title: Novel regulatory mechanism of canonical Wnt signaling by dopamine D2 receptor through direct interaction with beta-catenin.
abstract: Classical G protein-coupled receptors (GPCRs) and canonical Wnt pathways were believed to use distinct signaling pathways. However, recent studies have shown that these two pathways interact each other by sharing several intermediate signaling components. Recent in vivo studies showed that antipsychotic drugs, which block dopamine D2-like receptors, increase the cellular levels of downstream signaling components of canonical Wnt pathways, such as dishevelled (Dvl), glycogen synthase kinase 3β (GSK3β), and β-catenin. These results suggest that some functional interactions might exist between Wnt pathway and D2-like receptors. In this study, we show that among five different dopamine receptor subtypes, D(2) receptor (D(2)R) selectively inhibited the Wnt signaling, which was measured by lymphoid enhancing factor-1 (LEF-1)-dependent transcriptional activities. D(2)R-mediated inhibition of Wnt signaling was agonist- and G protein-independent and did not require receptor phosphorylation or endocytosis. D(2)R inhibited the LEF-1-dependent transcriptional activities, and this inhibitory activity was not affected by the inhibition of GSK-3β, suggesting that D(2)R inhibited the Wnt signaling by acting on the downstream of GSK3β. D(2)R directly interacted with β-catenin through the second and third loops, leading to a reduction of β-catenin distribution in the nucleus, resulting in an inhibition of LEF-1-dependent transcription. This is a novel mechanism for the regulation of canonical Wnt signaling by GPCRs, in which receptor proteins recruit β-catenin from cytosol to the plasma membrane, resulting in the decrement of the β-catenin/LEF-1-dependent transcription in the nucleus.
authors.affiliation: Department of Pharmacology, College of Pharmacy, Chonnam National University, Gwang-Ju 500-757, Korea.
authors.forename: Chengchun
authors.initials: C
authors.lastname: Min
authors.forename: Dong-Im
authors.initials: DI
authors.lastname: Cho
authors.forename: Kyoung-Ja
authors.initials: KJ
authors.lastname: Kwon
authors.forename: Kwon-Sup
authors.initials: KS
authors.lastname: Kim
authors.forename: Chan Young
authors.initials: CY
authors.lastname: Shin
authors.forename: Kyeong-Man
authors.initials: KM
authors.lastname: Kim
mesh_terms: D002460:Cell Line; D002467:Cell Nucleus / Q000378:metabolism; D017077:Culture Media, Conditioned; D006801:Humans; D011485:Protein Binding; D017448:Receptors, Dopamine D2 / Q000378:metabolism*; D020449:Repetitive Sequences, Amino Acid; D015398:Signal Transduction; D013347:Subcellular Fractions / Q000378:metabolism; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000737:chemistry / Q000378:metabolism*
chemical_list: D017077:Culture Media, Conditioned; D017448:Receptors, Dopamine D2; D051153:Wnt Proteins; D051176:beta Catenin