V736V, hepcidin promoter assay, population genotyping with serum hepcidin measurements Blood Medium 21873547
2013 Inflammation down-regulates TMPRSS6 expression in vitro and in vivo through decreased STAT5 phosphorylation; STAT5 directly binds a STAT5 element on the Tmprss6 promoter and positively regulates its transcription. Loss of TMPRSS6 via this mechanism contributes to inflammation-induced hepcidin elevation. IL-6 treatment of hepatoma cells, LPS injection in mice, STAT5 ChIP and promoter binding assay, phosphorylation analysis PLoS One High 24376517
2015 TMPRSS6 cleaves hemojuvelin at arginine residues 121 and 326 in both the full-length and heterodimeric HJV isoforms; mutagenesis of these arginines abolishes or alters the cleavage fragment pattern, and molecular dynamics modeling supports their solvent-accessibility in the HJV structure. Site-directed mutagenesis of HJV arginine residues, co-expression with TMPRSS6, fragment analysis in conditioned media, molecular dynamics simulation Journal of Cellular and Molecular Medicine High 25704252
2014 IRIDA patient missense mutations in TMPRSS6 impair matriptase-2 autocatalytic activation and/or its ability to cleave membrane HJV and inhibit HJV-dependent hepcidin activation; genotype-phenotype analysis shows patients with two nonsense mutations have more severe anemia and higher hepcidin than those with partial-loss mutations. In vitro expression of IRIDA patient mutants, autocatalytic activation assay, HJV cleavage assay, hepcidin promoter reporter assay, genotype-phenotype correlation in patients Human Mutation High 25156943
2012 Deletion of Tmprss6 in Hbb(th3/+) β-thalassemia mice upregulates hepcidin, inhibits iron absorption and recycling, reduces ineffective erythropoiesis, splenomegaly, and iron loading; Tmprss6 is essential for hepcidin inhibition by the erythroid regulator in thalassemia. Double-knockout mouse model (Tmprss6−/−/Hbbth3/+), hematological and iron parameter analysis, hepcidin mRNA measurement Blood High 22490684
2014 Genetic epistasis shows that hepatic TFR2 acts upstream of TMPRSS6 in the hepcidin-regulation pathway; Hfe and Tfr2 are not substrates for Tmprss6 protease activity (double mutant mice show Tmprss6-phenotype dominance for hepcidin), while erythroid Tfr2 modulates erythropoiesis independently of hepcidin. Double-knockout mouse models (Tmprss6−/−/Tfr2−/− and Tmprss6−/−/Tfr2LCKO), hepcidin and iron parameter analysis Haematologica High 24658816
2019 Peptidomimetic and non-peptidic inhibitors of TMPRSS6 block TMPRSS6-dependent hemojuvelin cleavage in hepatocytes and increase HAMP expression and secreted hepcidin levels in HepG2 cells and human primary hepatocytes. TMPRSS6 inhibitor treatment of hepatic cell lines and primary hepatocytes, HJV cleavage assay, hepcidin mRNA and protein measurement Cell Chemical Biology High 31543462

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1985 Infection of HTLV-III/LAV in HTLV-I-carrying cells MT-2 and MT-4 and application in a plaque assay. Science (New York, N.Y.) 898 2992081
2005 Functional MT1 and MT2 melatonin receptors in mammals. Endocrine 640 16217123
2015 MT1 and MT2 Melatonin Receptors: A Therapeutic Perspective. Annual review of pharmacology and toxicology 466 26514204
2008 The serine protease TMPRSS6 is required to sense iron deficiency. Science (New York, N.Y.) 462 18451267
1975 Metabolism of toluene and xylenes by Pseudomonas (putida (arvilla) mt-2: evidence for a new function of the TOL plasmid. Journal of bacteriology 453 1176436
2008 The serine protease matriptase-2 (TMPRSS6) inhibits hepcidin activation by cleaving membrane hemojuvelin. Cell metabolism 437 18976966
2003 New selective ligands of human cloned melatonin MT1 and MT2 receptors. Naunyn-Schmiedeberg's archives of pharmacology 202 12764576
2013 Reducing TMPRSS6 ameliorates hemochromatosis and β-thalassemia in mice. The Journal of clinical investigation 194 23524968
2012 An RNAi therapeutic targeting Tmprss6 decreases iron overload in Hfe(-/-) mice and ameliorates anemia and iron overload in murine β-thalassemia intermedia. Blood 173 23223430
2004 Preferential formation of MT1/MT2 melatonin receptor heterodimers with distinct ligand interaction properties compared with MT2 homodimers. Molecular pharmacology 167 15266022
2005 Reduced hippocampal MT2 melatonin receptor expression in Alzheimer's disease. Journal of pineal research 164 15617532
