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TLR4 Gene

protein-coding   GIFtS: 71
GCID: GC09P120466

Toll-Like Receptor 4

  See related diseases
at  

(According to 1HGNC, 2Entrez Gene,
3UniProtKB/Swiss-Prot, 4UniProtKB/TrEMBL, 5OMIM, 6GeneLoc, 7Ensembl, 8DME, 9miRBase, 10fRNAdb, 12H-InvDB, 13NCBI, 14NONCODE, and/or 15RNAdb)
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Aliases
Toll-Like Receptor 41 2     TLR-42
hToll2 3     TOLL2
ARMD102 5     Homolog Of Drosophila Toll2
CD2842     CD284 Antigen3

External Ids:    HGNC: 118501   Entrez Gene: 70992   Ensembl: ENSG000001368697   OMIM: 6030305   UniProtKB: O002063   

Export aliases for TLR4 gene to outside databases

Previous GC identifers: GC09P111571 GC09P112113 GC09P113920 GC09P115842 GC09P117546 GC09P119506 GC09P090084


(According to Entrez Gene, GeneCards, Tocris Bioscience, Wikipedia's Gene Wiki, PharmGKB,
UniProtKB/Swiss-Prot, and/or UniProtKB/TrEMBL)
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Entrez Gene summary for TLR4 Gene:
The protein encoded by this gene is a member of the Toll-like receptor (TLR) family which plays a fundamental role
in pathogen recognition and activation of innate immunity. TLRs are highly conserved from Drosophila to humans
and share structural and functional similarities. They recognize pathogen-associated molecular patterns that are
expressed on infectious agents, and mediate the production of cytokines necessary for the development of
effective immunity. The various TLRs exhibit different patterns of expression. This receptor has been implicated
in signal transduction events induced by lipopolysaccharide (LPS) found in most gram-negative bacteria. Mutations
in this gene have been associated with differences in LPS responsiveness. Multiple transcript variants encoding
different isoforms have been found for this gene. (provided by RefSeq, Jan 2012)

GeneCards Summary for TLR4 Gene:
TLR4 (toll-like receptor 4) is a protein-coding gene. Diseases associated with TLR4 include endotoxin hyporesponsiveness, and macular degeneration, age-related, 10. GO annotations related to this gene include lipopolysaccharide binding and receptor activity. An important paralog of this gene is ENSG00000173366.

UniProtKB/Swiss-Prot: TLR4_HUMAN, O00206
Function: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide
(LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory
response. Also involved in LPS-independent inflammatory responses triggered by Ni(2+). These responses require
non-conserved histidines and are, therefore, species-specific

summary for TLR4 Gene:
Toll-like receptors (TLRs) are single transmembrane cell-surface receptors, which have a key role in the
innate immune system. TLRs generally exist as homodimers (although TLR2-TLR6 heterodimers have been
reported) and are found on immune cells such as macrophages, B lymphocytes and mast cells. Toll-like
receptors are activated by molecules associated with biological threat and are highly specific towards
evolutionary conserved entities on microbes, such as bacterial cell-surface lipopolysaccharides, flagella
and unmethylated CpG islands. It has been suggested that some toll-like receptors may have endogenous
ligands, such as Hsp60 and fibrinogen, and this has promoted speculation that endogenous toll-like receptor
activators may have a pathological role in autoimmune disease. Activation of toll-like receptors initiates
downstream signaling cascades, initially via the adapter molecules MyD88, Trap, Trif and Tram, which
converge on the PI 3-K and NF-kappaB pathways and regulate intracellular kinases and gene expression. This
can stimulate an inflammatory and/or antigen-specific immune response. The signaling cascade coupled to
toll-like receptor activation is very similar to that of interleukin-1 receptor (IL-1R) activation.

Gene Wiki entry for TLR4 (TLR 4) Gene


(According to GeneLoc and/or HGNC, and/or
Entrez Gene (NCBI build 37),
and/or miRBase,
Genomic Views according to UCSC (hg19) and Ensembl (release 75), Regulatory elements and Epigenetics data according to QIAGEN, and/or SwitchGear Genomics)
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RefSeq DNA sequence:
NC_000009.12  NC_018920.2  NT_008470.20  
Regulatory elements:
   Regulatory transcription factor binding sites in the TLR4 gene promoter:
         Sp1   AP-1   ATF-2   PPAR-alpha   AREB6   POU2F1   POU2F1a   c-Jun   
         Other transcription factors

SwitchGear Promoter luciferase reporter plasmidTLR4 promoter sequence
   Search Chromatin IP Primers for TLR4

Epigenetics:
DNA Methylation CpG Assay Predesigned for Pyrosequencing in human, mouse, rat TLR4


Genomic Location:
Genomic View: UCSC Golden Path with GeneCards custom track

Entrez Gene cytogenetic band: 9q33.1   Ensembl cytogenetic band:  9q33.1   HGNC cytogenetic band: 9q33.1

TLR4 Gene in genomic location: bands according to Ensembl, locations according to (and/or Entrez Gene and/or Ensembl if different)
TLR4 gene location

GeneLoc information about chromosome 9         GeneLoc Exon Structure

GeneLoc location for GC09P120466:  view genomic region     (about GC identifiers)

Start:
120,466,460 bp from pter      End:
120,479,768 bp from pter
Size:
13,309 bases      Orientation:
plus strand

