TMEM59 potentiates Wnt signaling by promoting signalosome formation

Abstract

SignificanceWnt/β-catenin signaling is crucial for adult homeostasis and stem cell maintenance, and its dysregulation is strongly associated to cancer. Upon Wnt binding, Wnt receptors assemble into large complexes called signalosomes that provide a platform for interactions with downstream effector proteins. The assembly and regulation of these signalosomes remains largely elusive. Here, we use internally tagged Wnt ligands as a tool to isolate and analyze the composition and regulation of endogenous Wnt receptor complexes. We identify a positive regulator of Wnt signaling that facilitates signalosome formation by promoting intramembrane receptor interactions. Our results reveal that the assembly of multiprotein Wnt signalosomes proceeds along well-ordered steps and involves regulated intramembrane interactions.

Wnt/Beta-Catenin Signaling Regulation and a Role for Biomolecular Condensates

“…How do post-translational modifications govern condensate assembly or disassembly? How do newly identified components of the Wnt receptor complex, like TMEM59 (Gerlach et al, 2018), Gpr124, and Reck (Eubelen et al, 2018) affect supermolecular assembly of the signalosome and downregulation of destruction complex function? How do different supermolecular complexes, such as the destruction complex and the SCF-E3 ligase, communicate with one another to control the flow of molecules and information?…”

Wnt signalling: conquering complexity

“…In the presence of Wnt ligands, the cytoplasmic tail of Lrp6 is phosphorylated by Gsk3 and Ck1, resulting in binding of Axin (Tamai et al, 2004;Zeng et al, 2005). In a process that involves Dishevelled (Dvl), which binds to the Frizzled cytoplasmic tail, these membrane-proximal signalling events result in the formation of large 'signalosomes' (Bilic et al, 2007;Gammons et al, 2016;Gerlach et al, 2018). This ultimately leads to either translocation or disruption of the destruction complex, causing the stabilization and accumulation of β-catenin.…”

Age-Dependent Changes in the Progenitor Translatome Coordinated in part byTsc1Increase Perception of Signaling Inputs to End Nephrogenesis

“…They included Dkk1, Kremen1, and Kremen2, which together target the Lrp co-receptors for degradation (arrows in Figure 4B), and Znrf3/Rnf43 which, in the absence of R-spondin/Lgr5 proteins targets the Wnt/Fzd complex for degradation (all marked with red dots in Figure 4B, (Nusse and Clevers, 2017)). Importantly, key Wnt agonists were among the transcripts translated less efficiently in P0 Six2 TGC;Tsc1 relative to P0 Six2 TGC NPCs (blue box, Figure 4B): Rspo1, and Rspo3; required to engage Znrf3/Rnf43 and prolong the half-life of the Wnt/Fzd complex, and Tmem59, coding for a molecule thought to cluster Fzd proteins thus increasing avidity/signal strength of WNT signaling (Gerlach et al, 2018). This combination of increased antagonists and decreased agonists was unique to the Wnt signal transduction pathway (Supplemental Figure S3), suggesting the compelling hypothesis that hamartin/Tsc1 regulates the strength of the Wnt9b signal by affecting the translation of key transcripts, and the impact on nephrogenesis in Tsc1 hemizygotes might be due to reduced Wnt signal input below the threshold required for completion of MET, increasing the fraction of Wnt4+, Cited1+ NPC, and delaying NPC exit from the niche and cessation of nephrogenesis.…”

“…(reducing avidity to Wnt9b and downstream signaling components; (Gerlach et al, 2018)) both increased nephron endowment. These findings provide a potential therapeutic framework for delaying cessation and increasing nephron endowment in at risk populations.…”