TMEM59 potentiates Wnt signaling by promoting signalosome formation

Jan P Gerlach, Ingrid Jordens, Daniele V F Tauriello, Ineke van 't Land-Kuper, Jeroen M Bugter, Ivar Noordstra, Johanneke van der Kooij, Teck Y Low, Felipe X Pimentel-Muiños, Despina Xanthakis, Nicola Fenderico, Catherine Rabouille, Albert J R Heck, David A Egan, Madelon M Maurice

Research output: Contribution to journal/periodicalArticleScientificpeer-review

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.

Original languageEnglish
Pages (from-to)E3996-E4005
JournalProceedings of the National Academy of Sciences of the United States of America
Volume115
Issue number17
DOIs
Publication statusPublished - 24 Apr 2018

Keywords

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

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  • Cite this

    Gerlach, J. P., Jordens, I., Tauriello, D. V. F., van 't Land-Kuper, I., Bugter, J. M., Noordstra, I., van der Kooij, J., Low, T. Y., Pimentel-Muiños, F. X., Xanthakis, D., Fenderico, N., Rabouille, C., Heck, A. J. R., Egan, D. A., & Maurice, M. M. (2018). TMEM59 potentiates Wnt signaling by promoting signalosome formation. Proceedings of the National Academy of Sciences of the United States of America, 115(17), E3996-E4005. https://doi.org/10.1073/pnas.1721321115