title: RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer.
abstract: Wnt family members play diverse roles in development and disease. Noncanonical Wnt ligands can inhibit canonical Wnt signaling depending on the cellular context; however, the underlying mechanism of this antagonism remains poorly understood. Here we identify a specific mechanism of orphan nuclear receptor RORalpha-mediated inhibition of canonical Wnt signaling in colon cancer. Wnt5a/PKCalpha-dependent phosphorylation on serine residue 35 of RORalpha is crucial to link RORalpha to Wnt/beta-catenin signaling, which exerts inhibitory function of the expression of Wnt/beta-catenin target genes. Intriguingly, there is a significant correlation of reduction of RORalpha phosphorylation in colorectal tumor cases compared to their normal counterpart, providing the clinical relevance of the findings. Our data provide evidence for a role of RORalpha, functioning at the crossroads between the canonical and the noncanonical Wnt signaling pathways, in mediating transrepression of the Wnt/beta-catenin target genes, thereby providing new approaches for the development of therapeutic agents for human cancers.
authors.affiliation: Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea.
authors.forename: Ji Min
authors.initials: JM
authors.lastname: Lee
authors.forename: Ik Soo
authors.initials: IS
authors.lastname: Kim
authors.forename: Hyunkyung
authors.initials: H
authors.lastname: Kim
authors.forename: Jason S
authors.initials: JS
authors.lastname: Lee
authors.forename: Kyeongkyu
authors.initials: K
authors.lastname: Kim
authors.forename: Hwa Young
authors.initials: HY
authors.lastname: Yim
authors.forename: Jiyeong
authors.initials: J
authors.lastname: Jeong
authors.forename: Jung Hwa
authors.initials: JH
authors.lastname: Kim
authors.forename: Ji-Young
authors.initials: JY
authors.lastname: Kim
authors.forename: Hanna
authors.initials: H
authors.lastname: Lee
authors.forename: Sang-Beom
authors.initials: SB
authors.lastname: Seo
authors.forename: Hogeun
authors.initials: H
authors.lastname: Kim
authors.forename: Michael G
authors.initials: MG
authors.lastname: Rosenfeld
authors.forename: Keun Il
authors.initials: KI
authors.lastname: Kim
authors.forename: Sung Hee
authors.initials: SH
authors.lastname: Baek
mesh_terms: D002277:Carcinoma / Q000378:metabolism*; D002460:Cell Line; D003110:Colonic Neoplasms / Q000378:metabolism*; D005786:Gene Expression Regulation; D006801:Humans; D057094:Nuclear Receptor Subfamily 1, Group F, Member 1 / Q000737:chemistry / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation; D051571:Protein Kinase C-alpha / Q000378:metabolism*; D051153:Wnt Proteins / Q000378:metabolism*; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D051571:Protein Kinase C-alpha