2015 Anatomical and cellular localization of melatonin MT1 and MT2 receptors in the adult rat brain. Journal of pineal research 144 25726952
2008 A mutation in the TMPRSS6 gene, encoding a transmembrane serine protease that suppresses hepcidin production, in familial iron deficiency anemia refractory to oral iron. Haematologica 143 18603562
2012 Deletion of TMPRSS6 attenuates the phenotype in a mouse model of β-thalassemia. Blood 137 22490684
2013 MT1 and MT2 melatonin receptors: ligands, models, oligomers, and therapeutic potential. Journal of medicinal chemistry 131 24228714
2001 Functional expression of MT2 (Mel1b) melatonin receptors in human PAZ6 adipocytes. Endocrinology 131 11564683
2013 Heteromeric MT1/MT2 melatonin receptors modulate photoreceptor function. Science signaling 124 24106342
2010 Down-regulation of Bmp/Smad signaling by Tmprss6 is required for maintenance of systemic iron homeostasis. Blood 124 20200349
2019 Differential Function of Melatonin MT1 and MT2 Receptors in REM and NREM Sleep. Frontiers in endocrinology 117 30881340
2014 Unveiling the role of melatonin MT2 receptors in sleep, anxiety and other neuropsychiatric diseases: a novel target in psychopharmacology. Journal of psychiatry & neuroscience : JPN 115 23971978
2009 Pharmacology of ramelteon, a selective MT1/MT2 receptor agonist: a novel therapeutic drug for sleep disorders. CNS neuroscience & therapeutics 114 19228178
2009 Matriptase-2 (TMPRSS6): a proteolytic regulator of iron homeostasis. Haematologica 96 19377077
2017 Regulation of bone mass through pineal-derived melatonin-MT2 receptor pathway. Journal of pineal research 94 28512916
2011 Regulation of TMPRSS6 by BMP6 and iron in human cells and mice. Blood 94 21622652
2015 Convergence of melatonin and serotonin (5-HT) signaling at MT2/5-HT2C receptor heteromers. The Journal of biological chemistry 91 25770211
2011 TMPRSS6 rs855791 modulates hepcidin transcription in vitro and serum hepcidin levels in normal individuals. Blood 91 21873547
2005 Impaired hippocampal long-term potentiation in melatonin MT2 receptor-deficient mice. Neuroscience letters 91 16203090
2010 Regulation of type II transmembrane serine proteinase TMPRSS6 by hypoxia-inducible factors: new link between hypoxia signaling and iron homeostasis. The Journal of biological chemistry 87 20966077
1996 Molecular epidemiology and MT-2 cell tropism of Russian HIV type 1 variant. AIDS research and human retroviruses 84 8947294
2019 MT1 and MT2 melatonin receptors are expressed in nonoverlapping neuronal populations. Journal of pineal research 81 30937953
2011 Association of HFE and TMPRSS6 genetic variants with iron and erythrocyte parameters is only in part dependent on serum hepcidin concentrations. Journal of medical genetics 80 21785125
2018 Inhibiting MT2-TFE3-dependent autophagy enhances melatonin-induced apoptosis in tongue squamous cell carcinoma. Journal of pineal research 79 29149494
2015 Selective melatonin MT2 receptor ligands relieve neuropathic pain through modulation of brainstem descending antinociceptive pathways. Pain 78 25599452
2023 Melatonin Ameliorates Hepatic Ferroptosis in NAFLD by Inhibiting ER Stress via the MT2/cAMP/PKA/IRE1 Signaling Pathway. International journal of biological sciences 77 37564204
2006 Pineal and cortical melatonin receptors MT1 and MT2 are decreased in Alzheimer's disease. European journal of histochemistry : EJH 77 17213040
2012 Melatonin suppresses apoptosis and stimulates progesterone production by bovine granulosa cells via its receptors (MT1 and MT2). Theriogenology 72 22980085
2000 Selective MT(2) melatonin receptor antagonist blocks melatonin-induced antinociception in rats. Neuroscience letters 72 10717416
2014 Melatonin regulates the development and function of bovine Sertoli cells via its receptors MT1 and MT2. Animal reproduction science 62 24768045
2014 The MT2 receptor stimulates axonogenesis and enhances synaptic transmission by activating Akt signaling. Cell death and differentiation 61 25501601
2017 Enhancement of high glucose-induced PINK1 expression by melatonin stimulates neuronal cell survival: Involvement of MT2 /Akt/NF-κB pathway. Journal of pineal research 59 28580603
2006 TIMP independence of matrix metalloproteinase (MMP)-2 activation by membrane type 2 (MT2)-MMP is determined by contributions of both the MT2-MMP catalytic and hemopexin C domains. The Journal of biological chemistry 58 16825197
