TMEM59 potentiates Wnt signaling by promoting signalosome formation

Proc Natl Acad Sci U S A. 2018 Apr 24;115(17):E3996-E4005. doi: 10.1073/pnas.1721321115. Epub 2018 Apr 9.


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.

Keywords: Frizzled; Wnt signaling; multimerization; protein–protein interactions; signalosome.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • HEK293 Cells
  • Humans
  • Low Density Lipoprotein Receptor-Related Protein-6 / genetics
  • Low Density Lipoprotein Receptor-Related Protein-6 / metabolism*
  • Membrane Proteins / genetics
  • Membrane Proteins / metabolism*
  • Mice
  • Multiprotein Complexes / genetics
  • Multiprotein Complexes / metabolism*
  • Nerve Tissue Proteins / genetics
  • Nerve Tissue Proteins / metabolism*
  • Wnt Signaling Pathway / physiology*
  • Wnt3A Protein / genetics
  • Wnt3A Protein / metabolism*


  • LRP6 protein, human
  • Low Density Lipoprotein Receptor-Related Protein-6
  • Membrane Proteins
  • Multiprotein Complexes
  • Nerve Tissue Proteins
  • TMEM59 protein, human
  • WNT3A protein, human
  • Wnt3A Protein