Daple Is a Novel Non-Receptor GEF Required for Trimeric G Protein Activation in Wnt Signaling

Elife. 2015 Jun 30;4:e07091. doi: 10.7554/eLife.07091.

Abstract

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.

Keywords: G proteins; GEF; PI3K/Akt; Rac1; biophysics; cell biology; human; structural biology; tumor suppressor.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Frizzled Receptors / metabolism*
  • Heterotrimeric GTP-Binding Proteins / metabolism*
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Microfilament Proteins / metabolism*
  • Wnt Signaling Pathway*

Substances

  • CCDC88C protein, human
  • Frizzled Receptors
  • Intracellular Signaling Peptides and Proteins
  • Microfilament Proteins
  • Heterotrimeric GTP-Binding Proteins