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

Autophagy
Hua WuJian-Ming Li

Abstract

Aberrant CTNNB1 signaling is one of the fundamental processes in cancers, especially colorectal cancer (CRC). Here, we reported that TRAF6, an E3 ubiquitin ligase important for inflammatory signaling, inhibited epithelial-mesenchymal transition (EMT) and CRC metastasis through driving a selective autophagic CTNNB1 degradation machinery. Mechanistically, TRAF6 interacted with MAP1LC3B/LC3B through its LC3-interacting region 'YxxL' and catalyzed K63-linked polyubiquitination of LC3B. The K63-linked ubiquitination of LC3B promoted the formation of the LC3B-ATG7 complex and was critical to the subsequent recognition of CTNNB1 by LC3B for the selective autophagic degradation. However, TRAF6 was phosphorylated at Thr266 by GSK3B in most clinical CRC, which triggered K48-linked polyubiquitination and degradation of TRAF6 and thereby attenuated its inhibitory activity towards the autophagy-dependent CTNNB1 signaling. Clinically, decreased expression of TRAF6 was associated with elevated GSK3B protein levels and activity and reduced overall survival in CRC patients. Pharmacological inhibition of GSK3B activity stabilized the TRAF6 protein, promoted CTNNB1 degradation, and effectively suppressed EMT and CRC metastasis. Thus, targeting TR...Continue Reading

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Citations

Jun 4, 2019·Hepatology : Official Journal of the American Association for the Study of Liver Diseases·Hua WuJian-Ming Li
Mar 3, 2020·Journal of Cellular and Molecular Medicine·Yahong LiuLili Zhou
Jun 27, 2020·Frontiers in Cell and Developmental Biology·Valentina SoraElena Papaleo
Dec 29, 2020·Frontiers in Molecular Biosciences·Shixin XiangZhangang Xiao
Dec 15, 2020·Biochimica Et Biophysica Acta. Molecular Cell Research·Shahrokh LorzadehNegar Azarpira
May 4, 2021·Pharmacological Research : the Official Journal of the Italian Pharmacological Society·Chunhui JiangLei Gu
Sep 2, 2021·Journal of Experimental & Clinical Cancer Research : CR·Yi LiaoHaidong Wang
Dec 14, 2021·Frontiers in Cell and Developmental Biology·Suna ZhouYouyou Xie

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Methods Mentioned

BETA
xenograft
immunoprecipitation
transmission electron microscopy
CoIP
confocal microscopy
ubiquitination
transfection
coimmunoprecipitation
lipidation
PCR

Software Mentioned

Dmetrix
Elements D
NIS
Proteome Discoverer
Mascot

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