Go Annotations as Summary Text (Tabular View) (GO Graph)

GO curators for mouse genes have assigned the following annotations to the gene product of Tlr4. (This text reflects annotations as of Wednesday, January 23, 2013.)

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Summary from NCBI RefSeq

[Summary is not available for the mouse gene. This summary is for the human ortholog.] 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]

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Summary text based on GO annotations supported by experimental evidence in mouse

• Researchers have inferred from direct assay, that the gene product of Tlr4
  • participates in the following biological processes:
    • positive regulation of chemokine production ^[10]
    • positive regulation of ERK1 and ERK2 cascade ^[6]
    • positive regulation of I-kappaB kinase/NF-kappaB cascade ^{[2, 6, 12]}
    • positive regulation of interferon-alpha production ^[10]
    • positive regulation of interferon-beta production ^[10]
    • positive regulation of interleukin-1 production ^[10]
    • positive regulation of interleukin-10 production ^[10]
    • positive regulation of interleukin-12 production ^[10]
    • positive regulation of interleukin-6 production ^{[6, 10]}
    • positive regulation of JNK cascade ^{[6, 12]}
    • positive regulation of nitric-oxide synthase biosynthetic process ^[10]
    • positive regulation of nucleotide-binding oligomerization domain containing 1 signaling pathway ^[6]
    • positive regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway ^[6]
    • positive regulation of stress-activated MAPK cascade ^[6]
    • positive regulation of transcription from RNA polymerase II promoter ^[10]
    • positive regulation of tumor necrosis factor production ^{[6, 10]}
• The gene product of Tlr4 has been shown to bind to the gene products of Ly96. ^[5]
• Researchers have inferred, based on phenotypic analysis of mouse mutants, that the gene product of Tlr4
  • participates in the following biological processes:
    • activation of innate immune response ^[8]
    • activation of MAPK activity ^[4]
    • cellular response to lipopolysaccharide ^[4]
    • cellular response to lipoteichoic acid ^[14]
    • defense response to Gram-negative bacterium ^[8]
    • intestinal epithelial structure maintenance ^[4]
    • negative regulation of ERK1 and ERK2 cascade ^[4]
    • negative regulation of interferon-gamma production ^[4]
    • negative regulation of interleukin-17 production ^{[4, 7]}
    • negative regulation of interleukin-23 production ^[7]
    • negative regulation of interleukin-6 production ^{[4, 7]}
    • negative regulation of tumor necrosis factor production ^[4]
    • nitric oxide production involved in inflammatory response ^[9]
    • positive regulation of B cell proliferation ^[14]
    • positive regulation of interferon-beta biosynthetic process ^[8]
    • positive regulation of interferon-gamma production ^[7]
    • positive regulation of interleukin-6 production ^[14]
    • positive regulation of lymphocyte proliferation ^[15]
    • positive regulation of macrophage cytokine production ^[14]
    • positive regulation of MHC class II biosynthetic process ^[14]
    • positive regulation of nitric oxide biosynthetic process ^[14]
    • positive regulation of platelet activation ^[13]
    • positive regulation of tumor necrosis factor production ^{[9, 14, 15]}
    • regulation of inflammatory response ^[7]
    • response to bacterium ^[1]
    • response to lipopolysaccharide ^{[3, 14, 15, 16]}
• Researchers have inferred, based on genetic interactions, that the gene product of Tlr4
  • participates in the following biological processes:
    • interferon-gamma production based on interactions with Il12rb2 ^[11]
    • positive regulation of JNK cascade based on interactions with Map3k7 ^[12]
    • response to lipopolysaccharide based on interactions with Il12rb2 ^[11]

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Summary text based on GO annotations supported by experimental evidence in other organisms

• From comparative sequence analysis (see table for details), MGI curators have determined that the gene product of Tlr4:
  • participates in the following biological processes:
    • defense response to bacterium
    • detection of lipopolysaccharide
    • I-kappaB phosphorylation
    • innate immune response-activating signal transduction
    • lipopolysaccharide-mediated signaling pathway
    • macrophage activation
    • microglial cell activation involved in immune response
    • pathogen-associated molecular pattern dependent induction by symbiont of host innate immune response
    • positive regulation of apoptotic process
    • positive regulation of chemokine production
    • positive regulation of DNA binding
    • positive regulation of inflammatory response
    • positive regulation of interleukin-12 biosynthetic process
    • positive regulation of interleukin-6 production
    • positive regulation of interleukin-8 biosynthetic process
    • positive regulation of interleukin-8 production
    • positive regulation of NF-kappaB import into nucleus
    • positive regulation of NF-kappaB transcription factor activity
    • positive regulation of peptidyl-tyrosine phosphorylation
    • positive regulation of sequence-specific DNA binding transcription factor activity
    • positive regulation of tumor necrosis factor biosynthetic process
    • regulation of sensory perception of pain
    • response to ethanol
    • response to fatty acid
    • response to lipopolysaccharide
    • response to oxidative stress
    • toll-like receptor signaling pathway
  • performs the following molecular functions:
    • lipopolysaccharide binding
    • lipopolysaccharide receptor activity
    • phosphatidylinositol 3-kinase binding
    • receptor activity
  • is located in the following cellular components:
    • cell surface
    • cytoplasm
    • external side of plasma membrane
    • integral to plasma membrane
    • lipopolysaccharide receptor complex
    • membrane raft
    • perinuclear region of cytoplasm
    • plasma membrane