(According to 1UniProtKB, HORDE, 2neXtProt, Ensembl, and/or Reactome, Modification sites according to PhosphoSitePlus, Specific Peptides from DME, RefSeq according to NCBI, PDB rendering according to OCA and/or Proteopedia, Recombinant Proteins from EMD Millipore, R&D Systems, GenScript, Enzo Life Sciences, OriGene, Novus Biologicals, Sino Biological, ProSpec, and/or Cloud-Clone Corp.,
Biochemical Assays by EMD Millipore, R&D Systems, OriGene, GenScript, Cell Signaling Technology, Enzo Life Sciences, and/or Cloud-Clone Corp., Antibodies by EMD Millipore, R&D Systems, Cell Signaling Technology, OriGene, Novus Biologicals, Thermo Fisher Scientific, LSBio, Abcam, Cloud-Clone Corp, and/or others.)
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UniProtKB/Swiss-Prot: TLR4_HUMAN, O00206 (See protein sequence)
Recommended Name: Toll-like receptor 4 precursor  
Size: 839 amino acids; 95680 Da
Subunit: Belongs to the lipopolysaccharide (LPS) receptor, a multi-protein complex containing at least CD14, LY96
and TLR4. Binding to bacterial LPS leads to homodimerization. Interacts with LY96 via the extracellular domain.
Interacts with MYD88 and TIRAP via their respective TIR domains. Interacts with NOX4. Interacts with CNPY3 (By
similarity). Interacts with HSP90B1. The interaction with both CNPY3 and HSP90B1 is required for proper folding
in the endoplasmic reticulum. Interacts with MLK4; this interaction leads to negative regulation of TLR4
signaling
Miscellaneous: His-456 and His-458 are found in TLR4 of human and several other primate species and may be
responsible for inflammatory responses triggered by nickel (Ni(2+)). Ni(2+) may cross-link the two receptor
monomers through specific histidines, triggering the formation of a dimer that structurally resembles that
induced by LPS. This process may be the basis for the development of contact allergy to Ni(2+). A mouse model of
contact allergy to Ni(2+) in which TLR4-deficient mice expresses human TLR4 has been proposed
Selected PDB 3D structures from and Proteopedia for TLR4 (see all 10):
2Z62 (3D)        2Z63 (3D)        2Z65 (3D)        2Z66 (3D)        3FXI (3D)        3UL7 (3D)    
Secondary accessions: A8K1Y8 A9XLP9 A9XLQ0 A9XLQ1 B4E194 D1CS52 D1CS53 Q5VZI8 Q5VZI9 Q9UK78
Q9UM57
Alternative splicing: 3 isoforms:  O00206-1   O00206-2   O00206-3   (No experimental confirmation available)

Explore the universe of human proteins at neXtProt for TLR4: NX_O00206

Explore proteomics data for TLR4 at MOPED

Post-translational modifications: 

  • N-glycosylated. Glycosylation of Asn-526 and Asn-575 seems to be necessary for the expression of TLR4 on the cell
    surface and the LPS-response. Likewise, mutants lacking two or more of the other N-glycosylation sites were
    deficient in interaction with LPS1
  • Glycosylation2 at Asn35, Asn173, Asn205, Asn282, Asn309, Asn497, Asn526, Asn575, Asn624, Asn630
  • Modification sites at PhosphoSitePlus

  • See TLR4 Protein Expression from SPIRE MOPED, PaxDB, and MaxQB

    REFSEQ proteins (3 alternative transcripts): 
    NP_003257.1  NP_612564.1  NP_612567.1  

    ENSEMBL proteins: 
     ENSP00000377997   ENSP00000363089  
    Reactome Protein details: O00206

    TLR4 Human Recombinant Protein Products:

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    R&D Systems Recombinant & Natural Proteins for TLR4 (TLR4/MD-2 Complex, TLR4)
    Enzo Life Sciences proteins for TLR4
    OriGene Purified Protein for TLR4
    OriGene Protein Over-expression Lysate for TLR4
    OriGene MassSpec for TLR4
    OriGene Custom Protein Services for TLR4
    GenScript Custom Purified and Recombinant Proteins Services for TLR4
    Novus Biologicals TLR4 Proteins
    Novus Biologicals TLR4 Lysates
    Sino Biological Recombinant Protein for TLR4
    Sino Biological Cell Lysate for TLR4
    Browse ProSpec Recombinant Proteins
    Cloud-Clone Corp. Proteins for TLR4

    TLR4 Antibody Products:

    EMD Millipore Mono- and Polyclonal Antibodies for the study of TLR4
    R&D Systems Antibodies for TLR4
    Cell Signaling Technology (CST) Antibodies for TLR4 
    OriGene Antibodies for TLR4
    OriGene Custom Antibody Services for TLR4
    Novus Biologicals TLR4 Antibodies
    Abcam antibodies for TLR4 (Q9Y6Y9, O00206)
    Cloud-Clone Corp. Antibodies for TLR4
    ThermoFisher Antibodies for TLR4
    LSBio Antibodies in human, mouse, rat for TLR4

    TLR4 Assay Products:

    Browse Kits and Assays available from EMD Millipore
    OriGene Custom Assay Services for TLR4
    R&D Systems Proteome Profiler Antibody Arrays for TLR4
    GenScript Custom Assay Services for TLR4
    Browse Enzo Life Sciences for kits & assays
    Cloud-Clone Corp. ELISAs for TLR4
    Cloud-Clone Corp. CLIAs for TLR4


    (According to HGNC, IUPHAR, InterPro, ProtoNet, UniProtKB, and/or BLOCKS, Sets of similar genes according to GeneDecks)
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    HGNC Gene Families:
    CD: CD molecules

    IUPHAR Guide to PHARMACOLOGY protein family classification: TLR4
    Toll-like receptor family

    Selected InterPro protein domains (see all 7):
     IPR000483 Cys-rich_flank_reg_C
     IPR027168 TLR4
     IPR001611 Leu-rich_rpt
     IPR025875 Leu-rich_rpt_4
     IPR000157 TIR_dom

