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, Low Teck Yew, Felipe X. Pimentel-Muiños, Despina Xanthakis, Nicola Fenderico, Catherine Rabouille, Albert J.R. Heck, David A. Egan, Madelon M. Maurice

Research output: Contribution to journalArticle

4 Citations (Scopus)

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 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 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

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Wnt3A Protein
Wnt Receptors
Catenins
LDL Receptors
Proteomics
Mass Spectrometry
Membrane Proteins
Homeostasis
Cell Proliferation
Genes
Proteins

Keywords

  • Frizzled
  • multimerization
  • protein–protein interactions
  • signalosome
  • Wnt signaling

ASJC Scopus subject areas

  • General

Cite this

Gerlach, J. P., Jordens, I., Tauriello, D. V. F., Land-Kuper, I. V. T., Bugter, J. M., Noordstra, I., ... 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

TMEM59 potentiates Wnt signaling by promoting signalosome formation. / Gerlach, Jan P.; Jordens, Ingrid; Tauriello, Daniele V.F.; Land-Kuper, Ineke van t.; Bugter, Jeroen M.; Noordstra, Ivar; van der Kooij, Johanneke; Teck Yew, Low; Pimentel-Muiños, Felipe X.; Xanthakis, Despina; Fenderico, Nicola; Rabouille, Catherine; Heck, Albert J.R.; Egan, David A.; Maurice, Madelon M.

In: Proceedings of the National Academy of Sciences of the United States of America, Vol. 115, No. 17, 24.04.2018, p. E3996-E4005.

Research output: Contribution to journalArticle

Gerlach, JP, Jordens, I, Tauriello, DVF, Land-Kuper, IVT, Bugter, JM, Noordstra, I, van der Kooij, J, Teck Yew, L, Pimentel-Muiños, FX, Xanthakis, D, Fenderico, N, Rabouille, C, Heck, AJR, Egan, DA & Maurice, MM 2018, 'TMEM59 potentiates Wnt signaling by promoting signalosome formation', Proceedings of the National Academy of Sciences of the United States of America, vol. 115, no. 17, pp. E3996-E4005. https://doi.org/10.1073/pnas.1721321115
Gerlach, Jan P. ; Jordens, Ingrid ; Tauriello, Daniele V.F. ; Land-Kuper, Ineke van t. ; Bugter, Jeroen M. ; Noordstra, Ivar ; van der Kooij, Johanneke ; Teck Yew, Low ; Pimentel-Muiños, Felipe X. ; Xanthakis, Despina ; Fenderico, Nicola ; Rabouille, Catherine ; Heck, Albert J.R. ; Egan, David A. ; Maurice, Madelon M. / TMEM59 potentiates Wnt signaling by promoting signalosome formation. In: Proceedings of the National Academy of Sciences of the United States of America. 2018 ; Vol. 115, No. 17. pp. E3996-E4005.
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