Phosphorylation of β-catenin by cyclic AMP-dependent protein kinase

Sebastien Taurin, Nathan Sandbo, Yimin Qin, Darren Browning, Nickolai O. Dulin

Research output: Contribution to journalArticle

290 Scopus citations

Abstract

β-Catenin is a signaling molecule that promotes cell proliferation by the induction of gene transcription through the activation of T-cell factor (TCF)/lymphoid enhancer factor (LEF) transcription factors. The canonical mechanism of the regulation of β-catenin involves its phosphorylation by casein kinase 1 at the Ser-45 site and by glycogen synthase kinase 3 (GSK3) at the Thr-41, Ser-37, and Ser-33 sites. This phosphorylation targets β-catenin to ubiquitination and degradation by the proteasome system. Mitogenic factors promote β-catenin signaling through the inhibition of GSK3, resulting in reduced β-catenin phosphorylation, its stabilization, and subsequent accumulation in the nucleus, where it stimulates TCF/LEF-dependent gene transcription. In the present study, we have shown that (i) β-catenin can be phosphorylated by protein kinase A (PKA) in vitro and in intact cells at two novel sites, Ser-552 and Ser-675; (ii) phosphorylation by PKA promotes the transcriptional activity (TCF/LEF transactivation) of β-catenin; (iii) mutation of Ser-675 attenuates the promoting effect of PKA; (iv) phosphorylation by PKA does not affect the GSK3-dependent phosphorylation of β-catenin, its stability, or intracellular localization; and (v) phosphorylation at the Ser-675 site promotes the binding of β-catenin to its transcriptional coactivator, CREB-binding protein. In conclusion, this study identifies a novel, noncanonical mechanism of modulation of β-catenin signaling through direct phosphorylation of β-catenin by PKA, promoting its interaction with CREB-binding protein.

Original languageEnglish (US)
Pages (from-to)9971-9976
Number of pages6
JournalJournal of Biological Chemistry
Volume281
Issue number15
DOIs
StatePublished - Apr 14 2006

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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