Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling
Nicolas Aznar,
Krishna K Midde,
Ying Dunkel,
Inmaculada Lopez-Sanchez,
Yelena Pavlova,
Arthur Marivin,
Jorge Barbazán,
Fiona Murray,
Ulrich Nitsche,
Klaus-Peter Janssen,
Karl Willert,
Ajay Goel,
Miguel Abal,
Mikel Garcia-Marcos,
Pradipta Ghosh
Affiliations
Nicolas Aznar
Department of Medicine, University of California, San Diego, San Diego, United States
Krishna K Midde
Department of Medicine, University of California, San Diego, San Diego, United States
Ying Dunkel
Department of Medicine, University of California, San Diego, San Diego, United States
Inmaculada Lopez-Sanchez
Department of Medicine, University of California, San Diego, San Diego, United States
Yelena Pavlova
Department of Medicine, University of California, San Diego, San Diego, United States
Arthur Marivin
Department of Biochemistry, Boston University School of Medicine, Boston, United States
Jorge Barbazán
Translational Medical Oncology Laboratory, Health Research Institute of Santiago, Servizo Galego de Saúde, Santiago de Compostela, Spain
Fiona Murray
Department of Medicine, University of California, San Diego, San Diego, United States
Ulrich Nitsche
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
Klaus-Peter Janssen
Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
Karl Willert
Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, United States
Ajay Goel
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
Miguel Abal
Translational Medical Oncology Laboratory, Health Research Institute of Santiago, Servizo Galego de Saúde, Santiago de Compostela, Spain
Mikel Garcia-Marcos
Department of Biochemistry, Boston University School of Medicine, Boston, United States
Pradipta Ghosh
Department of Medicine, University of California, San Diego, San Diego, United States; Moores Cancer Center, University of California, San Diego, San Diego, United States
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.
