Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling

Ng, Victoria; Bian, Hang; Sawyer, Leah; Neitzel, Leif R.; Crispi, Emily E.; Rose, Kristie L.; Popay, Tessa M.; Zhong, Alison; Lee, Laura A.; Tansey, William P.; Huppert, Stacey S.; Lee, Ethan

doi:10.1242/jcs.210575

Cited by 12 publications

(10 citation statements)

References 26 publications

(35 reference statements)

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“…NQO1 inhibitor or NQO1 knock-down/knock-out reduced the level of XIAP protein via decreasing the phosphorylation status of XIAP at ser87. It has been reported that XIAP was phosphorylated and stabilized by AKT at Ser87 [31–34], we then analyzed whether NQO1 regulated AKT expression and activation. Interestingly, knock-down/knock-out of NQO1 reduced the phosphorylation status of AKT without affecting total expression of AKT, whereas NQO1 overexpression increased the level of phosphorylated AKT (Fig.…”

Section: Resultsmentioning

confidence: 99%

NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma

et al. 2019

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BackgroundOur previous study has demonstrated that NAD(P)H: quinone oxidoreductase 1 (NQO1) is significantly upregulated in human liver cancer where it potentiates the apoptosis evasion of liver cancer cell. However, the underlying mechanisms of the oncogenic function of NQO1 in HCC have not been fully elucidated.MethodsExpression of NQO1, SIRT6, AKT and X-linked inhibitor of apoptosis protein (XIAP) protein were measured by western blotting and immunohistochemistry. Additionally, the interaction between NQO1 and potential proteins were determined by immunoprecipitation assays. Furthermore, the effect of NQO1 and SIRT6 on tumor growth was determined in cell model and orthotopic tumor implantation model.ResultsWe found that NQO1 overexpression in HCC enhanced SIRT6 protein stability via inhibiting ubiquitin-mediated 26S proteasome degradation. High level of SIRT6 reduced acetylation of AKT which resulted in increased phosphorylation and activity of AKT. Activated AKT subsequently phosphorylated anti-apoptotic protein XIAP at Ser87 which determined its protein stability. Reintroduction of SIRT6 or AKT efficiently rescued NQO1 knock-out-mediated inhibition of growth and induction of apoptosis. In orthotopic mouse model, NQO1 knock-out inhibited tumor growth and induced apoptosis while this effect was effectively rescued by SIRT6 overexpression or MG132 treatment partially.ConclusionsCollectively, these results reveal an oncogenic function of NQO1 in sustaining HCC cell proliferation through SIRT6/AKT/XIAP signaling pathway.

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Section: Resultsmentioning

confidence: 99%

NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma

et al. 2019

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“…XIAP is phosphorylated by several protein kinases, including protein kinase B (AKT), IkB kinase ε (IKKε), Tank-binding kinase 1 (TBK1), cyclin-dependent kinase 1 (CDK1)/cyclin-B1, and glycogen synthase kinase 3 (GSK3) at serine or threonine residues that affects the activity and stability of XIAP 44 – 47 . This study found that XIAP undergoes O-GlcNAc modification at serine 406.…”

Section: Discussionmentioning

confidence: 99%

Mutual regulation between OGT and XIAP to control colon cancer cell growth and invasion

et al. 2020

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O-GlcNAc transferase (OGT) is an enzyme that catalyzes the O-GlcNAc modification of nucleocytoplasmic proteins and is highly expressed in many types of cancer. However, the mechanism regulating its expression in cancer cells is not well understood. This study shows that OGT is a substrate of the E3 ubiquitin ligase X-linked inhibitor of apoptosis (XIAP) which plays an important role in cancer pathogenesis. Although LSD2 histone demethylase has already been reported as an E3 ubiquitin ligase in lung cancer cells, we identified XIAP as the main E3 ubiquitin ligase in colon cancer cells. Interestingly, OGT catalyzes the O-GlcNAc modification of XIAP at serine 406 and this modification is required for the E3 ubiquitin ligase activity of XIAP toward specifically OGT. Moreover, O-GlcNAcylation of XIAP suppresses colon cancer cell growth and invasion by promoting the proteasomal degradation of OGT. Therefore, our findings regarding the reciprocal regulation of OGT and XIAP provide a novel molecular mechanism for controlling cancer growth and invasion regulated by OGT and O-GlcNAc modification.

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“…The interaction between Gro/TLE and TCF/LEF may also be regulated by ubiquitination. The E3 ligase X-linked inhibitor of apoptosis (XIAP), upon phosphorylation by GSK3 in a Wnt-dependent manner, has been shown to ubiquitinate TLE, thereby decreasing its affinity for TCF/LEF [36,38]. Another E3 ubiquitin ligase, Hyd (hyperplastic discs)/UBR5, has also been proposed to ubiquitinate Gro/TLE [37].…”

Section: Groucho/transducing-like Enhancermentioning

confidence: 99%

Nuclear Regulation of Wnt/β-Catenin Signaling: It’s a Complex Situation

Anthony

Robbins

Ahmed

et al. 2020

Genes

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Wnt signaling is an evolutionarily conserved metazoan cell communication pathway required for proper animal development. Of the myriad of signaling events that have been ascribed to cellular activation by Wnt ligands, the canonical Wnt/β-catenin pathway has been the most studied and best understood. Misregulation of Wnt/β-catenin signaling has been implicated in developmental defects in the embryo and major diseases in the adult. Despite the latter, no drugs that inhibit the Wnt/β-catenin pathway have been approved by the FDA. In this review, we explore the least understood step in the Wnt/β-catenin pathway—nuclear regulation of Wnt target gene transcription. We initially describe our current understanding of the importation of β-catenin into the nucleus. We then focus on the mechanism of action of the major nuclear proteins implicated in driving gene transcription. Finally, we explore the concept of a nuclear Wnt enhanceosome and propose a modified model that describes the necessary components for the transcription of Wnt target genes.

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Phosphorylation of XIAP at threonine 180 controls its activity in Wnt signaling

Cited by 12 publications

References 26 publications

NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma

NQO1 potentiates apoptosis evasion and upregulates XIAP via inhibiting proteasome-mediated degradation SIRT6 in hepatocellular carcinoma

Mutual regulation between OGT and XIAP to control colon cancer cell growth and invasion

Nuclear Regulation of Wnt/β-Catenin Signaling: It’s a Complex Situation

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