Tumor Necrosis Factor (TNF) Receptor-associated Factor (TRAF)-interacting Protein (TRIP) Negatively Regulates the TRAF2 Ubiquitin-dependent Pathway by Suppressing the TRAF2-Sphingosine 1-Phosphate (S1P) Interaction

Park, Eui‐Soon; Choi, Seunga; Shin, Bongjin; Yu, Jungeun; Yu, Ji‐Yeon; Hwang, Jung Me; Yun, Hyo In; Chung, Young‐Ho; Choi, Jong-Soon; Choi, Yongwon; Rho, Jaerang

doi:10.1074/jbc.m114.609685

Cited by 54 publications

(70 citation statements)

References 48 publications

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“…As SphK1 also physically interacts with FLNA (9), FLNA may act as a scaffold to allow localized production of S1P, which in turn binds and activates TRAF2, leading to NF-B signaling. Recent studies have shown that TRAF-interacting protein (TRIP), a known cellular binding partner of TRAF2 (27), inhibits TNF-induced NF-B activation by inhibiting the binding of S1P to TRAF2 and thus suppressing its E3 ubiquitin ligase activity (28).…”

Section: Discussionmentioning

confidence: 99%

Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-κB Activation in Melanoma Cells by Inhibition of Akt Signaling

Campos

Rodríguez

Leopoldino

et al. 2016

Molecular and Cellular Biology

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d Sphingosine-1-phosphate (S1P) is a bioactive lipid mediator that regulates many processes in inflammation and cancer. S1P is a ligand for five G-protein-coupled receptors, S1PR1 to -5, and also has important intracellular actions. Previously, we showed that intracellular S1P is involved in tumor necrosis factor alpha (TNF)-induced NF-B activation in melanoma cell lines that express filamin A (FLNA). Here, we show that extracellular S1P activates NF-B only in melanoma cells that lack FLNA. In these cells, S1P, but not TNF, promotes IB kinase (IKK) and p65 phosphorylation, IB␣ degradation, p65 nuclear translocation, and NF-B reporter activity. NF-B activation induced by S1P was mediated via S1PR1 and S1PR2. Exogenous S1P enhanced the phosphorylation of protein kinase C␦ (PKC␦), and its downregulation reduced S1P-induced the phosphorylation of IKK and p65. In addition, silencing of Bcl10 also inhibited S1P-induced IKK phosphorylation. Surprisingly, S1P reduced Akt activation in melanoma cells that express FLNA, whereas in the absence of FLNA, high phosphorylation levels of Akt were maintained, enabling S1P-mediated NF-B signaling. In accord, inhibition of Akt suppressed S1P-mediated IKK and p65 phosphorylation and degradation of IB␣. Hence, these results support a negative role of FLNA in S1P-mediated NF-B activation in melanoma cells through modulation of Akt.

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Section: Discussionmentioning

confidence: 99%

Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-κB Activation in Melanoma Cells by Inhibition of Akt Signaling

Campos

Rodríguez

Leopoldino

et al. 2016

Molecular and Cellular Biology

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“…The GST-fused (GST-TRAF6), red fluorescent protein-fused (RFP-TRAF6), and Xp-tagged TRAF6 (Xp-TRAF6) and the FLAG-tagged TRAF6 deletion mutants were constructed by PCR amplification and insertion in pEBG (39), pDsRed-Monomer-N1 (BD Biosciences Clontech, Mountain View, CA), pcDNA3.1-His (Invitrogen), pFLAG-CMV2 (Sigma-Aldrich), and pMX-puro-FLAG (37), respectively. The FLAG-tagged TRAF members were described previously (29).…”

Section: Methodsmentioning

confidence: 99%

“…To generate T6BS-deficient mutants, all consensus Glu residues in the T6BSs were mutated to Ala by PCR amplification as previously described (39), and the mutated fragments were subcloned into pFLAG-CMV1 (FLAG-RANK-AAA) or pEBG (GST-RANK cyto -AAA). The retroviral expression plasmids for the chimeric receptor of human CD40 and murine RANK cyto (hCD40/mRK) and its T6BS-deficient mutant (hCD40/mRK-AAA) were described previously (12).…”

Section: Methodsmentioning

confidence: 99%

“…The expression plasmids carrying a double mutation of both T6BS and the IVVY motif were constructed by PCR amplification and insertion in pFLAG-CMV1 (FLAG-RANK-AAA/LAAF), pEBG (GST-RANK cyto -AAA/LAAF), and pMXs-puro (hCD40/mRK-AAA/ LAAF), respectively. The plasmids p(B) 3 -NF-B-Luc (NF-BLuc), pAP-1-luciferase (AP-1-Luc), and pcDNA3.0HisLacZ (Invitrogen) were described previously (38,39). The expression plasmid of HA-tagged ubiquitin (HA-Ub) was described previously (38,39).…”

Section: Methodsmentioning

confidence: 99%

“…The plasmids p(B) 3 -NF-B-Luc (NF-BLuc), pAP-1-luciferase (AP-1-Luc), and pcDNA3.0HisLacZ (Invitrogen) were described previously (38,39). The expression plasmid of HA-tagged ubiquitin (HA-Ub) was described previously (38,39). For the Vav3 knockdown (Vav3 KD ) plasmid DNA, a shRNA targeting the murine Vav3 gene was designed as previously described (39) Osteoclastogenesis and OC Analysis-Murine BMMs were prepared as previously described (37,41).…”

Section: Methodsmentioning

confidence: 99%

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Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis

