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.
journal_name
Proc Natl Acad Sci U S Aauthors
Gerlach JP,Jordens I,Tauriello DVF,van 't Land-Kuper I,Bugter JM,Noordstra I,van der Kooij J,Low TY,Pimentel-Muiños FX,Xanthakis D,Fenderico N,Rabouille C,Heck AJR,Egan DA,Maurice MMdoi
10.1073/pnas.1721321115subject
Has Abstractpub_date
2018-04-24 00:00:00pages
E3996-E4005issue
17eissn
0027-8424issn
1091-6490pii
1721321115journal_volume
115pub_type
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