Abstract
The highly conserved Wnt signaling pathway regulates cell proliferation and differentiation in vertebrates and invertebrates. Upon binding of a Wnt ligand to a receptor of the Fz family, Disheveled (Dsh/Dvl) transduces the signal during canonical and non-canonical Wnt signaling. The specific details of how this process occurs have proven difficult to study, especially as Dsh appears to function as a switch between different branches of Wnt signaling. Here we focus on the membrane-proximal events that occur once Dsh is recruited to the membrane. We show that membrane-tethering of the Dsh protein is sufficient to induce canonical Wnt signaling activation even in the absence of the Wnt co-receptor Arrow/LRP5/6. We map the protein domains required for pathway activation in membrane tethered constructs finding that both the DEP and PDZ domains are dispensable for canonical signaling only in membrane-tethered Dsh, but not in untethered/normal Dsh. These data lead to a signal activation model, where Arrow is required to localize Dsh to the membrane during canonical Wnt signaling placing Dsh downstream of Arrow.
Highlights
The canonical Wnt signaling pathway is activated by Wnt binding to its receptors, Fz and Arr
This sequence was originally used to tether Arm protein to the membrane, and we have found it highly effective for membrane localization of GSK3, Axin and APC16, 42–44
The identification of Dsh as an activator of the Wnt pathway and its placement in the pathway upstream of GSK3 and Arm led to a simple genetic description of the Wnt pathway
Summary
The canonical Wnt signaling pathway is activated by Wnt binding to its receptors, Fz and Arr. This turned out, not to be the case as Arr was shown to function downstream of Dsh[17,18,19,20,21,22] This discovery led to the current model of activation complex assembly, where the Fz receptor recruits Dsh to the membrane forming a binding site for other pathway components, and bringing the cytoplasmic, C-terminal portion of Arr into close proximity with GSK3 and CK1 leading to Arr phosphorylation. We find that Arr is required for canonical pathway activation only if Dsh is not membrane localized We find that both PDZ and DEP domains are dispensable for signaling when Dsh is membrane localized, but not when it is cytoplasmic
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