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MyD88:MAL(TIRAP) cascade initiated on plasma membrane
Stable Identifier
R-HSA-166058
DOI
10.3180/REACT_6788.8
Type
Pathway
Species
Homo sapiens
Related Species
Neisseria meningitidis serogroup B,
Chlamydia trachomatis
ReviewStatus
5/5
Locations in the PathwayBrowser
Expand all
Immune System (Homo sapiens)
Innate Immune System (Homo sapiens)
Toll-like Receptor Cascades (Homo sapiens)
Toll Like Receptor 2 (TLR2) Cascade (Homo sapiens)
Toll Like Receptor TLR1:TLR2 Cascade (Homo sapiens)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Homo sapiens)
Toll Like Receptor TLR6:TLR2 Cascade (Homo sapiens)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Homo sapiens)
Toll Like Receptor 4 (TLR4) Cascade (Homo sapiens)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Homo sapiens)
General
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The first known downstream component of TLR4 and TLR2 signaling is the adaptor MyD88. Another adapter MyD88-adaptor-like (Mal; also known as TIR-domain-containing adaptor protein or TIRAP) has also been described for TLR4 and TLR2 signaling. MyD88 comprises an N-terminal Death Domain (DD) and a C-terminal TIR, whereas Mal lacks the DD. The TIR homotypic interactions bring adapters into contact with the activated TLRs, whereas the DD modules recruit serine/threonine kinases such as interleukin-1-receptor-associated kinase (IRAK). Recruitment of these protein kinases is accompanied by phosphorylation, which in turn results in the interaction of IRAKs with TNF-receptor-associated factor 6 (TRAF6). The oligomerization of TRAF6 activates TAK1, a member of the MAP3-kinase family, and this leads to the activation of the IkB kinases. These kinases, in turn, phosphorylate IkB, leading to its proteolytic degradation and the translocation of NF-kB to the nucleus. Concomitantly, members of the activator protein-1 (AP-1) transcription factor family, Jun and Fos, are activated, and both AP-1 transcription factors and NF-kB are required for cytokine production, which in turn produces downstream inflammatory effects.
Literature References
PubMed ID
Title
Journal
Year
15276183
MD-2: the Toll 'gatekeeper' in endotoxin signalling
Gay, NJ
,
Gangloff, M
Trends Biochem Sci
2004
Participants
Events
TIRAP binds PIP2-rich regions in the plasma membrane
(Homo sapiens)
Activated TLR2/4 interacts with MAL (TIRAP)
(Homo sapiens)
Activated TLR2/4:TIRAP interacts with BTK
(Homo sapiens)
TIRAP is phosphorylated by BTK
(Homo sapiens)
MyD88 forms a complex with TIRAP:activated TLR2/4
(Homo sapiens)
MyD88 oligomerization within the complex of activated TLR:TIRAP:MyD88
(Homo sapiens)
IRAK4 binds to the activated TLR receptor:TIRAP:MyD88 complex
(Homo sapiens)
IRAK4 autophosphorylation in the complex with activated TLR:MyD88:TIRAP
(Homo sapiens)
IRAK1 or IRAK2 binds to the activated IRAK4 :activated TLR:MyD88:TIRAP complex
(Homo sapiens)
Phosphorylation of IRAK2 bound to the activated IRAK4:MyD88 oligomer:TIRAP:activated TLR complex
(Homo sapiens)
First phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:Mal
(Homo sapiens)
Second phosphorylation of IRAK1 by IRAK4 bound to activated TLR:MyD88:TIRAP
(Homo sapiens)
Multiple IRAK1 autophosphorylation steps
(Homo sapiens)
TRAF6 binds to hp- IRAK1
(Homo sapiens)
TRAF6 binds to p-IRAK2
(Homo sapiens)
Dissociation of hp-IRAK1:TRAF6 from the activated TLR:oligo-Myd88:TIRAP:p-IRAK4 complex
(Homo sapiens)
Dissociation of p-IRAK2:TRAF6 from the activated TLR:oligo-Myd88:TIRAP:p-IRAK4 complex
(Homo sapiens)
IRAK2 mediated activation of TAK1 complex
(Homo sapiens)
IRAK1 recruits IKK complex
(Homo sapiens)
TRAF6 binds MEKK1
(Homo sapiens)
TAK1-dependent IKK and NF-kappa-B activation
(Homo sapiens)
MAP kinase activation
(Homo sapiens)
Participates
as an event of
Toll Like Receptor 4 (TLR4) Cascade (Homo sapiens)
Toll Like Receptor TLR1:TLR2 Cascade (Homo sapiens)
Toll Like Receptor TLR6:TLR2 Cascade (Homo sapiens)
Event Information
Go Biological Process
MyD88-dependent toll-like receptor signaling pathway (0002755)
Orthologous Events
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Bos taurus)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Caenorhabditis elegans)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Canis familiaris)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Danio rerio)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Dictyostelium discoideum)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Drosophila melanogaster)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Gallus gallus)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Mus musculus)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Plasmodium falciparum)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Rattus norvegicus)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Saccharomyces cerevisiae)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Schizosaccharomyces pombe)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Sus scrofa)
MyD88:MAL(TIRAP) cascade initiated on plasma membrane (Xenopus tropicalis)
Cross References
BioModels Database
BIOMD0000000477
Authored
de Bono, B (2005-08-16)
Reviewed
Napetschnig, J (2012-11-16)
Gay, NJ (2006-04-24)
Gillespie, ME (2010-11-30)
Created
de Bono, B (2005-08-16)
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