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Summary text based on GO annotations supported by structural data

• Tlr4 encodes a protein or proteins that contain the following InterPro domains: Cysteine-rich flanking region, C-terminal, Toll-like receptor, Toll/interleukin-1 receptor homology (TIR) domain, indicating that the gene product:
  • participates in the following biological processes:
    • immune response
    • signal transduction
  • performs the following molecular functions:
    • transmembrane signaling receptor activity
  • is located in the following cellular components:
    • integral to membrane

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Summary text for additional MGI annotations

• Automated translation to GO terms of SwissProt keywords that describe Tlr4 indicates that it:
  • participates in the following biological processes:
    • inflammatory response
  • is located in the following cellular components:
    • integral to membrane
    • membrane

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References

1. Bihl F et al. (2001) LPS-hyporesponsiveness of mnd mice is associated with a mutation in Toll-like receptor 4. Genes Immun, 2:56-9. (PubMed:11294571)
2. Chang M et al. (2009) Peli1 facilitates TRIF-dependent Toll-like receptor signaling and proinflammatory cytokine production. Nat Immunol, 10:1089-95. (PubMed:19734906)
3. Fierer J et al. (2002) The role of lipopolysaccharide binding protein in resistance to Salmonella infections in mice. J Immunol, 168:6396-403. (PubMed:12055258)
4. Gonzalez-Navajas JM et al. (2010) TLR4 signaling in effector CD4+ T cells regulates TCR activation and experimental colitis in mice. J Clin Invest, 120:570-81. (PubMed:20051628)
5. Kim HM et al. (2007) Crystal structure of the TLR4-MD-2 complex with bound endotoxin antagonist Eritoran. Cell, 130:906-17. (PubMed:17803912)
6. Kim YG et al. (2008) The cytosolic sensors Nod1 and Nod2 are critical for bacterial recognition and host defense after exposure to Toll-like receptor ligands. Immunity, 28:246-57. (PubMed:18261938)
7. Marta M et al. (2008) Unexpected regulatory roles of TLR4 and TLR9 in experimental autoimmune encephalomyelitis. Eur J Immunol, 38:565-75. (PubMed:18203139)
8. O'Connell RM et al. (2005) Immune activation of type I IFNs by Listeria monocytogenes occurs independently of TLR4, TLR2, and receptor interacting protein 2 but involves TNFR-associated NF kappa B kinase-binding kinase 1. J Immunol, 174:1602-7. (PubMed:15661922)
9. Ohashi K et al. (2000) Cutting edge: heat shock protein 60 is a putative endogenous ligand of the toll-like receptor-4 complex. J Immunol, 164:558-61. (PubMed:10623794)
10. Olson JK et al. (2004) Microglia initiate central nervous system innate and adaptive immune responses through multiple TLRs. J Immunol, 173:3916-24. (PubMed:15356140)
11. Poltorak A et al. (2001) A point mutation in the il-12rbeta2 gene underlies the il-12 unresponsiveness of lps-defective c57bl/10sccr mice. J Immunol, 167:2106-11. (PubMed:11489994)
12. Shim JH et al. (2005) TAK1, but not TAB1 or TAB2, plays an essential role in multiple signaling pathways in vivo. Genes Dev, 19:2668-81. (PubMed:16260493)
13. Stahl AL et al. (2006) Lipopolysaccharide from enterohemorrhagic Escherichia coli binds to platelets through TLR4 and CD62 and is detected on circulating platelets in patients with hemolytic uremic syndrome. Blood, 108:167-76. (PubMed:16514062)
14. Takeuchi O et al. (1999) Differential roles of TLR2 and TLR4 in recognition of gram-negative and gram-positive bacterial cell wall components. Immunity, 11:443-51. (PubMed:10549626)
15. Takeuchi O et al. (2000) Cellular responses to bacterial cell wall components are mediated through MyD88-dependent signaling cascades. Int Immunol, 12:113-7. (PubMed:10607756)
16. Vogel SN et al. (1999) Cutting edge: functional characterization of the effect of the C3H/HeJ defect in mice that lack an Lpsn gene: in vivo evidence for a dominant negative mutation. J Immunol, 162:5666-70. (PubMed:10229796)

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Gene Ontology Evidence Code Abbreviations:

EXP Inferred from experiment

IC Inferred by curator

IDA Inferred from direct assay

IEA Inferred from electronic annotation

IGI Inferred from genetic interaction

IMP Inferred from mutant phenotype

IPI Inferred from physical interaction

ISS Inferred from sequence or structural similarity

ISO Inferred from sequence orthology

ISA Inferred from sequence alignment

ISM Inferred from sequence model

NAS Non-traceable author statement

ND No biological data available

RCA Reviewed computational analysis

TAS Traceable author statement

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