    Graphical View of Domain Structure for InterPro Entry O00206

    ProtoNet protein and cluster: O00206

    3 Blocks protein domains:
    IPB000157 TIR domain
    IPB000483 Cysteine-rich flanking region
    IPB001611 Leucine-rich repeat signature


    UniProtKB/Swiss-Prot: TLR4_HUMAN, O00206
    Domain: The TIR domain mediates interaction with NOX4
    Similarity: Belongs to the Toll-like receptor family
    Similarity: Contains 18 LRR (leucine-rich) repeats
    Similarity: Contains 1 LRRCT domain
    Similarity: Contains 1 TIR domain


    TLR4 for domains           About GeneDecksing


    (According to 1UniProtKB, Genatlas, LifeMap Discovery™, IUBMB, and/or 2DME, Human phenotypes from GenomeRNAi, Animal models from MGI Mar 06 2013, inGenious Targeting Laboratory, genOway,
    transcription factor targeting from QIAGEN and/or HOMER, miRNA Gene Targets from miRTarBase, shRNA from OriGene, siRNAs from OriGene, QIAGEN, microRNA from QIAGEN, SwitchGear Genomics, Gene Editing from DNA2.0, Clones from OriGene, GenScript, Sino Biological, DNA2.0, and Vector BioLabs, Cell Lines from GenScript, ESI BIO, In Situ Hybridization Assays from Advanced Cell Diagnostics, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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    Molecular Function:

         UniProtKB/Swiss-Prot Summary: TLR4_HUMAN, O00206
    Function: Cooperates with LY96 and CD14 to mediate the innate immune response to bacterial lipopolysaccharide
    (LPS). Acts via MYD88, TIRAP and TRAF6, leading to NF-kappa-B activation, cytokine secretion and the inflammatory
    response. Also involved in LPS-independent inflammatory responses triggered by Ni(2+). These responses require
    non-conserved histidines and are, therefore, species-specific

         Genatlas biochemistry entry for TLR4:
    Drosophila transmembrane receptor Toll homolog 4,specifically expressed in placenta,and on cells of the immune
    system binding directly to TLR2 and essential component of liposaccharides (LPS) receptor,inducing the LPS
    signaling pathway

         Gene Ontology (GO): 5 molecular function terms:    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0001530lipopolysaccharide binding NAS10835634
    GO:0001875lipopolysaccharide receptor activity IDA19252480
    GO:0004872receptor activity TAS10426995
    GO:0004888transmembrane signaling receptor activity NAS11970998
    GO:0005515protein binding IPI11441107
         
    TLR4 for ontologies           About GeneDecksing


    Phenotypes:
         1 GenomeRNAi human phenotype for TLR4:
     Increased viability with 4OH t 

         Selected MGI mutant phenotypes (inferred from 10 alleles(MGI details for Tlr4) (see all 23):
     adipose tissue  behavior/neurological  cardiovascular system  cellular  digestive/alimentary 
     growth/size/body  hearing/vestibular/ear  hematopoietic system  homeostasis/metabolism  immune system 
     integument  limbs/digits/tail  liver/biliary system  mortality/aging  muscle 

    TLR4 for phenotypes           About GeneDecksing

    Animal Models:
         MGI mouse knock-outs for TLR4: Tlr4tm1Aki Tlr4tm1.1Djh

       inGenious Targeting Laboratory: Let us create your new Knockout/Knockin mouse model for TLR4
       inGenious Targeting Laboratory: Contact us about creating complex and humanized mouse models for TLR4

       genOway customized KO model: permanent, tissue-specific or time-controlled inactivation for TLR4
       genOway customized Knockin model: humanization, point mutation, expression monitoring, etc. for TLR4

    miRNA
    Products:
        
    miRTarBase miRNAs that target TLR4:
    hsa-mir-21-5p (MIRT031004), hsa-mir-335-5p (MIRT018411), hsa-mir-146a-5p (MIRT006530), hsa-let-7i-5p (MIRT003050), hsa-mir-1 (MIRT023907)

    Block miRNA regulation of human, mouse, rat TLR4 using miScript Target Protectors
    Selected qRT-PCR Assays for microRNAs that regulate TLR4 (see all 16):
    hsa-miR-549 hsa-miR-140-5p hsa-miR-219-1-3p hsa-miR-3938 hsa-miR-642a hsa-miR-4328 hsa-miR-944 hsa-miR-3074-3p
    SwitchGear 3'UTR luciferase reporter plasmidTLR4 3' UTR sequence
    Inhib. RNA
    Products:
        
    OriGene RNAi products in human, mouse, rat for TLR4
    Predesigned siRNA for gene silencing in human, mouse, rat TLR4

    Gene Editing
    Products:
    DNA2.0 Custom Protein Engineering Service for TLR4

    Clone
    Products:
         
    OriGene clones in human, mouse for TLR4 (see all 8)
    OriGene ORF clones in mouse, rat for TLR4
    OriGene custom cloning services - gene synthesis, subcloning, mutagenesis, variant library, vector shuttling
    GenScript: all cDNA clones in your preferred vector: TLR4 (NM_138554)
    Sino Biological Human cDNA Clone for TLR4
    DNA2.0 Custom Codon Optimized Gene Synthesis Service for TLR4
    Vector BioLabs ready-to-use adenovirus/AAV for human, mouse, rat TLR4

    Cell Line
    Products:
         
    GenScript Custom overexpressing Cell Line Services for TLR4
    Browse ESI BIO Cell Lines and PureStem Progenitors for TLR4 
    In Situ Assay
    Products:
       

