Phosphorylation of ß-catenin at serine 663 regulates its transcriptional activity.
Biochem Biophys Res Commun
; 419(3): 543-9, 2012 Mar 16.
Article
em En
| MEDLINE
| ID: mdl-22369945
ABSTRACT
ß-Catenin, a component of Wnt signaling, plays a key role in colorectal carcinogenesis. The phosphorylation status of ß-catenin determines its fate and affects its cellular function, and serine 675 (S675) was previously identified as a common target of p21-activated kinase 1 (PAK1) and protein kinase A. In the present study, we explored the PAK1-specific phosphorylation site(s) in ß-catenin. Active PAK1 T423E but not inactive PAK1 K299R interacted with and phosphorylated ß-catenin. Mutagenesis followed by a kinase assay revealed that PAK1 phosphorylated S663 in addition to S675, and an anti-phospho-ß-catenin(S663) antibody detected the phosphorylation of S663 downstream of PAK1 in various human colon cancer cells. Furthermore, the Wnt3a-stimulated S663 phosphorylation was inhibited by the PAK1-specific inhibitor, IPA-3, but not by H-89 or LY294002. The non-phosphorylatable mutant forms of ß-catenin, S663A, S675A and S663/675A, showed similar defects in their PAK1-induced TCF/LEF transactivation, whereas the phosphomimetic form of ß-catenin, S663D, demonstrated a transcriptional activity that was comparable to that of ß-catenin S675D and ß-catenin S663D/S675D. Taken together, these results provide evidence that PAK1 specifically phosphorylates ß-catenin at S663 and that this phosphorylation is essential for the PAK1-mediated transcriptional activation of ß-catenin.
Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Serina
/
Ativação Transcricional
/
Beta Catenina
/
Quinases Ativadas por p21
Tipo de estudo:
Prognostic_studies
Limite:
Humans
Idioma:
En
Revista:
Biochem Biophys Res Commun
Ano de publicação:
2012
Tipo de documento:
Article