2014 The role of TMPRSS6/matriptase-2 in iron regulation and anemia. Frontiers in pharmacology 55 24966834
2009 Polymorphisms and mutations of human TMPRSS6 in iron deficiency anemia. Blood cells, molecules & diseases 53 19818657
2018 Targeting Melatonin MT2 Receptors: A Novel Pharmacological Avenue for Inflammatory and Neuropathic Pain. Current medicinal chemistry 52 28183259
2012 Association of TMPRSS6 polymorphisms with ferritin, hemoglobin, and type 2 diabetes risk in a Chinese Han population. The American journal of clinical nutrition 52 22301935
2007 The MT2 melatonin receptor subtype is present in human retina and decreases in Alzheimer's disease. Current Alzheimer research 52 17316165
2014 Melatonin MT₁ and MT₂ receptors display different molecular pharmacologies only in the G-protein coupled state. British journal of pharmacology 51 24117008
2011 A new perspective in Oral health: potential importance and actions of melatonin receptors MT1, MT2, MT3, and RZR/ROR in the oral cavity. Archives of oral biology 51 21459362
2015 Circadian Pattern of Melatonin MT1 and MT2 Receptor Localization in the Rat Suprachiasmatic Nucleus. Journal of circadian rhythms 49 27103927
2014 Functional and clinical impact of novel TMPRSS6 variants in iron-refractory iron-deficiency anemia patients and genotype-phenotype studies. Human mutation 49 25156943
1994 MT-2 cell tropism of human immunodeficiency virus type 1 isolates as a marker for response to treatment and development of drug resistance. The Journal of infectious diseases 48 7995974
2013 Mammalian MT1 and MT2 metallothioneins differ in their metal binding abilities. Metallomics : integrated biometal science 45 23925449
2017 Melatonin MT₁ and MT₂ Receptors in the Ram Reproductive Tract. International journal of molecular sciences 44 28335493
2022 Activation of MT1/MT2 to Protect Testes and Leydig Cells against Cisplatin-Induced Oxidative Stress through the SIRT1/Nrf2 Signaling Pathway. Cells 42 35626727
2022 Melatonergic Receptors (Mt1/Mt2) as a Potential Additional Target of Novel Drugs for Depression. Neurochemical research 41 35689787
2019 Activation of MT2 receptor ameliorates dendritic abnormalities in Alzheimer's disease via C/EBPα/miR-125b pathway. Aging cell 41 30706990
2015 Highly Potent and Selective MT2 Melatonin Receptor Full Agonists from Conformational Analysis of 1-Benzyl-2-acylaminomethyl-tetrahydroquinolines. Journal of medicinal chemistry 40 26334942
2013 Minireview: Toward the establishment of a link between melatonin and glucose homeostasis: association of melatonin MT2 receptor variants with type 2 diabetes. Molecular endocrinology (Baltimore, Md.) 40 23798576
2008 Molecular cloning and pharmacological characterization of rat melatonin MT1 and MT2 receptors. Biochemical pharmacology 39 18384758
2002 Role of endogenous melatonin and its MT2 receptor in the modulation of caerulein-induced pancreatitis in the rat. Journal of physiology and pharmacology : an official journal of the Polish Physiological Society 38 12510864
2017 Melatonin promotes triacylglycerol accumulation via MT2 receptor during differentiation in bovine intramuscular preadipocytes. Scientific reports 37 29118419
2010 A novel TMPRSS6 mutation that prevents protease auto-activation causes IRIDA. The Biochemical journal 37 20704562
2003 Mutagenesis studies of the human MT2 melatonin receptor. Biochemical pharmacology 36 12826274
2015 Antinociceptive properties of selective MT(2) melatonin receptor partial agonists. European journal of pharmacology 35 26162699
2014 The erythroid function of transferrin receptor 2 revealed by Tmprss6 inactivation in different models of transferrin receptor 2 knockout mice. Haematologica 34 24658816
2010 Genetic variability of TMPRSS6 and its association with iron deficiency anaemia. British journal of haematology 32 20738301
2015 The role of TMPRSS6 polymorphisms in iron deficiency anemia partially responsive to oral iron treatment. American journal of hematology 31 25557470
2017 Orphan GPR61, GPR62 and GPR135 receptors and the melatonin MT2 receptor reciprocally modulate their signaling functions. Scientific reports 30 28827538
2016 MT2-MMP induces proteolysis and leads to EMT in carcinomas. Oncotarget 30 27374080
