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PMID: 15733829
The N-terminal region of the protein recognizes the ligand, dsRNA, in the lumen of endosomes whereas the C-terminal signaling domain resides in the cytoplasm.</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829, 11130078
TLR9, on the other hand, recognizes DNA containing unmethylated CpG motifs common to both bacterial and viral genomes.

PMID: 15733829, 12119352
Finally, PI3 kinase plays a critical role in shuttling CpG DNA to TLR9.</csml:comment>
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<csml:comment type="text">

PMID: 15733829, 15123819
mouse TLR7 or human TLR8 recognizes viral single-stranded RNAs.</csml:comment>
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<csml:comment type="text">

PMID: 15733829, 15123819
mouse TLR7 or human TLR8 recognizes viral single-stranded RNAs.</csml:comment>
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<csml:comments>
<csml:comment type="text">

PMID: 15733829
For RSV, it is the F protein and for MMTV it is the envelope protein that activates TLR4.</csml:comment>
</csml:comments>
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<csml:comment type="text">

PMID: 15733829
HCMV gB protein and MV H protein activate TLR2 and CpG DNA of HSV-1, HSV-2 and MCMV can activate TLR9.</csml:comment>
</csml:comments>
</csml:process>
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<csml:comment type="text">

PMID: 15733829
HCMV gB protein and MV H protein activate TLR2 and CpG DNA of HSV-1, HSV-2 and MCMV can activate TLR9.</csml:comment>
</csml:comments>
</csml:process>
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Indirect</csml:comment>
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PMID: 15733829
Upon activation by dsRNA, TLR3 is tyrosine-phosphorylated at Tyr759 and Tyr858 at the cytoplasmic domain by an unknown protein tyrosine kinase (PTK).</csml:comment>
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PMID: 15733829
PI3 kinase is recruited by Tyr759 and activated.

PMID: 15733829
Thus, the recruitment of the two signaling kinases, TBK1 and PI3 kinase, by TLR3 can be mediated by phosphorylated Tyr858 and Tyr759, respectively.</csml:comment>
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PMID: 15733829
Activated TLR3 also activate TBK1 via TRIF, which causes serine phosphorylation of IRF-3 resulting in its dimerization and nuclear translocation.

PMID: 15733829
Thus, the recruitment of the two signaling kinases, TBK1 and PI3 kinase, by TLR3 can be mediated by phosphorylated Tyr858 and Tyr759, respectively.</csml:comment>
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PMID: 15733829
PI3 kinase is recruited by Tyr759 and activated.</csml:comment>
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</csml:comment>
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PMID: 15733829
TRIF recruits TRAF6 via a specific TRAF6-binding sequence and initiates the NF-kappaB signaling pathway.</csml:comment>
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PMID: 15733829, 12609980
Recruitment of TRAF6 by TRIF leads to recruitment of TAB2, TAK1 and PKR followed by release of the whole complex to the cytoplasm and activation of the IKK complex and MAP kinases.</csml:comment>
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PMID: 15733829
Activated TLR3 also activate TBK1 via TRIF, which causes serine phosphorylation of IRF-3 resulting in its dimerization and nuclear translocation.</csml:comment>
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PMID: 15733829, 12609980
Recruitment of TRAF6 by TRIF leads to recruitment of TAB2, TAK1 and PKR followed by release of the whole complex to the cytoplasm and activation of the IKK complex and MAP kinases.</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829, 12609980
Recruitment of TRAF6 by TRIF leads to recruitment of TAB2, TAK1 and PKR followed by release of the whole complex to the cytoplasm and activation of the IKK complex and MAP kinases.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829, 12609980
Recruitment of TRAF6 by TRIF leads to recruitment of TAB2, TAK1 and PKR followed by release of the whole complex to the cytoplasm and activation of the IKK complex and MAP kinases.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
In vitro biochemical analyses established that TBK1 can directly bind to IRF-3 and phosphorylate its critical residues.</csml:comment>
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PMID: 15733829
In vitro biochemical analyses established that TBK1 can directly bind to IRF-3 and phosphorylate its critical residues.</csml:comment>
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PMID: 15733829
It is likely that TLR3, TRIF, TBK1 and IRF-3 form a multi-component protein complex from which phosphorylated IRF-3 is released to transmit the signal to the nucleus.</csml:comment>
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PMID: 15733829
It is likely that TLR3, TRIF, TBK1 and IRF-3 form a multi-component protein complex from which phosphorylated IRF-3 is released to transmit the signal to the nucleus.</csml:comment>
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PMID: 15733829
Activated TLR3 also activate TBK1 via TRIF, which causes serine phosphorylation of IRF-3 resulting in its dimerization and nuclear translocation.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
Activated TLR3 also activate TBK1 via TRIF, which causes serine phosphorylation of IRF-3 resulting in its dimerization and nuclear translocation.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
A complete activation of IRF-3 requires further phosphorylation by PI3 kinase/Akt mediated pathway so that it can form a stable transcription complex with CBP/co-activator at ISRE cis-element to activate gene transcription.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
A complete activation of IRF-3 requires further phosphorylation by PI3 kinase/Akt mediated pathway so that it can form a stable transcription complex with CBP/co-activator at ISRE cis-element to activate gene transcription.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829
These factors can coordinately induce transcription of some genes, such as the IFN-beta gene, or they can act individually to induce transcription of different sets of genes.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
when IRF-3 is fully activated by both the TBK1 pathway and the PI3 kinase pathway, it can bind to the promoter and CBP and drive transcription of the ISG56 gene.

