Modulation of β-catenin signaling by glucagon receptor activation

Jiyuan Ke, Chenghai Zhang, Kaleeckal G. Harikumar, Cassandra R. Zylstra-Diegel, Liren Wang, Laura E. Mowry, Laurence J. Miller, Bart O. Williams, H. Eric Xu

Research output: Contribution to journalArticle

13 Scopus citations

Abstract

The glucagon receptor (GCGR) is a member of the class B G protein-coupled receptor family. Activation of GCGR by glucagon leads to increased glucose production by the liver. Thus, glucagon is a key component of glucose homeostasis by counteracting the effect of insulin. In this report, we found that in addition to activation of the classic cAMP/protein kinase A (PKA) pathway, activation of GCGR also induced β-catenin stabilization and activated β-catenin-mediated transcription. Activation of β-catenin signaling was PKA-dependent, consistent with previous reports on the parathyroid hormone receptor type 1 (PTH1R) and glucagon-like peptide 1 (GLP-1R) receptors. Since low-density-lipoprotein receptor-related protein 5 (Lrp5) is an essential co-receptor required for Wnt protein mediated β-catenin signaling, we examined the role of Lrp5 in glucagon-induced β-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced β-catenin stabilization and TCF promoter-mediated transcription. Inhibiting Lrp5/6 function using Dickkopf-1(DKK1) or by expression of the Lrp5 extracellular domain blocked glucagon-induced β-catenin signaling. Furthermore, we showed that Lrp5 physically interacted with GCGR by immunoprecipitation and bioluminescence resonance energy transfer assays. Together, these results reveal an unexpected crosstalk between glucagon and β-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations.

Original languageEnglish (US)
Article numbere33676
JournalPloS one
Volume7
Issue number3
DOIs
StatePublished - Mar 16 2012

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Ke, J., Zhang, C., Harikumar, K. G., Zylstra-Diegel, C. R., Wang, L., Mowry, L. E., Miller, L. J., Williams, B. O., & Xu, H. E. (2012). Modulation of β-catenin signaling by glucagon receptor activation. PloS one, 7(3), [e33676]. https://doi.org/10.1371/journal.pone.0033676