2012 N-(Phenoxyalkyl)amides as MT(1) and MT(2) ligands: antioxidant properties and inhibition of Ca(2+)/CaM-dependent kinase II. Bioorganic & medicinal chemistry 30 23332368
1988 Entry of human immunodeficiency virus (HIV) into MT-2, human T cell leukemia virus carrier cell line. Archives of virology 30 2904253
2014 Effect of melatonin and analogues on corneal wound healing: involvement of Mt2 melatonin receptor. Current eye research 29 24892818
2011 Single nucleotide polymorphisms and mRNA expression for melatonin MT(2) receptor in depression. Psychiatry research 29 21353709
2009 Role of matriptase-2 (TMPRSS6) in iron metabolism. Acta haematologica 29 19907145
2023 TMPRSS6 as a Therapeutic Target for Disorders of Erythropoiesis and Iron Homeostasis. Advances in therapy 28 36690839
2020 Dysfunction of serotonergic activity and emotional responses across the light-dark cycle in mice lacking melatonin  MT2 receptors. Journal of pineal research 28 32239546
2019 Discovery and Development of TMPRSS6 Inhibitors Modulating Hepcidin Levels in Human Hepatocytes. Cell chemical biology 28 31543462
2013 Structure-based virtual screening of MT2 melatonin receptor: influence of template choice and structural refinement. Journal of chemical information and modeling 28 23541165
2003 Design and synthesis of 3-phenyl tetrahydronaphthalenic derivatives as new selective MT2 melatoninergic ligands. Bioorganic & medicinal chemistry 28 12538005
2014 Genetic deletion of MT₁/MT₂ melatonin receptors enhances murine cognitive and motor performance. Neuroscience 26 25046530
2012 Severe microcytic anemia but increased erythropoiesis in mice lacking Hfe or Tfr2 and Tmprss6. Blood cells, molecules & diseases 26 22244935
2010 The role of MT2-MMP in cancer progression. Biochemical and biophysical research communications 26 20117087
2000 A new melatonin receptor ligand with mt1-agonist and MT2-antagonist properties. Journal of pineal research 26 11068946
2018 The Mechanism of Melatonin and Its Receptor MT2 Involved in the Development of Bovine Granulosa Cells. International journal of molecular sciences 25 30002300
2017 The role of TMPRSS6 and HFE variants in iron deficiency anemia in celiac disease. American journal of hematology 25 29194702
2012 Design, synthesis and pharmacological evaluation of new series of naphthalenic analogues as melatoninergic (MT1/MT2) and serotoninergic 5-HT2C dual ligands (I). European journal of medicinal chemistry 25 22301214
2011 Liver hemojuvelin protein levels in mice deficient in matriptase-2 (Tmprss6). Blood cells, molecules & diseases 24 21612955
2008 The role of proline residues in the structure and function of human MT2 melatonin receptor. Journal of pineal research 23 18544139
2014 Regional upregulation of hippocampal melatonin MT2 receptors by valproic acid: therapeutic implications for Alzheimer's disease. Neuroscience letters 22 24909617
2013 Inflammation regulates TMPRSS6 expression via STAT5. PloS one 22 24376517
2011 Essential role of endocytosis of the type II transmembrane serine protease TMPRSS6 in regulating its functionality. The Journal of biological chemistry 22 21724843
2009 2-[(2,3-dihydro-1H-indol-1-yl)methyl]melatonin analogues: a novel class of MT2-selective melatonin receptor antagonists. Journal of medicinal chemistry 22 19193160
2008 Physiological states and energetic adaptation during growth of Pseudomonas putida mt-2 on glucose. Archives of microbiology 22 18493743
2017 Brain injury results in lower levels of melatonin receptors subtypes MT1 and MT2. Neuroscience letters 21 28377323
2015 Identification of TMPRSS6 cleavage sites of hemojuvelin. Journal of cellular and molecular medicine 21 25704252
2019 Higher melatonin in the follicle fluid and MT2 expression in the granulosa cells contribute to the OHSS occurrence. Reproductive biology and endocrinology : RB&E 20 30979376
2011 Molecular pharmacology of the mouse melatonin receptors MT₁ and MT₂. European journal of pharmacology 20 22202844
2021 MT1 and MT2 melatonin receptors play opposite roles in brain cancer progression. Journal of molecular medicine (Berlin, Germany) 19 33392634
2017 Ramelteon, a selective MT1/MT2 receptor agonist, suppresses the proliferation and invasiveness of endometrial cancer cells. Human cell 19 28382516
2014 MT2-MMP expression associates with tumor progression and angiogenesis in human lung cancer. International journal of clinical and experimental pathology 19 25031779