Phosphorylation of beta-Catenin by Cyclic AMP-dependent Protein Kinase

Section of Pulmonary and Critical Care Medicine, Department of Medicine, University of Chicago, 5841 S. Maryland Avenue, Chicago, IL 60637, USA.
Journal of Biological Chemistry (Impact Factor: 4.57). 05/2006; 281(15):9971-6. DOI: 10.1074/jbc.M508778200
Source: PubMed


Beta-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 beta-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 beta-catenin to ubiquitination and degradation by the proteasome system. Mitogenic factors promote beta-catenin signaling through the inhibition of GSK3, resulting in reduced beta-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) beta-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 beta-catenin; (iii) mutation of Ser-675 attenuates the promoting effect of PKA; (iv) phosphorylation by PKA does not affect the GSK3-dependent phosphorylation of beta-catenin, its stability, or intracellular localization; and (v) phosphorylation at the Ser-675 site promotes the binding of beta-catenin to its transcriptional coactivator, CREB-binding protein. In conclusion, this study identifies a novel, noncanonical mechanism of modulation of beta-catenin signaling through direct phosphorylation of beta-catenin by PKA, promoting its interaction with CREB-binding protein.

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Available from: Sebastien Taurin, Dec 29, 2015
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    • "It remains to be clarified whether ghrelininduced í µí»½-catenin stabilization via cAMP-dependent protein kinase activation involves only the inhibition of GSK-3í µí»½. A number of recent reports showed that the phosphorylation of í µí»½-catenin on ser552 by PKA enhances the transcriptional ability of í µí»½-catenin independent of the phosphorylation of í µí»½-catenin in the N-terminal domain at canonical sites regulated by Wnt pathway [32] [33]. This molecular mechanism of PKA-dependent í µí»½-catenin stabilization could be involved in ghrelin-induced í µí»½-catenin cytoplasmatic accumulation . "
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    • "Although this is an appealing hypothesis, it warrants very careful evaluation of the in vivo interactions between both pathways. Indeed, although some experimental data suggests a potential repressive effect of PKA on -catenin activity (Kang et al., 2002), most of the current literature shows that PKA can phosphorylate and inactivate GSK3 or directly phosphorylate -catenin serine residues 552 and 675, which results in stabilisation of catenin and potentially increased recruitment of cofactors (Fang et al., 2000; Hino et al., 2005; Taurin et al., 2006). Consistent with this scenario, some human adrenal tumours with constitutive PKA signalling showed accumulation of -catenin and overexpression of some potential WNT target genes. "
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    • "Analyses of phospho-isoforms of b-CATENIN after treatment with Ivermectin or Selamectin under PP2A/PP1 protein phosphataseblocked conditions suggest that these drugs may act by enhancing, directly or indirectly, phosphatase activity involved in dephosphorylating P-Ser552/P-Ser675. This effect can help explain the phenotype of Ivermectin-treated cells since P-Ser552-and P-Ser675-b-CATENIN show enhanced transcriptional activity in cooperation with TCF factors and are essential for WNT signaling in colon cancer cells (Hino et al, 2005; Taurin et al, 2006; Fang et al, 2007; Zhu et al, 2012a). Support for an involvement of PP2A also derives from the finding that its Ba (PR55a) subunit is required to downregulate the levels of P-Ser552 and P-Ser675 C-terminal phosphoforms of b- CATENIN in colon cancer cells (Zhang et al, 2009). "
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