TMEM59 potentiates Wnt signaling by promoting signalosome formation.

Autor:	Gerlach JP; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., Jordens I; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.; Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., Tauriello DVF; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., van 't Land-Kuper I; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., Bugter JM; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.; Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., Noordstra I; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., van der Kooij J; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., Low TY; Department of Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, University of Utrecht, 3584 CH Utrecht, The Netherlands.; Utrecht Institute for Pharmaceutical Sciences, Science4life, University of Utrecht, 3584 CH Utrecht, The Netherlands.; Netherlands Proteomics Centre, University of Utrecht, 3584 CH Utrecht, The Netherlands., Pimentel-Muiños FX; Instituto de Biología Molecular y Celular del Cáncer, Centro de Investigación del Cáncer, Consejo Superior de Investigaciones Científicas-Universidad de Salamanca, 37007 Salamanca, Spain., Xanthakis D; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.; Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., Fenderico N; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.; Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., Rabouille C; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.; Hubrecht Institute of the Royal Netherlands Academy of Arts and Sciences and University Medical Center Utrecht, 3584 CT Utrecht, The Netherlands., Heck AJR; Department of Biomolecular Mass Spectrometry and Proteomics, Bijvoet Center for Biomolecular Research, University of Utrecht, 3584 CH Utrecht, The Netherlands.; Utrecht Institute for Pharmaceutical Sciences, Science4life, University of Utrecht, 3584 CH Utrecht, The Netherlands.; Netherlands Proteomics Centre, University of Utrecht, 3584 CH Utrecht, The Netherlands., Egan DA; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands., Maurice MM; Cell Biology, Center for Molecular Medicine, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands; M.M.Maurice@umcutrecht.nl.; Oncode Institute, University Medical Center Utrecht, 3584 CX Utrecht, The Netherlands.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2018 Apr 24; Vol. 115 (17), pp. E3996-E4005. Date of Electronic Publication: 2018 Apr 09.
DOI:	10.1073/pnas.1721321115
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest. (Copyright © 2018 the Author(s). Published by PNAS.)
Databáze:	MEDLINE
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