2. Academic Validation
  3. Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling

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.
Nicolas Aznar 1,  Krishna K Midde 1,  Ying Dunkel 1,  Inmaculada Lopez-Sanchez 1,  Yelena Pavlova 1,  Arthur Marivin 2,  Jorge Barbazán 3,  Fiona Murray 1,  Ulrich Nitsche 4,  Klaus-Peter Janssen 4,  Karl Willert 5,  Ajay Goel 6,  Miguel Abal 3,  Mikel Garcia-Marcos 2,  Pradipta Ghosh 1
Affiliations

Affiliations

  • 1 Department of Medicine, University of California, San Diego, San Diego, United States.
  • 2 Department of Biochemistry, Boston University School of Medicine, Boston, United States.
  • 3 Translational Medical Oncology Laboratory, Health Research Institute of Santiago, Servizo Galego de Saúde, Santiago de Compostela, Spain.
  • 4 Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
  • 5 Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, United States.
  • 6 Division of Gastroenterology, Department of Internal Medicine and Charles A Sammons Cancer Center and Baylor Research Institute, Baylor University Medical Center, Dallas, Texas, United States.
PMID: 26126266 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.

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