     
    Advanced Cell Diagnostics RNAscope RNA in situ hybridization assays for TLR4


    (According to UniProtKB, COMPARTMENTS Subcellular localization database, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene.)
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    Subcellular locations from UniProtKB/Swiss-Prot
    TLR4_HUMAN, O00206: Membrane; Single-pass type I membrane protein
    Subcellular locations from COMPARTMENTS: 

    CompartmentConfidence
    plasma membrane5
    endosome4
    extracellular3
    nucleus3
    cytoskeleton2
    cytosol2
    endoplasmic reticulum2
    golgi apparatus2
    lysosome2
    vacuole2
    mitochondrion1
    peroxisome1

    Gene Ontology (GO): Selected cellular component terms (see all 8):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0005737cytoplasm IDA19740627
    GO:0005886plasma membrane TAS--
    GO:0005887integral component of plasma membrane IDA15027902
    GO:0009897external side of plasma membrane IDA16514062
    GO:0010008endosome membrane TAS--

    TLR4 for ontologies           About GeneDecksing


    (SuperPaths according to PathCards, Pathways according to R&D Systems, Cell Signaling Technology, KEGG, PharmGKB, BioSystems, Sino Biological, Reactome, Tocris Bioscience, GeneGo (Thomson Reuters), QIAGEN, and/or UniProtKB, Sets of similar genes according to GeneDecks, Interaction Networks according to QIAGEN, and/or STRING, Interactions according to 1UniProtKB, 2MINT, 3I2D, and/or 4STRING, with links to IntAct and Ensembl, Ontologies according to Gene Ontology Consortium 01 Apr 2014 via Entrez Gene).
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    SuperPaths for TLR4 About   (see all 41)  
    See pathways by source

    SuperPathContained pathways About
    1NOD-like Receptor Signaling Pathways
    Toll-Like receptor Signaling Pathways0.58
    Inflammasome Activation Pathways0.51
    NOD-like Receptor Signaling Pathways0.58
    Immune response Role of TLRs 3 and 4 in cell antiviral response TICAM1 specific signaling pathways0.33
    2Toll-like receptor signaling pathway
    Toll-like receptor signaling pathway0.94
    Chagas disease (American trypanosomiasis)0.32
    Toll-like receptor signaling pathway0.94
    Hepatitis B0.31
    Regulation of toll-like receptor signaling pathway0.93
    3Toll Comparative Pathway
    Toll Comparative Pathway0.61
    Immune response MIF in innate immunity response0.46
    TLR-TRIF Pathway0.61
    iNOS Signaling0.34
    4Immune response Bacterial infections in normal airways
    Immune response Bacterial infections in normal airways0.78
    Immune response Toll like receptor TLR ligands and common TLR signaling pathway leading to cell proinflammatory response0.47
    Bacterial infections in CF airways0.78
    Transcription NF kB signaling pathway0.32
    5Development Slit Robo signaling
    Pathogenic Escherichia coli infection0.43
    Pathogenic Escherichia coli infection0.41

    Pathways by source                                                                                                                                                                 See SuperPaths
    Show all pathways

    Selected R&D Systems Pathways for TLR4 (see all 7)
        NOD-like Receptor Signaling Pathways
    Inflammasome Activation Pathways
    IL-21 Signaling and its Primary Biological Effects in Different Immune Cell Types
    A-beta Uptake & Degradation
    Th1 Differentiation

    Selected Downloadable PowerPoint Slides of GeneGlobe Pathway Central Maps for TLR4 (see all 21)
        14-3-3 Induced Apoptosis
    MSP-RON Signaling
    Toll-Like Receptors Pathway
    TRAF Pathway
    IL-10 Pathway

    1 Cell Signaling Technology (CST) Pathway for TLR4
        NF-kappaB Signaling

    1 Tocris Bioscience Pathway for TLR4
        Toll-like Receptor Pathway

    Selected GeneGo (Thomson Reuters) Pathways for TLR4 (see all 8)
        Immune response TLR3 and TLR4 induce TICAM1-specific signaling pathway
    Immune response Bacterial infections in normal airways
    Immune response MIF in innate immunity response
    Immune response TLR signaling pathways
    Bacterial infections in CF airways

    5 BioSystems Pathways for TLR4
        Spinal Cord Injury
    Toll-like receptor signaling pathway
    Corticotropin-releasing hormone
    Pathogenic Escherichia coli infection
    Regulation of toll-like receptor signaling pathway

    1 Sino Biological Pathway for TLR4
        NF-kB (NFkB) Pathway

    Selected Reactome Pathways for TLR4 (see all 7)
        IKK complex recruitment mediated by RIP1
    TRIF-mediated programmed cell death
    MyD88-independent cascade
    Toll Like Receptor 4 (TLR4) Cascade
    Activation of IRF3/IRF7 mediated by TBK1/IKK epsilon


    Selected Kegg Pathways  (Kegg details for TLR4) (see all 21):
        NF-kappa B signaling pathway
    HIF-1 signaling pathway
    Phagosome
    PI3K-Akt signaling pathway
    Toll-like receptor signaling pathway


    TLR4 for pathways           About GeneDecksing

        Pathway & Disease-focused RT2 Profiler PCR Arrays including TLR4 (see all 17): 
              Toll-Like Receptor Signaling Pathway in human mouse rat
              Liver Cancer in human mouse rat
              Inflammatory Response & Autoimmunity in human mouse rat
              T-cell & B-cell Activation in human mouse rat
              Inflammatory Response & Autoimmunity 384HT in human mouse rat

    Interactions:

        GeneGlobe Interaction Network for TLR4

    STRING Interaction Network Preview (showing 5 interactants - click image to see 25)

