NF-κB1/p105 Regulates Lipopolysaccharide-Stimulated MAP Kinase Signaling by Governing the Stability and Function of the Tpl2 Kinase

Waterfield, Michael; Zhang, Minying; Norman, Lourdes P.; Sun, Shao Cong

doi:10.1016/s1097-2765(03)00070-4

Cited by 203 publications

(336 citation statements)

References 36 publications

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“…2A). A similar JNK and p38a phosphorylation state was observed between WT and Cot/tpl2 KO BMDMs within the first 40 min following LPS stimulation, in accordance with earlier studies [17,36,39]. However, p38a and JNK phosphorylation were sustained for longer in LPS-stimulated Cot/tpl2 KO BMDMs versus WT BMDMs.…”

Section: Increased P38a and Jnk Phosphorylation And Impaired Ijba Recsupporting

confidence: 90%

“…Cot/tpl-2 (MAP3K8) is the sole MAP3K that activates the MKK1-Erk1/2 pathway in response to the activation of receptors of the TLR/IL-1 superfamily, as well as some of the TNF receptor family [17,[28][29][30][31][32][33][34]. Thus, Cot/tpl-2 is involved in innate immunity and inflammatory hypernociception [35], its role in mediating pro-inflammatory signals unique from any other protein.…”

Section: Introductionmentioning

confidence: 99%

“…In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-kB and ABIN2 (A20-binding inhibitor of NF-kB2), among other proteins, protecting Cot/tpl-2 from degradation. The partial proteolysis of p105 NFkB to p50 NF-kB releases Cot/tpl-2 from the complex [15][16][17][18][19][20]. Dissociated and adequately phosphorylated Cot/tpl2 [21][22][23][24] fully activates MKK1 and consequently Erk1/2, prior to being rapidly degraded through the proteasome pathway [16,17,[25][26][27].…”

mentioning

confidence: 99%

“…Dissociated and adequately phosphorylated Cot/tpl2 [21][22][23][24] fully activates MKK1 and consequently Erk1/2, prior to being rapidly degraded through the proteasome pathway [16,17,[25][26][27]. Cot/tpl-2 (MAP3K8) is the sole MAP3K that activates the MKK1-Erk1/2 pathway in response to the activation of receptors of the TLR/IL-1 superfamily, as well as some of the TNF receptor family [17,[28][29][30][31][32][33][34]. Thus, Cot/tpl-2 is involved in innate immunity and inflammatory hypernociception [35], its role in mediating pro-inflammatory signals unique from any other protein.…”

mentioning

confidence: 99%

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Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

et al. 2011

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LPS stimulation activates IKK and different MAP kinase pathways, as well as the PI3K-AktmTOR-p70 S6k pathway, a negative regulator of these MyD88-dependent intracellular signals. Here, we show that Cot/tpl2, a MAP3K responsible for the activation of the MKK1-Erk1/2, controls P-Ser473 Akt and P-Thr389 p70 S6k phosphorylation in LPS-stimulated macrophages. Analysis of the intracellular signalling in Cot/tpl2 KO macrophages versus WT macrophages reveals lower IjBa recovery and higher phosphorylation of JNK and p38a after 1 h of LPS stimulation. Moreover, Cot/tpl2 deficiency increases LPS-induced NO synthase 2 (NOS2) expression in macrophages. Inhibition of the PI3K pathway abolishes the differences in IjBa and NOS2 expression between Cot/tpl2 KO and WT macrophages following LPS administration. Furthermore, in zymosan-and polyI:C-stimulated macrophages, Cot/tpl2 mediates P-Ser473 Akt phosphorylation, increases IjBa levels and decreases NOS2 expression. In conclusion, these data reveal a novel role for the Cot/tpl2 pathway in mediating TLR activation of the Akt-mTOR-p70 S6k pathway, allowing Cot/tpl2 to fine-control the activation state of other signalling pathways.Key words: Akt . Cot/tpl2 . Macrophage . NO synthase 2 . p70 S6k . TLR See accompanying Commentary by Martinez Supporting Information available online IntroductionStimulation of TLRs by the different PAMPs triggers macrophage activation, starting a specific functional program that culminates in the production of inflammatory mediators. With the exception of TLR3, TLRs use MyD88 as a central intracellular adaptor, thereby activating multiple downstream intracellular pathways including IKK. TLR3 and TLR4 recruit the TRIF adaptor, which also activates IKK, but specifically activating TBK1 and the transcription factor IRF3 (reviewed in [1,2]). Translocation of IRF3 to the nucleus is necessary, although not sufficient, to induce IFN-b expression [3]. Most TLRs also activate the PI3K-Akt-mTOR-p70 S6k pathway, which is considered to be a negative regulator of TLR activation in macrophages and myeloid dendritic cells. Inhibition of this PI3K-Akt-mTOR-p70 S6k pathway in TLR-activated cells augments NO synthase 2 (NOS2) expression [4][5][6][7][8].Adequate TLR4 stimulation induces the formation of a TLR receptor complex that recruits proteins such as MyD88 and p85 PI3 K [9]. PI3K subsequently activates the Akt-mTOR-p70 S6k pathway. Moreover, TLR-bound MyD88 recruits IRAK4 and IRAK1. The phosphorylation of IRAK1 by IRAK4 facilitates TRAF6 [1,10]). Activated IKK-b phosphorylates p105 NF-kB at multiple residues [11][12][13], which targets the rapid degradation of p105 NF-kB to p50 NF-kB [11][12][13][14]. In resting cells, Cot/tpl-2 forms a stable and inactive complex with p105 NF-kB and ABIN2 (A20-binding inhibitor of NF-kB2), among other proteins, protecting Cot/tpl-2 from degradation. The partial proteolysis of p105 NFkB to p50 NF-kB releases Cot/tpl-2 from the complex [15][16][17][18][19][20]. Dissociated and adequately phosphorylated Cot/tpl2 [21][22][23][24] fully...

