Rac1 augments Wnt signaling by stimulating ß-catenin-lymphoid enhancer factor-1 complex assembly independent of ß-catenin nuclear import.
J Cell Sci
; 128(21): 3933-46, 2015 Nov 01.
Article
em En
| MEDLINE
| ID: mdl-26403202
ABSTRACT
ß-Catenin transduces the Wnt signaling pathway and its nuclear accumulation leads to gene transactivation and cancer. Rac1 GTPase is known to stimulate ß-catenin-dependent transcription of Wnt target genes and we confirmed this activity. Here we tested the recent hypothesis that Rac1 augments Wnt signaling by enhancing ß-catenin nuclear import; however, we found that silencing/inhibition or up-regulation of Rac1 had no influence on nuclear accumulation of ß-catenin. To better define the role of Rac1, we employed proximity ligation assays (PLA) and discovered that a significant pool of Rac1-ß-catenin protein complexes redistribute from the plasma membrane to the nucleus upon Wnt or Rac1 activation. More importantly, active Rac1 was shown to stimulate the formation of nuclear ß-catenin-lymphoid enhancer factor 1 (LEF-1) complexes. This regulation required Rac1-dependent phosphorylation of ß-catenin at specific serines, which when mutated (S191A and S605A) reduced ß-catenin binding to LEF-1 by up to 50%, as revealed by PLA and immunoprecipitation experiments. We propose that Rac1-mediated phosphorylation of ß-catenin stimulates Wnt-dependent gene transactivation by enhancing ß-catenin-LEF-1 complex assembly, providing new insight into the mechanism of cross-talk between Rac1 and canonical Wnt/ß-catenin signaling.
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Texto completo:
1
Coleções:
01-internacional
Base de dados:
MEDLINE
Assunto principal:
Proteínas rac1 de Ligação ao GTP
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Beta Catenina
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Fator 1 de Ligação ao Facilitador Linfoide
Limite:
Animals
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Humans
Idioma:
En
Ano de publicação:
2015
Tipo de documento:
Article