    Selected Interacting proteins for TLR4 (O002061, 2, 3 ENSP000003630894) via UniProtKB, MINT, STRING, and/or I2D (see all 114)
    InteractantInteraction Details
    GeneCardExternal ID(s)
    LY96Q9Y6Y91, 3, ENSP000002848184EBI-528701,EBI-1539247 I2D: score=6 STRING: ENSP00000284818
    TIRAPP587531, 3, ENSP000003764454EBI-528701,EBI-528644 I2D: score=5 STRING: ENSP00000376445
    ENSG00000184494Q995193I2D: score=1 
    ENSG00000223957Q995193I2D: score=1 
    ENSG00000227129Q995193I2D: score=1 
    About this table

    Gene Ontology (GO): Selected biological process terms (see all 72):    About this table

    GO IDQualified GO termEvidencePubMed IDs
    GO:0000187activation of MAPK activity ISS--
    GO:0002218activation of innate immune response ----
    GO:0002224toll-like receptor signaling pathway TAS--
    GO:0002322B cell proliferation involved in immune response IEA--
    GO:0002537nitric oxide production involved in inflammatory response IEA--

    TLR4 for ontologies           About GeneDecksing



    (Chemical Compounds according to UniProtKB, Enzo Life Sciences, EMD Millipore, Tocris Bioscience, ApexBio, HMDB, BitterDB, and/or Novoseek, Ligands according to IUPHAR, and Drugs according to DrugBank, Enzo Life Sciences, and/or PharmGKB)
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    Browse Small Molecules at EMD Millipore
       Enzo Life Sciences drugs & compounds for TLR4
      Browse compounds at ApexBio 

    Compounds for TLR4 available from Tocris Bioscience    About this table
    CompoundAction CAS #
    Pam2CSK4TLR2/6 agonist; induces TNF-alpha production[868247-72-7]
    ResiquimodToll-like receptor 7 (TLR7) agonist[144875-48-9]
    Pam3CSK4TLR1/2 agonist; induces cytokine production[112208-00-1]
    Poly(I:C)TLR3 agonist[42424-50-0]
    ImiquimodToll-like receptor 7 (TLR7) agonist[99011-02-6]

    3 DrugBank Compounds for TLR4    About this table
    CompoundSynonyms CAS #TypeActionsPubMed Ids
    3-Hydroxy-Myristic Acid-- --target--10592235
    MYRISTIC ACID-- --target--10592235
    NaloxoneEN 1530 Base (see all 7)465-65-6targetinhibitor22520687

    2 IUPHAR Ligands for TLR4 (TLR4)    About this table
    LigandTypeActionAffinityPubmed IDs
    LPS
    AgonistAgonist9851930
    taxol
    AgonistAgonist10644670

    Selected Novoseek inferred chemical compound relationships for TLR4 gene (see all 95)    About this table
    Compound   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    lipoteichoic acid 83.8 64 12691617 (3), 12011760 (3), 11160242 (2), 17296755 (2) (see all 37)
    endotoxin 81.3 302 17977838 (9), 18519568 (5), 17121827 (5), 19368968 (5) (see all 99)
    peptidoglycan 80.9 106 12874299 (6), 16239565 (3), 15142865 (2), 17942642 (2) (see all 65)
    poly(i-c) 73.7 15 14991609 (1), 16115611 (1), 16365459 (1), 16380383 (1) (see all 15)
    flagellin 73.5 28 18397908 (2), 16365459 (1), 18256754 (1), 19955831 (1) (see all 25)
    muramyl dipeptide 68.4 4 15617523 (1), 15839897 (1), 16299289 (1)
    drosomycin 67.8 10 10489372 (1), 8808632 (1), 10973475 (1), 19934223 (1) (see all 7)
    loxoribine 65.2 1 15749901 (1)
    polyinosinic-polycytidylic acid 63.3 17 18031817 (1), 19578865 (1), 18184197 (1), 19863438 (1) (see all 11)
    hbd2 60.8 11 16219107 (5), 15854033 (1), 17241164 (1), 20008534 (1)



    TLR4 for compounds           About GeneDecksing



    (Secondary structures according to fRNAdb,
    GenBank/EMBL/DDBJ Accessions according to
    Unigene (Build 236 Homo sapiens; Apr 25 2013) or GenBank,
    RefSeq according to Entrez Gene,
    DOTS (version 10), and/or AceView, transcript ids from Ensembl with links to UCSC,
    exon structure from GeneLoc, alternative splicing isoforms according to ASD and/or ECgene,
    siRNAs from OriGene, QIAGEN, shRNA from OriGene, microRNA from QIAGEN, SwitchGear Genomics,
    Tagged/untagged cDNA clones from OriGene, GenScript, DNA2.0, Vector BioLabs, Primers from OriGene, and/or QIAGEN )
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    REFSEQ mRNAs for TLR4 gene (4 alternative transcripts): 
    NM_003266.3  NM_138554.4  NM_138557.2  NM_138556.1  

    Unigene Cluster for TLR4:

    Toll-like receptor 4
    Hs.174312  [show with all ESTs]
    Unigene Representative Sequence: NM_003266
    4 Ensembl transcripts including schematic representations, and UCSC links where relevant:
    ENST00000394487 ENST00000355622(uc004bka.3 uc004bjz.3 uc004bkb.3)
    ENST00000472304 ENST00000490685
    miRNA
    Products:
         
