Toll Like Receptor signaling (Mus musculus)

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Toll-like receptors (TLRs) are a class of proteins that play a key role in the innate immune system. They are single, membrane-spanning, non-catalytic receptors usually expressed in sentinel cells such as macrophages and dendritic cells, that recognize structurally conserved molecules derived from microbes. Once these microbes have breached physical barriers such as the skin or intestinal tract mucosa, they are recognized by TLRs, which activate immune cell responses. The TLRs include TLR1, TLR2, TLR3, TLR4, TLR5, TLR6, TLR7, TLR8, TLR9, TLR10, TLR11, TLR12, and TLR13.

TLR signaling is divided into two distinct signaling pathways, the MyD88-dependent and TRIF-dependent pathway. The MyD88-dependent response occurs on dimerization of the TLR receptor, and is utilized by every TLR except TLR3. Its primary effect is activation of NFκB and Mitogen-activated protein kinase. Ligand binding and conformational change that occurs in the receptor recruits the adaptor protein MyD88, a member of the TIR family. MyD88 then recruits IRAK4, IRAK1 and IRAK2. IRAK kinases then phosphorylate and activate the protein TRAF6, which in turn polyubiquinates the protein TAK1, as well as itself in order to facilitate binding to IKK-β. On binding, TAK1 phosphorylates IKK-β, which then phosphorylates IκB causing its degradation and allowing NFκB to diffuse into the cell nucleus and activate transcription and consequent induction of inflammatory cytokines. Both TLR3 and TLR4 utilize the TRIF-dependent pathway, which is triggered by dsRNA and LPS, respectively. For TLR3, dsRNA leads to activation of the receptor, recruiting the adaptor TRIF. TRIF activates the kinases TBK1 and RIPK1, which creates a branch in the signaling pathway. The TRIF/TBK1 signaling complex phosphorylates IRF3 allowing its translocation into the nucleus and production of Interferon type I. Meanwhile, activation of RIPK1 causes the polyubiquitination and activation of TAK1 and NFκB transcription in the same manner as the MyD88-dependent pathway.

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80116view21:44, 7 May 2015KhanspersModified description
69199view18:23, 8 July 2013MaintBotUpdated to 2013 gpml schema
67703view11:51, 26 June 2013DdiglesOntology Term : 'Toll-like receptor signaling pathway' added !
41390view00:29, 2 March 2011MaintBotRemoved redundant pathway information and comments
33544view09:38, 1 December 2009MaintBotRemoved group label
28161view23:42, 28 January 2009AlexanderPicoModified categories
28146view10:09, 28 January 2009Thomasreplaced labels by gene ids
20865view11:30, 14 November 2008MaintBot[[Pathway:Mus musculus:Toll Like Receptor signaling]] moved to [[Pathway:WP88]]: Moved to stable identifier
18411view19:03, 19 August 2008PietergoossensSpecify description
18409view18:55, 19 August 2008PietergoossensSpecify description
18407view18:48, 19 August 2008PietergoossensPeriodical save, work in progress
18405view18:19, 19 August 2008PietergoossensPeriodical save, work in progress
18403view18:09, 19 August 2008PietergoossensPeriodical save, work in progress
18401view17:39, 19 August 2008PietergoossensPeriodical save, work in progress
18399view17:13, 19 August 2008PietergoossensPeriodical save, work in progress
18397view17:03, 19 August 2008PietergoossensNew pathway

External references


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NameTypeDatabase referenceComment
Caspase-3GeneProduct12367 (Entrez Gene)
Caspase-8GeneProduct12370 (Entrez Gene)
FaddGeneProduct14082 (Entrez Gene)
IKBaGeneProduct17121 (Entrez Gene)
IKK1GeneProduct12675 (Entrez Gene)
IKK2GeneProduct16150 (Entrez Gene)
IKKepsilonGeneProduct56489 (Entrez Gene)
IRAK-2GeneProduct108960 (Entrez Gene)
IRAK-MGeneProduct73914 (Entrez Gene)
Irak1GeneProduct16179 (Entrez Gene)
Irak4GeneProduct266632 (Entrez Gene)
Irf3GeneProduct54131 (Entrez Gene)
MKK6GeneProduct26399 (Entrez Gene)
MalGeneProduct17153 (Entrez Gene)
Myd88GeneProduct17874 (Entrez Gene)
NAP1GeneProduct11308 (Entrez Gene)
NEMOGeneProduct16151 (Entrez Gene)
Nfkb1GeneProduct18033 (Entrez Gene)
Nfkb2GeneProduct18034 (Entrez Gene)
PkrGeneProduct19106 (Entrez Gene)
Rip1GeneProduct19765 (Entrez Gene)
TAK1GeneProduct22026 (Entrez Gene)
TRAMGeneProduct225471 (Entrez Gene)
TRIFGeneProduct106759 (Entrez Gene)
Tab2GeneProduct68652 (Entrez Gene)
Tbk1GeneProduct56480 (Entrez Gene)
TirapGeneProduct117149 (Entrez Gene)
Tlr2GeneProduct24088 (Entrez Gene)
Tlr3GeneProduct142980 (Entrez Gene)
Tlr4GeneProduct21898 (Entrez Gene)
Traf3GeneProduct22031 (Entrez Gene)
Traf6GeneProduct22034 (Entrez Gene)
p38MAPKGeneProduct26416 (Entrez Gene)

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