Yun

Shin

et al. 2016

Journal of Biological Chemistry

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The signaling pathway downstream of stimulation of receptor activator of nuclear factor B (RANK) by RANK ligand is crucial for osteoclastogenesis. RANK recruits TNF receptor-associated factor 6 (TRAF6) to TRAF6-binding sites (T6BSs) in the RANK cytoplasmic tail (RANK cyto ) to trigger downstream osteoclastogenic signaling cascades. RANK cyto harbors an additional highly conserved domain (HCR) that also activates crucial signaling during RANK-mediated osteoclastogenesis. However, the functional cross-talk between T6BSs and the HCR in the RANK signaling complex remains unclear. To characterize the cross-talk between T6BSs and the HCR, we screened TRAF6-interacting proteins using a proteomics approach. We identified Vav3 as a novel TRAF6 binding partner and evaluated the functional importance of the TRAF6-Vav3 interaction in the RANK signaling complex. We demonstrated that the coiled-coil domain of TRAF6 interacts directly with the Dbl homology domain of Vav3 to form the RANK signaling complex independent of the TRAF6 ubiquitination pathway. TRAF6 is recruited to the RANK cyto mutant, which lacks T6BSs, via the Vav3 interaction; conversely, Vav3 is recruited to the RANK cyto mutant, which lacks the IVVY motif, via the TRAF6 interaction. Finally, we determined that the TRAF6-Vav3 interaction resulting from cross-talk between T6BSs and the IVVY motif in RANK cyto enhances downstream NF-B, MAPK, and NFATc1 activation by further strengthening TRAF6 signaling, thereby inducing RANK-mediated osteoclastogenesis. Thus, Vav3 is a novel TRAF6 interaction partner that functions in the activation of cooperative signaling between T6BSs and the IVVY motif in the RANK signaling complex.The integrity of the skeletal system is maintained by the process of bone remodeling, in which old and damaged bone is continuously replaced with new bone through the balanced action of bone-resorbing osteoclasts (OCs) 3 and bone-forming osteoblasts (1-3). As the only cells with bone-resorbing activity, OCs are clinically important in bone-related diseases; accelerated bone destruction by OCs results in pathological bone loss associated with rheumatoid arthritis, multiple myeloma, metastatic cancer, and osteoporosis, whereas impaired function of OCs leads to osteopetrotic disorders (2, 4).OCs are multinucleated giant cells that are formed by the fusion of monocyte/macrophage lineage precursors through the process of OC differentiation or osteoclastogenesis (2). The signaling pathways of receptor activator of nuclear factor B ligand (RANKL) and macrophage colony-stimulating factor (M-CSF) play key roles in osteoclastogenesis (2, 5). Mice lacking either RANK or RANKL exhibit severe osteopetrotic phenotypes, highlighting the importance of RANK-RANKL signaling as a crucial regulator of OC differentiation, activation, and survival (6, 7). RANK-RANKL signaling is initiated primarily by the recruitment of cytoplasmic TNF receptor-associated factors (TRAFs) that trigger the activation of signaling cascades downstream of adaptors/kinases, such as nuclear fa...

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Tripartite motif‐containing 37 (TRIM37) promotes the aggressiveness of non‐small‐cell lung cancer cells by activating the NF‐κB pathway

Deng

Zhao

et al. 2018

The Journal of Pathology

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Non-small-cell lung cancer (NSCLC), in which the NF-κB pathway is constitutively activated, is one of the most common malignancies. Herein, we identify an E3 ubiquitin ligase, tripartite motif-containing 37 (TRIM37), participating in the K63 polyubiquitination of TRAF2, which is a significant step in the activation of NF-κB signaling. Both the mRNA and the protein expression levels of TRIM37 were much higher in NSCLC cell lines and tissues than in normal bronchial epithelial cells and matched adjacent non-tumor tissues. TRIM37 expression correlated closely with clinical stage and poor survival in NSCLC. Overexpression of TRIM37 antagonized cisplatin-induced apoptosis, induced angiogenesis and proliferation, and increased the aggressiveness of NSCLC cells in vitro and in vivo, whereas inhibition of TRIM37 led to the opposite effects. Gene set enrichment analysis (GSEA) showed that TRIM37 expression significantly correlated with NF-κB signaling. Furthermore, we found that TRIM37 bound to TRAF2 and promoted K63-linked ubiquitination of TRAF2, sustaining the eventual activation of the NF-κB pathway. Mutation in the ring finger domain of TRIM37, a hallmark of E3 ubiquitin ligases, led to loss of the ability to promote K63 polyubiquitination of TRAF2 and activate NF-κB signaling. Taken together, our findings provide evidence that TRIM37 plays an important role in constitutive NF-κB pathway activation and could serve as a prognostic factor and therapeutic target in NSCLC. Copyright © 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

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Tumor Necrosis Factor (TNF) Receptor-associated Factor (TRAF)-interacting Protein (TRIP) Negatively Regulates the TRAF2 Ubiquitin-dependent Pathway by Suppressing the TRAF2-Sphingosine 1-Phosphate (S1P) Interaction

Cited by 54 publications

References 48 publications

Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-κB Activation in Melanoma Cells by Inhibition of Akt Signaling

Filamin A Expression Negatively Regulates Sphingosine-1-Phosphate-Induced NF-κB Activation in Melanoma Cells by Inhibition of Akt Signaling

Interaction of Tumor Necrosis Factor Receptor-associated Factor 6 (TRAF6) and Vav3 in the Receptor Activator of Nuclear Factor κB (RANK) Signaling Complex Enhances Osteoclastogenesis

Tripartite motif‐containing 37 (TRIM37) promotes the aggressiveness of non‐small‐cell lung cancer cells by activating the NF‐κB pathway

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