    Block miRNA regulation of human, mouse, rat TLR4 using miScript Target Protectors
    Selected qRT-PCR Assays for microRNAs that regulate TLR4 (see all 16):
    hsa-miR-549 hsa-miR-140-5p hsa-miR-219-1-3p hsa-miR-3938 hsa-miR-642a hsa-miR-4328 hsa-miR-944 hsa-miR-3074-3p
    SwitchGear 3'UTR luciferase reporter plasmidTLR4 3' UTR sequence
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    Additional mRNA sequence: 

    AB445638.1 AK226155.1 AK290053.1 AK293068.1 AK303730.1 BC025294.1 BC117422.1 BC143841.1 
    U69193.1 U88880.1 

    5 DOTS entries:

    DT.97839126  DT.100020339  DT.99941363  DT.121172426  DT.75168146 

    Selected AceView cDNA sequences (see all 70):

    AA598398 BM931788 AW016347 AX752005 BX473935 BQ020285 AI332385 BQ019419 
    AI082399 CA442537 NM_138556 N42522 BX642592 NM_138554 BX280079 AA490278 
    AI263086 BU675644 Z42560 AI074098 NM_138557 AI356888 AI371874 NM_003266 

    GeneLoc Exon Structure

    4 Alternative Splicing Database (ASD) splice patterns (SP) for TLR4    About this scheme

    ExUns: 1a · 1b · 1c ^ 2 ^ 3a · 3b ^ 4a · 4b · 4c
    SP1:                                -                     
    SP2:                    -           -                     
    SP3:                    -     -     -                     
    SP4:                                                      


    ECgene alternative splicing isoforms for TLR4

    (RNA expression data according to H-InvDB, NONCODE, miRBase, and RNAdb, Expression images according to data from BioGPS, Illumina Human BodyMap, and CGAP SAGE, Sets of similar genes according to GeneDecks, in vivo and in vitro expression data from LifeMap Discovery™, Protein expression images according to data from SPIRE 1MOPED, 2PaxDb, and 3MaxQB, plus additional links to SOURCE, and/or BioGPS, and/or UniProtKB,
    PCR Arrays from QIAGEN, Primers from OriGene, and/or QIAGEN, In Situ Hybridization Assays from Advanced Cell Diagnostics)
    About This Section

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    TLR4 expression in normal human tissues (normalized intensities)
    See probesets specificity/sensitivity at GeneAnnot
    About this imageBioGPS <intensity>2/3
    CGAP TAG: TTAAGTGTTC
    TLR4 Expression
    About this image


    TLR4 expression in embryonic tissues and stem cells    About this table
    Data from LifeMap, the Embryonic Development and Stem Cells Database
     selected tissues (see all 8) fully expand
     
     Epithelial Cells
             Duct Cells Pancreatic Ducts
     
     Heart (Cardiovascular System)
             Cardiac Fibroblasts Myocardium
     
     Pancreas (Endocrine System)
             Duct Cells Pancreatic Ducts
     
     Fibroblasts
             Cardiac Fibroblasts Myocardium
     
     NULL (Uncategorized)
             CD31, CD144 positive cells
    TLR4 Protein expression data from MOPED1, PaxDb2 and MaxQB3    About this image

    TLR4 Protein Expression

    SOURCE GeneReport for Unigene cluster: Hs.174312

    UniProtKB/Swiss-Prot: TLR4_HUMAN, O00206
    Tissue specificity: Highly expressed in placenta, spleen and peripheral blood leukocytes. Detected in monocytes,
    macrophages, dendritic cells and several types of T-cells

        Pathway & Disease-focused RT2 Profiler PCR Arrays including TLR4 (see all 17): 
              Toll-Like Receptor Signaling Pathway in human mouse rat
              Liver Cancer in human mouse rat
              Inflammatory Response & Autoimmunity in human mouse rat
              T-cell & B-cell Activation in human mouse rat
              Inflammatory Response & Autoimmunity 384HT in human mouse rat

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    (Orthologs according to 1,2HomoloGene (2older version, for species not in 1newer version), 3euGenes, 4SGD , 5MGI Mar 06 2013, with possible further links to Flybase and/or WormBase, and/or 6Ensembl pan taxonomic compara , Gene Trees according to Ensembl and TreeFam)
    About This Section

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    This gene was present in the common ancestor of chordates.

    Orthologs for TLR4 gene from Selected species (see all 10)    About this table
    Organism Taxonomic
    classification
    Gene Description Human
    Similarity
    Orthology
    Type
    Details
    mouse
    (Mus musculus)
    Mammalia Tlr41 , 5 toll-like receptor 41, 5 75.16(n)1
    67.84(a)1
      4 (34.66 cM)5
    218981  NM_021297.21  NP_067272.11 
     668275845 
    chicken
    (Gallus gallus)
    Aves TLR41 toll-like receptor 4 55.84(n)
    46.69(a)
      417241  NM_001030693.1  NP_001025864.1 
    lizard
    (Anolis carolinensis)
    Reptilia TLR46
    toll-like receptor 4
    44(a)
    1 ↔ 1
    GL343450.1(656032-664419)
    zebrafish
    (Danio rerio)
    Actinopterygii tlr4ba1 toll-like receptor 4b, duplicate a 50.6(n)
    40.3(a)
      403131  NM_001131051.1  NP_001124523.1 


    ENSEMBL Gene Tree for TLR4 (if available)
    TreeFam Gene Tree for TLR4 (if available)

    (Paralogs according to 1HomoloGene,
    2Ensembl, and 3SIMAP, Pseudogenes according to 4Pseudogene.org Build 68)
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    Paralogs for TLR4 gene
    ENSG000001733662  CD1802  TLR72  TLR12  TLR92  TLR52  TLR102  TLR82  
    TLR62  TLR32  TLR22  
    2 SIMAP similar genes for TLR4 using alignment to 10 protein entries:     TLR4_HUMAN (see all proteins):
    TLR-4    SLIT2

