TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation

Wu, Hua; Lu, Xing-Xing; Wang, Jingru; Yang, Tianyu; Li, Xiu-Ming; He, Xiaoshun; Li, Yang; Ye, Wen-Long; Wu, Yong; Gan, Wen-Juan; Guo, Peng-Da; Li, Jianming

doi:10.1080/15548627.2019.1586250

Cited by 100 publications

(69 citation statements)

References 34 publications

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“…One of the novel findings in the present study is that the transcription factors STAT3 and STAT6 could regulate GSK3β/β‐catenin signalling in renal tubular cells (Figure ).This observation, for the first time, unequivocally links intercellular messenger's signals to β‐catenin activation, which would provide broad implications beyond tubular pathology. GSK3β is the serine/threonine protein kinase mediating β‐catenin degradation . Compared with the inhibitors of β‐catenin signalling such as ICG‐001, GSK3β inducers would undoubtedly provide unique inhibition to β‐catenin signalling, as it would trigger the degradation of β‐catenin other than the single inhibition of transcriptional activity.…”

Section: Discussionmentioning

confidence: 99%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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Chronic kidney disease (CKD) has a high prevalence worldwide. Renal fibrosis is the common pathological feature in various types of CKD. However, the underlying mechanisms are not determined. Here, we adopted different CKD mouse models and cultured human proximal tubular cell line to examine the expression of C-X-C motif chemokine receptor 4 (CXCR4) and β-catenin signalling, as well as their relationship in renal fibrosis. In CKD mice and humans with a variety of nephropathies, CXCR4 was dramatically up-regulated in tubules, with a concomitant activation of β-catenin. CXCR4 expression level was positively correlated with the expression of β-catenin target MMP-7. AMD3100, a CXCR4 receptor blocker, and gene knockdown of CXCR4 significantly inhibited the activation of JAK/STAT and β-catenin signalling, protected against tubular injury and renal fibrosis. CXCR4-induced renal fibrosis was inhibited by treatment with ICG-001, an inhibitor of β-catenin signalling. In HKC-8 cells, overexpression of CXCR4 induced activation of β-catenin and deteriorated cell injury. These effects were inhibited by ICG-001. Stromal cell-derived factor (SDF)-1α, the ligand of CXCR4, stimulated the activation of JAK2/STAT3 and JAK3/STAT6 signalling in HKC-8 cells. Overexpression of STAT3 or STAT6 decreased the abundance of GSK3β mRNA. Silencing of STAT3 or STAT6 significantly blocked SDF-1α-induced activation of β-catenin and fibrotic lesions. These results uncover a novel mechanistic linkage between CXCR4 and β-catenin activation in renal fibrosis in association with JAK/STAT/GSK3β pathway. Our studies also suggest that targeted inhibition of CXCR4 may provide better therapeutic effects on renal fibrosis by inhibiting multiple downstream signalling cascades.

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Section: Discussionmentioning

confidence: 99%

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Liu

Feng

Miao

et al. 2020

J Cellular Molecular Medi

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“…AP2A1 (Tian et al, 2013), Bcl2-L-13 (Murakawa et al, 2015), JIP-1 (Sandilands et al, 2011), SEC62 (Fumagalli et al, 2016), paxillin (Sharifi et al, 2016), SHC1 (Onnis et al, 2018), NUFIP1 (Wyant et al, 2018), NLRX1 (Zhang et al, 2019), JMY (Coutts and La Thangue, 2015), VHL (Kang et al, 2019), TRAF6 (Wu et al, 2019), PHB2 (Wei et al, 2017), PEBP-1 (Noh et al, 2016), optineurin (Rogov et al, 2013), TEX264 (Chino et al, 2019), Trim5α (also known as MURF2B) (Pizon et al, 2013), HGF receptor (also called MET) (Huang et al, 2019), KAT2A (Ouyang et al, 2019), and Fas-apoptotic inhibitory molecule 2 (FAIM2) interact with LC3B via a LIR motif (Jeeyeon et al, 2020). These LIRs were not tested for binding with other ATG8 proteins.…”

Section: Unknown Specificitymentioning

confidence: 99%

Structure and Dynamics in the ATG8 Family From Experimental to Computational Techniques

Sora

Kumar

Maiani

et al. 2020

Front. Cell Dev. Biol.

