Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling
Wnt signaling is essential for tissue homeostasis and its dysregulation causes cancer. Wnt ligands trigger signaling by activating Frizzled receptors (FZDRs), which belong to the G-protein coupled receptor superfamily. However, the mechanisms of G protein activation in Wnt signaling remain controversial. In this study, we demonstrate that FZDRs activate G proteins and trigger non-canonical Wnt signaling via the Dishevelled-binding protein, Daple. Daple contains a Gα-binding and activating (GBA) motif, which activates Gαi proteins and an adjacent domain that directly binds FZDRs, thereby linking Wnt stimulation to G protein activation. This triggers non-canonical Wnt responses, that is, suppresses the β-catenin/TCF/LEF pathway and tumorigenesis, but enhances PI3K-Akt and Rac1 signals and tumor cell invasiveness. In colorectal cancers, Daple is suppressed during adenoma-to-carcinoma transformation and expressed later in metastasized tumor cells. Thus, Daple activates Gαi and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis.DOI:http://dx.doi.org/10.7554/eLife.07091.001
[…] The structure of the synthetic peptide KB-752 bound to Gαi1 (PDB:1Y3A) was used as the template to generate the modeling project in Deep View/Swiss-PdbViewer v3.7 for Daple (aa 1668–1679) in complex with Gαi3. The modeling project was submitted to the Swiss-Model Server (http://swissmodel.expasy.org//SWISS-MODEL.html) (), and model images were generated by MolsoftICM (San Diego, CA). […]
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