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Section: Increased P38a and Jnk Phosphorylation And Impaired Ijba Recsupporting

confidence: 90%

Section: Introductionmentioning

confidence: 99%

mentioning

confidence: 99%

mentioning

confidence: 99%

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Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

et al. 2011

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“…Later on, ABIN-2 was shown to form a ternary complex with the ERK kinase TPL-2 and the NF-B precursor p105 [61]. Both p105 and ABIN-2 are 17 required for TPL-2 protein stabilization as demonstrated in p105 deficient [62,63] as well as in ABIN-2 deficient cells [53,61], respectively. Conversely, ABIN-2 itself is stabilized by its binding to p105.…”

Section: Abin-2mentioning

confidence: 99%

ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

Verstrepen¹,

Carpentier²,

Verhelst³

et al. 2009

Biochemical Pharmacology

157

126

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ABINs have been described as three different proteins (ABIN-1, ABIN-2, that bind the ubiquitin-editing nuclear factor-B (NF-B) inhibitor protein A20 and which show limited sequence homology. Overexpression of ABINs inhibits NF-B activation by tumor necrosis factor (TNF) and several other stimuli. Similar to A20, ABIN-1 and ABIN-3 expression is NF-B dependent, implicating a potential role for the A20/ABIN complex in the

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Mutational activation of the MAP3K8 protooncogene in lung cancer

Clark

Reynolds

Anderson

et al. 2004

Genes Chromosomes & Cancer

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The MAP3K8 protooncogene (Cot/Tpl-2) activates the MAP kinase, SAP kinase, and NF-kappaB signaling pathways. MAP3K8 mutations occur in the rat homologue, but activating mutations have yet to be identified in primary human tumors. We have identified MAP3K8 as a transforming gene from a human lung adenocarcinoma and characterized a 3' end mutation in the cDNA. In addition, we confirmed that the mutation occurs in the original lung tumor, and we screened a series of lung cancer cell lines to determine whether the MAP3K8 mutation is a common occurrence in lung tumorigenesis. The oncogene was isolated and identified with the NIH3T3 nude mouse tumorigenicity assay and cDNA library screening. The gene was analyzed by polymerase chain reaction (PCR), single-strand conformational polymorphism (SSCP), and 3'RACE for mutations. The mutation was localized to MAP3K8 exon 8 and confirmed in the primary tumor DNA. Both wild-type and mutant MAP3K8 cDNAs transformed NIH3T3 cells, but the transforming activity of the mutant was much greater than that of the wild type. PCR-SSCP screening of cell line cDNAs identified one silent polymorphism in cell line SK-LU-1. Although we were unable to find additional activating mutations, these data support a role for MAP3K8 activity in cellular transformation, but suggest that mutational activation of the gene is a rare event in lung cancer.

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NF-κB1/p105 Regulates Lipopolysaccharide-Stimulated MAP Kinase Signaling by Governing the Stability and Function of the Tpl2 Kinase

Cited by 203 publications

References 36 publications

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

Cot/tpl2 activity is required for TLR‐induced activation of the Akt p70 S6k pathway in macrophages: Implications for NO synthase 2 expression

ABINs: A20 binding inhibitors of NF-κB and apoptosis signaling

Mutational activation of the MAP3K8 protooncogene in lung cancer

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