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Autophagy is a conserved and essential intracellular mechanism for the removal of damaged components. Since autophagy deregulation is linked to different kinds of pathologies, it is fundamental to gain knowledge on the fine molecular and structural details related to the core proteins of the autophagy machinery. Among these, the family of human ATG8 proteins plays a central role in recruiting other proteins to the different membrane structures involved in the autophagic pathway. Several experimental structures are available for the members of the ATG8 family alone or in complex with their different biological partners, including disordered regions of proteins containing a short linear motif called LC3 interacting motif. Recently, the first structural details of the interaction of ATG8 proteins with biological membranes came into light. The availability of structural data for human ATG8 proteins has been paving the way for studies on their structure-function-dynamic relationship using biomolecular simulations. Experimental and computational structural biology can help to address several outstanding questions on the mechanism of human ATG8 proteins, including their specificity toward different interactors, their association with membranes, the heterogeneity of their conformational ensemble, and their regulation by post-translational modifications. We here summarize the main results collected so far and discuss the future perspectives within the field and the knowledge gaps. Our review can serve as a roadmap for future structural and dynamics studies of the ATG8 family members in health and disease.

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“…Tumor necrosis factor receptor–associated factor 6 (TRAF6), a member of the TRAF family, has been identified as a key player in the regulation of inflammation and immunity . Recent studies have indicated that TRAF6 plays critical roles in cancer . Elevated TRAF6 expression is observed in HCC .…”

mentioning

confidence: 99%

Tumor Necrosis Factor Receptor–Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c‐Myc Gene Expression and Protein Stability

Yang

et al. 2019

Hepatology

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The oncogene c‐Myc is aberrantly expressed and plays a key role in malignant transformation and progression of hepatocellular carcinoma (HCC). Here, we report that c‐Myc is significantly up‐regulated by tumor necrosis factor receptor–associated factor 6 (TRAF6), an E3 ubiquitin ligase, in hepatocarcinogenesis. High TRAF6 expression in clinical HCC samples correlates with poor prognosis, and the loss of one copy of the Traf6 gene in Traf6+/– mice significantly impairs liver tumorigenesis. Mechanistically, TRAF6 first interacts with and ubiquitinates histone deacetylase 3 (HDAC3) with K63‐linked ubiquitin chains, which leads to the dissociation of HDAC3 from the c‐Myc promoter and subsequent acetylation of histone H3 at K9, thereby epigenetically enhancing the mRNA expression of c‐Myc. Second, the K63‐linked ubiquitination of HDAC3 impairs the HDAC3 interaction with c‐Myc and promotes c‐Myc protein acetylation, which thereby enhances c‐Myc protein stability by inhibiting carboxyl terminus of heat shock cognate 70‐kDa–interacting protein–mediated c‐Myc ubiquitination and degradation. Importantly, TRAF6/HDAC3/c‐Myc signaling is also primed in hepatitis B virus–transgenic mice, unveiling a critical role for a mechanism in inflammation–cancer transition. In clinical specimens, TRAF6 positively correlates with c‐Myc at both the mRNA and protein levels, and high TRAF6 and c‐Myc expression is associated with an unfavorable prognosis, suggesting that TRAF6 collaborates with c‐Myc to promote human hepatocarcinogenesis. Consistently, curbing c‐Myc expression by inhibition of TRAF6 activity with a TRAF6 inhibitor peptide or the silencing of c‐Myc by small interfering RNA significantly suppressed tumor growth in mice. Conclusion: These findings demonstrate the oncogenic potential of TRAF6 during hepatocarcinogenesis by modulating TRAF6/HDAC3/c‐Myc signaling, with potential implications for HCC therapy.

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TRAF6 inhibits colorectal cancer metastasis through regulating selective autophagic CTNNB1/β-catenin degradation and is targeted for GSK3B/GSK3β-mediated phosphorylation and degradation

Cited by 100 publications

References 34 publications

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

C‐X‐C motif chemokine receptor 4 aggravates renal fibrosis through activating JAK/STAT/GSK3β/β‐catenin pathway

Structure and Dynamics in the ATG8 Family From Experimental to Computational Techniques

Tumor Necrosis Factor Receptor–Associated Factor 6 Promotes Hepatocarcinogenesis by Interacting With Histone Deacetylase 3 to Enhance c‐Myc Gene Expression and Protein Stability

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