期刊
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
卷 115, 期 17, 页码 E3996-E4005出版社
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1721321115
关键词
Wnt signaling; signalosome; Frizzled; multimerization; protein-protein interactions
资金
- Dutch Cancer Society
- European Research Council Starting Grant [242958]
- European Union [ITN 608180]
- Netherlands Organization for Scientific Research NWO VICI Grant [91815604]
- ECHO [711.013.012]
- large-scale proteomics facility Proteins@Work Project [184.032.201]
- Netherlands Organization for Scientific Research
- European Union Horizon Program FET-OPEN Project MSmed [686547]
- Spanish Government [SAF2014-53320R, SAF2017-88390R]
- European Research Council (ERC) [242958] Funding Source: European Research Council (ERC)
Wnt/beta-catenin signaling controls development and adult tissue homeostasis by regulating cell proliferation and cell fate decisions. Wnt binding to its receptors Frizzled (FZD) and low-density lipoprotein-related 6 (LRP6) at the cell surface initiates a signaling cascade that leads to the transcription of Wnt target genes. Upon Wnt binding, the receptors assemble into large complexes called signalosomes that provide a platform for interactions with downstream effector proteins. The molecular basis of signalosome formation and regulation remains elusive, largely due to the lack of tools to analyze its endogenous components. Here, we use internally tagged Wnt3a proteins to isolate and characterize activated, endogenous Wnt receptor complexes by mass spectrometry-based proteomics. We identify the single-span membrane protein TMEM59 as an interactor of FZD and LRP6 and a positive regulator of Wnt signaling. Mechanistically, TMEM59 promotes the formation of multi-meric Wnt-FZD assemblies via intramembrane interactions. Subsequently, these Wnt-FZD-TMEM59 clusters merge with LRP6 to form mature Wnt signalosomes. We conclude that the assembly of multi-protein Wnt signalosomes proceeds along well-ordered steps that involve regulated intramembrane interactions.
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