PMID: 15733829
Both LY294002 and Wortmannin inhibited, in a dose-dependent fashion, ISG56 induction by dsRNA.

PMID: 15733829
This induction is blocked by genestein, an inhibitor of tyrosine kinase activity.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829, 11526399, 14556004, 12721283
LPS activated TLR4 uses two adaptor proteins, TIRAP (also known as MAL) [62] and [63] and TRAM (also known as TICAM2 and TIRP) [64], [65] and [66] to imitate two independent signaling pathways.</csml:comment>
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PMID: 15733829, 11526399, 14556004, 12721283
LPS activated TLR4 uses two adaptor proteins, TIRAP (also known as MAL) [62] and [63] and TRAM (also known as TICAM2 and TIRP) [64], [65] and [66] to imitate two independent signaling pathways.</csml:comment>
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PMID: 15733829, 11526399, 14556004, 12721283
LPS activated TLR4 uses two adaptor proteins, TIRAP (also known as MAL) [62] and [63] and TRAM (also known as TICAM2 and TIRP) [64], [65] and [66] to imitate two independent signaling pathways.</csml:comment>
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PMID: 15733829
TIRAP recruits MyD88 and triggers the usual IRAK and TRAF6 dependent activation of IKKs and MAPKs.</csml:comment>
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PMID: 15733829
TIRAP recruits MyD88 and triggers the usual IRAK and TRAF6 dependent activation of IKKs and MAPKs.</csml:comment>
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PMID: 15733829
TIRAP recruits MyD88 and triggers the usual IRAK and TRAF6 dependent activation of IKKs and MAPKs.</csml:comment>
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PMID: 15733829
TIRAP recruits MyD88 and triggers the usual IRAK and TRAF6 dependent activation of IKKs and MAPKs.</csml:comment>
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PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829
TIRAP recruits MyD88 and triggers the usual IRAK and TRAF6 dependent activation of IKKs and MAPKs.</csml:comment>
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PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
</csml:comments>
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PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
</csml:comments>
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PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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Indirect</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829, 12900525
On the other hand, IRF-3 activation by TLR7 and TLR9 is MyD88-dependent [31].</csml:comment>
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Indirect</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829, 12900525
On the other hand, IRF-3 activation by TLR7 and TLR9 is MyD88-dependent [31].</csml:comment>
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PMID: 15733829
The TLR3&#8211;TRIF pathway causes activation of IRF-3, NF-kappaB, c-Jun and ATF2 via TRAF6 signalosome complex and TBK1.</csml:comment>
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PMID: 15733829
The TLR3&#8211;TRIF pathway causes activation of IRF-3, NF-kappaB, c-Jun and ATF2 via TRAF6 signalosome complex and TBK1.</csml:comment>
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PMID: 15733829
The TLR3&#8211;TRIF pathway causes activation of IRF-3, NF-kappaB, c-Jun and ATF2 via TRAF6 signalosome complex and TBK1.</csml:comment>
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PMID: 15733829
The TLR3&#8211;TRIF pathway causes activation of IRF-3, NF-kappaB, c-Jun and ATF2 via TRAF6 signalosome complex and TBK1.</csml:comment>
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PMID: 15733829, 11931769
phosphorylated NF-kappaB p65 isoform can bind to CBP and activate transcription.</csml:comment>
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PMID: 15733829
IkappaB phosphorylation releases NF-kappaB, which can now bind DNA and translocate to the nucleus.</csml:comment>
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PMID: 15733829
IkappaB phosphorylation releases NF-kappaB, which can now bind DNA and translocate to the nucleus.</csml:comment>
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PMID: 15733829, 15371334
These two proteins kinases are distantly related to the more well-known kinases, IKKalpha and IKKbeta, which are required for NF-kappaB activation.

