TMEM59 potentiates Wnt signaling by promoting signalosome formation

TY - JOUR

T1 - TMEM59 potentiates Wnt signaling by promoting signalosome formation

AU - Gerlach, Jan P

AU - Jordens, Ingrid

AU - Tauriello, Daniele V F

AU - van 't Land-Kuper, Ineke

AU - Bugter, Jeroen M

AU - Noordstra, Ivar

AU - van der Kooij, Johanneke

AU - Low, Teck Y

AU - Pimentel-Muiños, Felipe X

AU - Xanthakis, Despina

AU - Fenderico, Nicola

AU - Rabouille, Catherine

AU - Heck, Albert J R

AU - Egan, David A

AU - Maurice, Madelon M

N1 - Copyright © 2018 the Author(s). Published by PNAS.

PY - 2018/4/24

Y1 - 2018/4/24

N2 - 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.

AB - 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.

KW - Animals

KW - HEK293 Cells

KW - Humans

KW - Low Density Lipoprotein Receptor-Related Protein-6/genetics

KW - Membrane Proteins/genetics

KW - Mice

KW - Multiprotein Complexes/genetics

KW - Nerve Tissue Proteins/genetics

KW - Wnt Signaling Pathway/physiology

KW - Wnt3A Protein/genetics

U2 - 10.1073/pnas.1721321115

DO - 10.1073/pnas.1721321115

M3 - Article

C2 - 29632210

SN - 0027-8424

VL - 115

SP - E3996-E4005

JO - Proceedings of the National Academy of Sciences of the United States of America

JF - Proceedings of the National Academy of Sciences of the United States of America

IS - 17

ER -