    TLR4 for paralogs           About GeneDecksing



    (SNPs/Variants according to the 1NCBI SNP Database, 2Ensembl, 3PupaSUITE, 4UniProtKB, and DNA2.0, Linkage Disequilibrium by HapMap, Structural Variations(CNVs/InDels/Inversions) from the Database of Genomic Variants, Mutations from the Human Gene Mutation Database (HGMD), the Human Cytochrome P450 Allele Nomenclature Database, and the Locus Specific Mutation Databases (LSDB), Blood group antigen gene mutations by BGMUT, Resequencing Primers, Cancer Mutation PCR Arrays and Assays, and Copy Number PCR Arrays from QIAGEN)
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    Polymorphic Variants from UniProtKB/Swiss-Prot
    TLR4_HUMAN, O00206: Allele TLR4*B (Gly-299, Ile-399) is associated with a blunted response to inhaled LPS


    Selected SNPs for TLR4 (see all 688)    About this table    
    Genomic DataTranscription Related DataAllele Frequencies
    SNP IDValidClinical
    significance
    Chr 9 posSequence#AA
    Chg
    TypeMore#Allele
    freq
    PopTotal
    sample
    More
    ----------
    rs49867901,2,,4
    C,F,Hpathogenic1120487469(+) CGATGA/GTATTA 6 D G mis136Minor allele frequency- G:0.06MN NA EU NS EA CA WA 11133
    rs49867911,2,,4
    C,F,Hpathogenic1120487769(+) GACAAC/TCAGCC 6 T I mis124Minor allele frequency- T:0.05MN NA EU NS EA 7707
    rs1378539201,2
    C,Funtested1120487415(+) CCTGTG/ACAATT 6 /Y /C mis12Minor allele frequency- A:0.00NA EU 5863
    rs2002760331,2
    Cuntested1120487439(+) ATTCCA/GATTAG 6 Q R mis10--------
    rs59003071,2
    C--120466930(+) TTTGC-/AAAAAA 3 -- int1 trp31Minor allele frequency- A:0.00NA 2
    rs588877761,2
    C--120468240(+) AAAAA-/AGAAAC 3 -- int10--------
    rs115368821,2
    C,F--120472614(+) TTGTT-/TGTT  
            
    AATTT
    3 -- int13Minor allele frequency- TGTT:0.22NA EU 94
    rs50306431,2
    C--120474652(+) CTTTTT/-ATTCC 3 -- int11Minor allele frequency- -:0.50CSA 2
    rs115368621,2
    C,F,H--120476720(+) GAGCAA/GAGCTT 3 -- us2k17Minor allele frequency- G:0.00NA EU NS EA 514
    rs1494174311,2
    --120476811(+) ATGGTC/GCCTCA 3 -- us2k10--------

    HapMap Linkage Disequilibrium report for TLR4 (120466460 - 120479768 bp)

    Structural Variations
         Database of Genomic Variants (DGV) 2 variations for TLR4:    About this table    
    Variant IDTypeSubtypePubMed ID
    nsv831706CNV Gain17160897
    nsv7434OTHER Inversion18451855

    Human Gene Mutation Database (HGMD): TLR4
    Site Specific Mutation Identification with PCR Assays
    SeqTarget long-range PCR primers for resequencing TLR4
    DNA2.0 Custom Variant and Variant Library Synthesis for TLR4

    (in which this Gene is Involved, According to MalaCards, OMIM, UniProtKB, the University of Copenhagen DISEASES database, Novoseek, Genatlas, GeneTests, GAD, HuGE Navigator, and/or TGDB.)
    About This Section

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    OMIM gene information: 603030   
    OMIM disorders: 611488  114500  
    UniProtKB/Swiss-Prot: TLR4_HUMAN, O00206
  • Macular degeneration, age-related, 10 (ARMD10) [MIM:611488]: A form of age-related macular degeneration,
    a multifactorial eye disease and the most common cause of irreversible vision loss in the developed world. In
    most patients, the disease is manifest as ophthalmoscopically visible yellowish accumulations of protein and
    lipid that lie beneath the retinal pigment epithelium and within an elastin-containing structure known as Bruch
    membrane. Note=Disease susceptibility is associated with variations affecting the gene represented in this entry

  • Selected diseases for TLR4 (see all 282):    
    About MalaCards
    endotoxin hyporesponsiveness    macular degeneration, age-related, 10    spondylarthropathy    melioidosis
    pouchitis    tympanosclerosis    campylobacteriosis    aspergillosis
    behcet's disease    filariasis    anterior uveitis    colorectal cancer
    coccidioidomycosis    mucopolysaccharidosis i    hypersplenism    perinatal necrotizing enterocolitis
    boutonneuse fever    granulomatosis with polyangiitis    bone fracture    legionnaires' disease

    13 diseases from the University of Copenhagen DISEASES database for TLR4:
    Inflammatory bowel disease     Atherosclerosis     Periodontitis     Perinatal necrotizing enterocolitis
    Asthma     Pneumonia     Arthritis     Hypersensitivity reaction type II disease
    Mastitis     Hypersensitivity reaction type I disease     Cancer     Liver disease
    Heart disease

    TLR4 for disorders           About GeneDecksing

    Selected Novoseek inferred disease relationships for TLR4 gene (see all 93)    About this table