PMID: 15733829
TRAM on the other hand recruits the adaptor protein TRIF and leads to the activation of NF-kappaB, AP-1 and IRF-3 transcription factors using the same pathways used by TRIF bound to activate TLR3.</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829, 9697844
IFN-alpha induction by TLR7, TLR8 and TLR9 requires MyD88.</csml:comment>
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PMID: 15733829, 9697844
IFN-alpha induction by TLR7, TLR8 and TLR9 requires MyD88.</csml:comment>
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PMID: 15733829
The MyD88-dependent pathway is mediated by its interaction with the transcription factor, IRF-7 and the signaling proteins, TRAF6 and IRAK4.</csml:comment>
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PMID: 15733829
The MyD88-dependent pathway is mediated by its interaction with the transcription factor, IRF-7 and the signaling proteins, TRAF6 and IRAK4.</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829, 12154357
In dendritic cells, IL-12 production and MAPK activation, in response to LPS stimulation, are down-regulated by PI3 kinase.</csml:comment>
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PMID: 15733829, 12865424
In contrast, TLR4 activation by lauric acid and the resulting signaling is blocked by inhibitors of PI3 kinase or Akt.</csml:comment>
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PMID: 15733829, 12865424
In contrast, TLR4 activation by lauric acid and the resulting signaling is blocked by inhibitors of PI3 kinase or Akt.</csml:comment>
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PMID: 15733829, 11101877
For TLR2 signaling, both receptor tyrosine phosphorylation and PI3 kinase are required for NF-kappaB activation.</csml:comment>
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PMID: 15733829, 11101877
For TLR2 signaling, both receptor tyrosine phosphorylation and PI3 kinase are required for NF-kappaB activation.</csml:comment>
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PMID: 15733829
TLR2 mediated activation of ERK-1/2, but not p38 and JNK1/2, requires PI3 kinase.</csml:comment>
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PMID: 15733829
TLR2 mediated activation of ERK-1/2, but not p38 and JNK1/2, requires PI3 kinase.</csml:comment>
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PMID: 15733829
TLR2 mediated activation of ERK-1/2, but not p38 and JNK1/2, requires PI3 kinase.</csml:comment>
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PMID: 15733829
TLR2 mediated activation of ERK-1/2, but not p38 and JNK1/2, requires PI3 kinase.</csml:comment>
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PMID: 15733829, 12847238
Consequently, IL-10 production is suppressed but IL-12 production is enhanced in the absence of PI3 kinase action.</csml:comment>
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PMID: 15733829
This cytoplasmic protein has a helicase domain in the carboxyl terminus, which recognizes dsRNA.</csml:comment>
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Indirect</csml:comment>
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Indirect</csml:comment>
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PMID: 15733829
It remains possible that FADD and RIP1 connect RIG-I and TBK1.</csml:comment>
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Indirect</csml:comment>
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<csml:comment type="text">
PMID: 1573329
In its N-terminus is a caspase recruitment domain (CARD), which transmits downstream signals that results in the activation of NF-kappaB and IRF-3.</csml:comment>
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Indirect</csml:comment>
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<csml:comments>
<csml:comment type="text">
PMID: 1573329
In its N-terminus is a caspase recruitment domain (CARD), which transmits downstream signals that results in the activation of NF-kappaB and IRF-3.</csml:comment>
</csml:comments>
</csml:process>
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PMID: 15733829
PKR is the prototypic member of a family of dsRNA-binding protein and this cytoplasmic Ser/Thr protein kinase has been shown to mediate dsRNA-signaling in certain cell types.</csml:comment>
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PMID: 15733829
The PKR protein has TRAF-interacting motifs through which several members of this family of adaptor proteins have been shown to interact with dimerized activated PKR.</csml:comment>
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PMID: 15733829
The PKR protein has TRAF-interacting motifs through which several members of this family of adaptor proteins have been shown to interact with dimerized activated PKR.</csml:comment>
