TMEM59 potentiates Wnt signaling by promoting signalosome formation.

Abstract:

:Wnt/β-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 multimeric 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 multiprotein Wnt signalosomes proceeds along well-ordered steps that involve regulated intramembrane interactions.

authors

Gerlach JP,Jordens I,Tauriello DVF,van 't Land-Kuper I,Bugter JM,Noordstra I,van der Kooij J,Low TY,Pimentel-Muiños FX,Xanthakis D,Fenderico N,Rabouille C,Heck AJR,Egan DA,Maurice MM

doi

10.1073/pnas.1721321115

subject

Has Abstract

pub_date

2018-04-24 00:00:00

pages

E3996-E4005

issue

17

eissn

0027-8424

issn

1091-6490

pii

1721321115

journal_volume

115

pub_type

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