title: DVL as a scaffold protein capturing classical GPCRs.
abstract: The classical G-protein-coupled receptors (GPCRs) are characterized by their ability to interact with heterotrimeric G proteins upon activation and by structural features such as seven transmembrane spanning domains. Frizzleds (Fzs) are comparable seven transmembrane receptors (7 TMRs) that are activated via Wnts and play a critical role in embryogenesis, tissue hemostasis and oncogenicity. It remains controversial, however, whether they may be considered GPCRs. Hence, the ten members of Fzs constitute a distinct atypical family of seven-transmembrane receptors. Canonical Wnt/β-catenin signaling leads to the core process of β-catenin stabilization and, ultimately, to the translocation of β-catenin to the nucleus where it acts as a co-transcription factor and induces Wnt target gene transcription. we have documented that activation by proteinase-activated receptor1 (PAR(1)), a classical 7TMR, recruits dishevelled (DvL), an upstream Wnt signaling protein, to mediate β-catenin stabilization. DvL is selectively bound to activated G(α13) subunit, coupled to PAR(1) following activation. Formation of the PAR(1)-induced DvL-G(α13) axis is carried out independently of Wnt, Fz and the co-receptor LRP5/6 (low density lipoprotein-related protein 5/6) since neither siRNA-LRP5/6 co-receptors nor the presence of SFRPs; secreted Fz receptor proteins (Wnt antagonists) affect PAR(1)-induced β-catenin stabilization. Similarly, PAR(1) induced placenta cytotrophoblast physiological invasion process was not affected by inhibiting Wnt, but was abrogated by siRNA-DvL. we propose that DvL serves as a central mediator protein that links classical GPCRs to β-catenin stabilization in both pathological (tumor) and physiological (placenta) invasion processes.
authors.affiliation: Department of Oncology; Hadassah-Hebrew University Medical Center; Jerusalem, Israel.
authors.forename: Hagit
authors.initials: H
authors.lastname: Turm
authors.forename: Sorina
authors.initials: S
authors.lastname: Grisaru-Granvosky
authors.forename: Myriam
authors.initials: M
authors.lastname: Maoz
authors.forename: Stefan
authors.initials: S
authors.lastname: Offermanns
authors.forename: Rachel
authors.initials: R
authors.lastname: Bar-Shavit