Wnt regulation: exploring Axin-Disheveled interactions and defining mechanisms by which the SCF E3 ubiquitin ligase is recruited to the destruction complex

被引：15

作者：

Schaefer, Kristina N. ^{[1
]}

Pronobis, Mira I. ^{[1
]}

Williams, Clara E. ^{[2
]}

Zhang, Shiping ^{[2
]}

Bauer, Lauren ^{[2
]}

Goldfarb, Dennis ^{[3
,5
,6
]}

Yan, Feng ^{[3
]}

Ben Major, M. ^{[3
,4
,5
,7
]}

Peifer, Mark ^{[1
,2
,3
]}

机构：

[1] Univ N Carolina, Curriculum Genet & Mol Biol, Chapel Hill, NC 27599 USA

[2] Univ N Carolina, Dept Biol, Chapel Hill, NC 27599 USA

[3] Univ N Carolina, Lineberger Comprehens Canc Ctr, Chapel Hill, NC 27599 USA

[4] Univ N Carolina, Dept Cell Biol & Physiol, Chapel Hill, NC 27599 USA

[5] Washington Univ, Sch Med, Dept Cell Biol & Physiol, St Louis, MO 63110 USA

[6] Washington Univ, Sch Med, Inst Informat, St Louis, MO 63110 USA

[7] Washington Univ, Sch Med, Dept Otolaryngol, St Louis, MO 63110 USA

来源：

MOLECULAR BIOLOGY OF THE CELL | 2020年 / 31卷 / 10期

基金：

美国国家科学基金会; 美国国家卫生研究院;

关键词：

ADENOMATOUS POLYPOSIS-COLI; PHOSPHORYLATED BETA-CATENIN; TUMOR-SUPPRESSOR APC; F-BOX PROTEIN; SIGNALING PATHWAY; DEP DOMAIN; STRUCTURAL BASIS; GENE-EXPRESSION; DIX DOMAIN; DROSOPHILA;

D O I：

10.1091/mbc.E19-11-0647

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

Wnt signaling plays key roles in embryonic development and adult stem cell homeostasis and is altered in human cancer. Signaling is turned on and off by regulating stability of the effector beta-catenin (beta-cat). The multiprotein destruction complex binds and phosphorylates beta-cat and transfers it to the SCF-TrCP E3-ubiquitin ligase for ubiquitination and destruction. Wnt signals act though Dishevelled to turn down the destruction complex, stabilizing beta-cat. Recent work clarified underlying mechanisms, but important questions remain. We explore beta-cat transfer from the destruction complex to the E3 ligase, and test models suggesting Dishevelled and APC2 compete for association with Axin. We find that Slimb/TrCP is a dynamic component of the destruction complex biomolecular condensate, while other E3 proteins are not. Recruitment requires Axin and not APC, and Axin's RGS domain plays an important role. We find that elevating Dishevelled levels in Drosophila embryos has paradoxical effects, promoting the ability of limiting levels of Axin to turn off Wnt signaling. When we elevate Dishevelled levels, it forms its own cytoplasmic puncta, but these do not recruit Axin. Superresolution imaging in mammalian cells raises the possibility that this may result by promoting Dishevelled:Dishevelled interactions at the expense of Dishevelled: Axin interactions when Dishevelled levels are high.

引用

页码：992 / 1014

页数：23