RORalpha attenuates Wnt/beta-catenin signaling by PKCalpha-dependent phosphorylation in colon cancer.
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.
Lee
Ji Min
JM
Department of Biological Sciences, Creative Research Initiative Center for Chromatin Dynamics, Seoul National University, Seoul 151-742, South Korea.
Kim
Ik Soo
IS
Kim
Hyunkyung
H
Lee
Jason S
JS
Kim
Kyeongkyu
K
Yim
Hwa Young
HY
Jeong
Jiyeong
J
Kim
Jung Hwa
JH
Kim
Ji-Young
JY
Lee
Hanna
H
Seo
Sang-Beom
SB
Kim
Hogeun
H
Rosenfeld
Michael G
MG
Kim
Keun Il
KI
Baek
Sung Hee
SH
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*
D057094:Nuclear Receptor Subfamily 1, Group F, Member 1; C539738:RORA protein, human; D051153:Wnt Proteins; D051176:beta Catenin; D051571:Protein Kinase C-alpha