MAPK Signaling: Inflammatory Cytokines Pathway

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TNF
TNF
TNF R
TNF R
cIAP1/2
cIAP1/2
TRAF-3
TRAF-3
TRAF-2
TRAF-2
TRAF-6
TRAF-6
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IKK gamma
IKK gamma
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IKK gamma
IKK gamma
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26S
Proteasome
26S
Proteasome
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TAB2
TAB2
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TAK1
TAK1
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Uev1a
Uev1a
Ubc13
Ubc13
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MEKK1
MEKK1
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cIAP1/2
cIAP1/2
TRAF-2
TRAF-2
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IKK gamma
IKK gamma
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Ubc13
Ubc13
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MEKK1
MEKK1
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TRAF-6
TRAF-6
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IKK gamma
IKK gamma
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TAB2
TAB2
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TAK1
TAK1
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Inflammation

Inflammation

(Translation)
(Translation)
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MKK3/6
MKK3/6
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MKK4/7
MKK4/7
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JNK
JNK
p38
p38
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KSRP
KSRP
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MAPKAPK2
MAPKAPK2
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TTP
TTP
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p38
p38
JNK
JNK
MSK1/2
MSK1/2
AP-1
AP-1
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ATF2
ATF2
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CREB
CREB
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ATF1
ATF1
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NF-kappaB
NF-kappaB
Proinflammatory
Gene mRNA
Proinflammatory
Gene mRNA
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Otubain-1
Otubain-1
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Overview of Inflammatory Cytokine MAPK Signaling

The major output of MAPK signaling downstream of inflammatory cytokines is a proinflammatory response. TNF Receptor (TNFR) activation by TNF superfamily ligands leads to recruitment of TRAF-2, TRAF-3, TRAF-6, and IKK gamma to the TNFR complex. TRAF-2 and TRAF-6 are subsequently auto-polyubiquitinated with Lys63-linked chains in a Ubc13-Uev1a-dependent manner. Ubiquitinated TRAF-2 and TRAF-6 recruit MEKK1 and TAK1, respectively, with TAK1 being recruited via TAB2. TRAF-3 inhibits the activation of MEKK1 and TAK1 at the TNFR complex. cIAP1/2 is then recruited to the TNFR complex and polyubiquitinated with Lys63-linked chains by the Ubc13-Uev1a complex. Ubiquitinated cIAP1/2 then promotes the polyubiquitination of TRAF-3 with Lys48-linked chains, which leads to the degradation of TRAF-3 via the 26S Proteasome. Degradation of TRAF-3 releases the MEKK1 and TAK1 complexes, leading to the activation of MEKK1 and TAK1. MEKK1 and TAK1 subsequently phosphorylate and activate MKK4/7 and MKK3/6, which then phosphorylate JNK and p38, respectively. Activated JNK and p38 translocate to the nucleus where they activate multiple transcription factors, via MSK1/2 in the case of p38, including AP-1, ATF2, CREB, ATF1, and NF-kappa B. The activation of these transcription factors results in the transcription of genes encoding proinflammatory cytokines. In the cytoplasm, the translation of proinflammatory gene mRNA is inhibited by KSRP and TTP, both of which bind to and promote the degradation of mRNA. p38 directly inhibits KSRP and indirectly inhibits TTP, via MAPKAPK2, to promote inflammation via the stabilization and translation of proinflammatory gene mRNA.

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