Regulation of Wnt/β-catenin signalling by tankyrase-dependent poly(ADP-ribosyl) ation and scaffolding

被引：102

作者：

Mariotti, Laura ^{[1
,2
]}

Pollock, Katie ^{[1
,2
,3
]}

Guettler, Sebastian ^{[1
,2
]}

机构：

[1] Inst Canc Res, Div Struct Biol, London SW7 3RP, England

[2] Inst Canc Res, Div Canc Biol, London SW7 3RP, England

[3] Inst Canc Res, Div Canc Therapeut, London, England

来源：

BRITISH JOURNAL OF PHARMACOLOGY | 2017年 / 174卷 / 24期

基金：

英国惠康基金;

关键词：

ADENOMATOUS POLYPOSIS-COLI; SMALL-MOLECULE INHIBITORS; MESSENGER-RNA EXPRESSION; MUTATION CLUSTER REGION; STRUCTURE-BASED DESIGN; STERILE ALPHA MOTIF; BETA-CATENIN; STRUCTURAL BASIS; WNT PATHWAY; DOMAIN POLYMERIZATION;

D O I：

10.1111/bph.14038

中图分类号：

R9 [药学];

学科分类号：

1007 ;

摘要：

The Wnt/beta-catenin signalling pathway is pivotal for stem cell function and the control of cellular differentiation, both during embryonic development and tissue homeostasis in adults. Its activity is carefully controlled through the concerted interactions of concentration-limited pathway components and a wide range of post-translational modifications, including phosphorylation, ubiquitylation, sumoylation, poly(ADP-ribosyl) ation (PARylation) and acetylation. Regulation of Wnt/beta-catenin signalling by PARylation was discovered relatively recently. The PARP tankyrase PARylates AXIN1/2, an essential central scaffolding protein in the beta-catenin destruction complex, and targets it for degradation, thereby fine-tuning the responsiveness of cells to the Wnt signal. The past few years have not only seen much progress in our understanding of the molecular mechanisms by which PARylation controls the pathway but also witnessed the successful development of tankyrase inhibitors as tool compounds and promising agents for the therapy of Wnt-dependent dysfunctions, including colorectal cancer. Recent work has hinted at more complex roles of tankyrase in Wnt/beta-catenin signalling as well as challenges and opportunities in the development of tankyrase inhibitors. Here we review some of the latest advances in our understanding of tankyrase function in the pathway and efforts to modulate tankyrase activity to re-tune Wnt/beta-catenin signalling in colorectal cancer cells.

引用

页码：4611 / 4636

页数：26

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