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J Biol Chem. 2018 Dec 21;293(51):19710-19724. doi: 10.1074/jbc.RA118.004434. Epub 2018 Oct 25.

Oligomerization of Frizzled and LRP5/6 protein initiates intracellular signaling for the canonical WNT/β-catenin pathway.

Author information

1
From the Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China.
2
From the Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China jiyongwang73@gmail.com.
3
From the Key Laboratory of Metabolism and Molecular Medicine, Ministry of Education, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai 200032, China xiaoqinggan@fudan.edu.cn.

Abstract

Upon binding to the canonical WNT glycoproteins, Frizzled family receptors (FZDs) and low-density lipoprotein receptor-related protein 5/6 (LRP5/6) undergo a series of polymerizations on the cell surface that elicit canonical WNT/β-catenin signaling. The hyperactivation of WNT/β-catenin signaling is the major cause of tumorigenesis, but the mechanism in tumors such as hepatoma remains unclear. Here, we observed that WNT3A manifested the hyperactivity in β-catenin-dependent signaling after binding to FZD's competitive inhibitory molecule secreted Frizzled-related protein 2 (SFRP2). To understand the mechanism of FZDs in the presence of SFRP2, we explored how FZDs can bind and activate the LRP5/6 signalosome independently of WNT glycoproteins. Our findings further revealed that oligomerizations of FZDs and LRP5/6 can integrate the cytoplasmic protein Dishevelled into the LRP5/6 signalosome, resulting in a robust activation of ligand-independent β-catenin signaling. We propose that besides WNT-bridged FZD-WNT-LRP5/6 protein complexes, the homo- and hetero-oligomerizations of WNT receptors may contribute to the formation of the LRP5/6 signalosome on the cell surface. Of note, we identified four highly expressed FZDs in the hepatoma cell line HepG2, all of which significantly promoted ligand-independent LRP5/β-catenin signaling. As FZDs are ectopically expressed in numerous tumors, our findings may provide a new perspective on tumor pathologies. Furthermore, the results in our study suggest that the composition and stoichiometry of FZDs and LRP5/6 within the LRP5/6 signalosome may tune the selection of bound WNT glycoproteins and configure downstream WNT/β-catenin signaling.

KEYWORDS:

Frizzled; LRP5/6; SFRP2; Wnt signaling; cancer; cell signaling; hepatoma; receptor endocytosis; signalosome; tumor development

PMID:
30361437
PMCID:
PMC6314125
DOI:
10.1074/jbc.RA118.004434
[Indexed for MEDLINE]
Free PMC Article

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