Enhancement of β-catenin activity by BIG1 plus BIG2 via Arf activation and cAMP signals.

Proc Natl Acad Sci U S A 2016 May 9;113(21):5946-51. Epub 2016 May 9.

Cardiovascular and Pulmonary Branch, National Heart, Lung, and Blood Institute, National Institutes of Health, Bethesda, MD 20892;

Multifunctional β-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 β-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 β-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 β-catenin activation. Levels of PKA-phosphorylated β-catenin S675 and β-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 β-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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Source
http://www.pnas.org/lookup/doi/10.1073/pnas.1601918113
Publisher Site
http://dx.doi.org/10.1073/pnas.1601918113DOI Listing
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC4889387PMC
May 2016
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References

(Supplied by CrossRef)
Lack of beta-catenin affects mouse development at gastrulation
Haegel et al.
Development 1995

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