title: Daple is a novel non-receptor GEF required for trimeric G protein activation in Wnt signaling.
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.
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Aznar
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Krishna K
authors.initials: KK
authors.lastname: Midde
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Ying
authors.initials: Y
authors.lastname: Dunkel
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Inmaculada
authors.initials: I
authors.lastname: Lopez-Sanchez
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Yelena
authors.initials: Y
authors.lastname: Pavlova
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, United States.
authors.forename: Arthur
authors.initials: A
authors.lastname: Marivin
authors.affiliation: Translational Medical Oncology Laboratory, Health Research Institute of Santiago, Servizo Galego de Saúde, Santiago de Compostela, Spain.
authors.forename: Jorge
authors.initials: J
authors.lastname: Barbazán
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Fiona
authors.initials: F
authors.lastname: Murray
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Ulrich
authors.initials: U
authors.lastname: Nitsche
authors.affiliation: Department of Surgery, Klinikum rechts der Isar, Technische Universität München, Munich, Germany.
authors.forename: Klaus-Peter
authors.initials: KP
authors.lastname: Janssen
authors.affiliation: Sanford Consortium for Regenerative Medicine, University of California, San Diego, La Jolla, California, United States.
authors.forename: Karl
authors.initials: K
authors.lastname: Willert
authors.affiliation: 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.
authors.forename: Ajay
authors.initials: A
authors.lastname: Goel
authors.affiliation: Translational Medical Oncology Laboratory, Health Research Institute of Santiago, Servizo Galego de Saúde, Santiago de Compostela, Spain.
authors.forename: Miguel
authors.initials: M
authors.lastname: Abal
authors.affiliation: Department of Biochemistry, Boston University School of Medicine, Boston, United States.
authors.forename: Mikel
authors.initials: M
authors.lastname: Garcia-Marcos
authors.affiliation: Department of Medicine, University of California, San Diego, San Diego, United States.
authors.forename: Pradipta
authors.initials: P
authors.lastname: Ghosh
mesh_terms: D051157:Frizzled Receptors / Q000378:metabolism*; D020962:Heterotrimeric GTP-Binding Proteins / Q000378:metabolism*; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D008840:Microfilament Proteins / Q000378:metabolism*; D060449:Wnt Signaling Pathway
chemical_list: C580811:CCDC88C protein, human; D051157:Frizzled Receptors; D047908:Intracellular Signaling Peptides and Proteins; D008840:Microfilament Proteins; D020962:Heterotrimeric GTP-Binding Proteins
keywords: G proteins; GEF; PI3K/Akt; Rac1; biophysics; cell biology; human; structural biology; tumor suppressor