DVL as a scaffold protein capturing classical GPCRs

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 (PAR₁), 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 PAR₁ following activation. Formation of the PAR₁-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 PAR₁-induced β-catenin stabilization. Similarly, PAR₁ 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.