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PMID: 15733829
The PKR protein has TRAF-interacting motifs through which several members of this family of adaptor proteins have been shown to interact with dimerized activated PKR.</csml:comment>
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PMID: 15733829, 15563593
Like RIG-I, another interferon-inducible helicase, the CARD-containing helicase mda5, can also mediate dsRNA signaling.</csml:comment>
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Indirect</csml:comment>
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<csml:processKinetic calcStyle="csml-calcStyle:speed" kineticStyle="csml-kineticStyle:mass" fast="false">
<csml:parameter key="coefficient1" value="0.1"/>
<csml:parameter key="coefficient2" value="1.0"/>
</csml:processKinetic>
</csml:processSimulationProperty>
<csml:viewProperty>
<csml:position positionID="default" position="auto" x="489.0" y="1241.0"/>
<csml:shape shapeID="default" visible="true">
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<csml:comments>
<csml:comment type="text">
PMID: 15733829
Finally, there is evidence of still another pathway, where dsRNA activated protein kinase PKR can cause activation of MAP kinase kinase 6 (MKK6) to activate AP-1 transcription factors.</csml:comment>
</csml:comments>
</csml:process>
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Indirect</csml:comment>
</csml:comments>
</csml:connector>
<csml:connector id="c262" name="c262" refID="e99" type="cso30:c:OutputProcess">
<csml:connectorSimulationProperty>
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</csml:processKinetic>
</csml:processSimulationProperty>
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<csml:comments>
<csml:comment type="text">
PMID: 15733829
Finally, there is evidence of still another pathway, where dsRNA activated protein kinase PKR can cause activation of MAP kinase kinase 6 (MKK6) to activate AP-1 transcription factors.</csml:comment>
</csml:comments>
</csml:process>
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<csml:comment type="text"></csml:comment>
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<csml:parameter key="coefficient2" value="1.0"/>
</csml:processKinetic>
</csml:processSimulationProperty>
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<csml:comments>
<csml:comment type="text">
PMID: 15733829, 11733537
IL-1 activated phosphorylation of p65 has been shown to require PI3 kinase, Akt and IKKbeta.</csml:comment>
</csml:comments>
</csml:process>
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<csml:comments>
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Indirect</csml:comment>
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</csml:connector>
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<csml:comments>
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Indirect</csml:comment>
</csml:comments>
</csml:connector>
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<csml:comments>
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Indirect</csml:comment>
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</csml:connector>
<csml:connector id="c272" name="c272" refID="MO000000030" type="cso30:c:InputAssociation">
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<csml:comments>
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Indirect</csml:comment>
</csml:comments>
</csml:connector>
<csml:connector id="c268" name="c268" refID="e38" type="cso30:c:OutputProcess">
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PMID: 15733829, 11733537
IL-1 activated phosphorylation of p65 has been shown to require PI3 kinase, Akt and IKKbeta.</csml:comment>
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PMID: 15733829, 33361&#8211;33368
PI3 kinase activity is required for the phosphorylation of Ser727 of STAT1 when the activator is IFN-gamma, but not IL-1 and TNF-alpha.</csml:comment>
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PMID: 15733829, 11438544
PI3 kinase activity is required for the phosphorylation of Ser727 of STAT1 when the activator is IFN-gamma, but not IL-1 and TNF-alpha.</csml:comment>
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PMID: 15733829, 15064760
The kinase receptor-interacting protein, RIP1, is also recruited by TRIF by its carboxyl terminal region and RIP1 is required for NF-kappaB activation, but not IRF-3 or JNK activation.</csml:comment>
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PMID: 15733829, 15064760
The kinase receptor-interacting protein, RIP1, is also recruited by TRIF by its carboxyl terminal region and RIP1 is required for NF-kappaB activation, but not IRF-3 or JNK activation.</csml:comment>
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