Enhancement of ß-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals.
Proc Natl Acad Sci U S A
; 113(21): 5946-51, 2016 May 24.
Article
em En
| MEDLINE
| ID: mdl-27162341
ABSTRACT
Multifunctional ß-catenin, with critical roles in both cell-cell adhesion and Wnt-signaling pathways, was among HeLa cell proteins coimmunoprecipitated by antibodies against brefeldin A-inhibited guanine nucleotide-exchange factors 1 and 2 (BIG1 or BIG2) that activate ADP-ribosylation factors (Arfs) by accelerating the replacement of bound GDP with GTP. BIG proteins also contain A-kinase anchoring protein (AKAP) sequences that can act as scaffolds for multimolecular assemblies that facilitate and limit cAMP signaling temporally and spatially. Direct interaction of BIG1 N-terminal sequence with ß-catenin was confirmed using yeast two-hybrid assays and in vitro synthesized proteins. Depletion of BIG1 and/or BIG2 or overexpression of guanine nucleotide-exchange factor inactive mutant, but not wild-type, proteins interfered with ß-catenin trafficking, leading to accumulation at perinuclear Golgi structures. Both phospholipase D activity and vesicular trafficking were required for effects of BIG1 and BIG2 on ß-catenin activation. Levels of PKA-phosphorylated ß-catenin S675 and ß-catenin association with PKA, BIG1, and BIG2 were also diminished after BIG1/BIG2 depletion. Inferring a requirement for BIG1 and/or BIG2 AKAP sequence in PKA modification of ß-catenin and its effect on transcription activation, we confirmed dependence of S675 phosphorylation and transcription coactivator function on BIG2 AKAP-C sequence.
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MEDLINE
Assunto principal:
Sistemas do Segundo Mensageiro
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AMP Cíclico
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Fatores de Ribosilação do ADP
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Fatores de Troca do Nucleotídeo Guanina
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Beta Catenina
Idioma:
En
Ano de publicação:
2016
Tipo de documento:
Article