    Disease   -log (P-Val)   Hits   PubMed IDs for Articles with Shared Sentences (# sentences)
    inflammation 74.6 175 18928988 (3), 20067961 (3), 19390489 (3), 19359427 (3) (see all 99)
    necrosis 73.4 169 15325567 (4), 16970685 (2), 17304101 (2), 17529905 (2) (see all 99)
    gram-negative bacterial infections 73 20 19326213 (1), 18644971 (1), 17456342 (1), 18437214 (1) (see all 11)
    sepsis 67 128 15086396 (6), 15614130 (4), 17456342 (4), 15489631 (4) (see all 53)
    bacterial infections 66.3 34 12853386 (3), 16738534 (2), 11260138 (1), 11781369 (1) (see all 28)
    inflammatory bowel diseases 60.1 18 19710105 (2), 15655821 (1), 11083826 (1), 20375592 (1) (see all 17)
    shock septic 59.4 20 20441696 (2), 15328161 (1), 16878028 (1), 15520404 (1) (see all 15)
    tumors 53.9 233 19318560 (8), 19643479 (4), 15325567 (4), 19155492 (4) (see all 99)
    atherosclerosis 53.8 76 17367503 (4), 15894821 (3), 17872459 (2), 17849054 (2) (see all 50)
    colitis ulcerative 52.8 12 15207785 (3), 17538633 (1), 16085746 (1), 18942754 (1) (see all 11)

    Genetic Association Database (GAD): TLR4
    Human Genome Epidemiology (HuGE) Navigator: TLR4 (482 documents)

    Export disorders for TLR4 gene to outside databases

    (in PubMed. Associations of this gene to articles via 1Entrez Gene, 2UniProtKB/Swiss-Prot, 3HGNC, 4GAD, 5PharmGKB, 6HMDB, 7DrugBank, 8UniProtKB/TrEMBL, 9 Novoseek, and/or 10fRNAdb)
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    PubMed articles for TLR4 gene, integrated from 10 sources (see all 2734):
    (articles sorted by number of sources associating them with TLR4)
        Utopia: connect your pdf to the dynamic
    world of online information

    1. Toll-like receptor 4 variant D299G is associated with susceptibility to age-related macular degeneration. (PubMed id 15829498)1, 2, 4, 9 Zareparsi S.... Swaroop A. (Hum. Mol. Genet. 2005)
    2. A family of human receptors structurally related to Drosophila Toll. (PubMed id 9435236)1, 2, 3, 9 Rock F.L.... Bazan J.F. (Proc. Natl. Acad. Sci. U.S.A. 1998)
    3. TLR4 mutations are associated with endotoxin hyporesponsiveness in humans. (PubMed id 10835634)1, 2, 4 Arbour N.C.... Schwartz D.A. (Nat. Genet. 2000)
    4. A human homologue of the Drosophila Toll protein signals activation of adaptive immunity. (PubMed id 9237759)1, 2, 3 Medzhitov R.... Janeway C.A. Jr. (Nature 1997)
    5. Association of polymorphisms of toll-like receptor 4 with a reduced prevalence of hay fever and atopy. (PubMed id 18517079)1, 4, 9 Senthilselvan A....Dosman J.A. (amp 2008)
    6. Effects of toll-like receptor-4 gene polymorphisms on soluble P-selectin and von Willebrand factor levels in hypercholesterolemic patients. (PubMed id 17849054)1, 4, 9 Di Nisio M....Porreca E. (Thromb. Haemost. 2007)
    7. Association between polymorphisms in the Toll-like receptor 4, CD14, and CARD15/NOD2 and inflammatory bowel disease in the Greek population. (PubMed id 15655821)1, 4, 9 Gazouli M....Gorgoulis V.G. (World J. Gastroenterol. 2005)
    8. MD-2 and TLR4 N-linked glycosylations are important for a functional lipopolysaccharide receptor. (PubMed id 11706042)1, 2, 9 da Silva Correia J. and Ulevitch R.J. (J. Biol. Chem. 2002)
    9. Toll-like receptor 4 variants reduce airway response in human subjects at high endotoxin levels in a swine facility. (PubMed id 19368968)1, 4, 9 Senthilselvan A....Schwartz D.A. (J. Allergy Clin. Immunol. 2009)
    10. Impact of genetic variants of CD14 and TLR4 on subgingival periodontopathogens. (PubMed id 19046305)1, 4, 9 Schulz S....Reichert S. (Int. J. Immunogenet. 2008)

    (in PubMed, OMIM, and NCBI Bookshelf)
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     ANDOR
    Aliases
    Disorders
    Free Text  

      Query String
    PubMed
    OMIM
    NCBI Bookshelf
      (Note: In FireFox, select the above section and copy using Ctrl-C)

    (According to Entrez Gene, HGNC, AceView, euGenes, Ensembl, miRBase, ECgene, Kegg, and/or H-InvDB)
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    Entrez Gene: 7099 HGNC: 11850 AceView: TLR4 Ensembl:ENSG00000136869 euGenes: HUgn7099
    ECgene: TLR4 Kegg: 7099 H-InvDB: TLR4

    (According to HUGE)
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      --

    (According to PharmGKB, ATLAS, HORDE, IMGT, LEIDEN, UniProtKB/Swiss-Prot, UniProtKB/TrEMBL, and/or others, e.g. Wikipedia and GeneReviews, via UniProtKB/Swiss-Prot)
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    NameDescription
    PharmGKB entry for TLR4 Pharmacogenomics, SNPs, Pathways
    Protein Spotlighthttp://web.expasy.org/spotlight/back_issues/134

    (Patent information from GeneIP,
    Licensable technologies from WIS Yeda, Salk, Tufts,
    IP news from LifeMap Sciences, Inc.)
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    Patent Information for TLR4 gene:
    Search GeneIP for patents involving TLR4

    GeneCards and IP:
    Japan Patent Office Licenses GeneCards     European Patent Office Licenses GeneCards     Improving the IP Search



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