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 G?-binding and activating (GBA) motif, which activates G?i 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 ?-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 G?i and enhances non-canonical Wnt signaling by FZDRs, and its dysregulation can impact both tumor initiation and progression to metastasis.
Mesh Terms:
Frizzled Receptors, Heterotrimeric GTP-Binding Proteins, Humans, Intracellular Signaling Peptides and Proteins, Microfilament Proteins, Wnt Signaling Pathway
Elife
Date: Jun. 30, 2015
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