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- MyD88:Mal cascade initiated on plasma membrane
description
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
external resources
NCBI:1269237
REACTOME:R-HSA-166058
PUBMED:15276183
genes
AGER
,
APP
,
ATF1
,
BTK
,
CD14
,
CD36
,
CHUK
,
MAP3K8
,
CREB1
,
ATF2
,
MAPK14
,
DHX9
,
DUSP3
,
DUSP4
,
DUSP6
,
DUSP7
,
ELK1
,
FOS
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HMGB1
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IKBKB
,
IRAK1
,
IRAK2
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JUN
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MEF2A
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MEF2C
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MAP3K1
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MYD88
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NFKB1
,
NFKB2
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NFKBIA
,
NFKBIB
,
PPP2CA
,
PPP2CB
,
PPP2R1A
,
PPP2R1B
,
PPP2R5D
,
MAPK1
,
MAPK3
,
MAPK7
,
MAPK8
,
MAPK11
,
MAPK9
,
MAPK10
,
MAP2K1
,
MAP2K3
,
MAP2K6
,
MAP2K7
,
RELA
,
RPS6KA1
,
RPS6KA2
,
RPS6KA3
,
RPS27A
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S100A12
,
S100B
,
SAA1
,
MAP2K4
,
SKP1
,
MAP3K7
,
TLR1
,
TLR2
,
TLR4
,
TRAF6
,
UBA52
,
UBB
,
UBC
,
UBE2N
,
UBE2V1
,
MAPKAPK3
,
CUL1
,
IKBKG
,
SOCS1
,
RIPK2
,
BTRC
,
RPS6KA5
,
MAPKAPK2
,
TLR6
,
NOD1
,
TAB1
,
IRAK3
,
TAB2
,
FBXW11
,
LY96
,
IRAK4
,
VRK3
,
ECSIT
,
PELI2
,
PELI1
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SIGIRR
,
NOD2
,
TNIP2
,
TIRAP
,
PELI3
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TAB3
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MIR718
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