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 Citations (Scopus)

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

Fingerprint

Glucagon Receptors
Low Density Lipoprotein Receptor-Related Protein-5
Catenins
Glucagon
Chemical activation
glucagon
Modulation
lipoproteins
receptors
Low Density Lipoprotein Receptor-Related Protein-6
proteins
cAMP-dependent protein kinase
Transcription
Cyclic AMP-Dependent Protein Kinases
Stabilization
Wnt Proteins
Parathyroid Hormone Receptor Type 1
transcription (genetics)
Bioluminescence
Glucose

ASJC Scopus subject areas

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

Cite this

Ke, J., Zhang, C., Harikumar, K. G., Zylstra-Diegel, C. R., Wang, L., Mowry, L. E., ... 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

Modulation of β-catenin signaling by glucagon receptor activation. / Ke, Jiyuan; Zhang, Chenghai; Harikumar, Kaleeckal G.; Zylstra-Diegel, Cassandra R.; Wang, Liren; Mowry, Laura E.; Miller, Laurence J; Williams, Bart O.; Xu, H. Eric.

In: PLoS One, Vol. 7, No. 3, e33676, 16.03.2012.

Research output: Contribution to journalArticle

Ke, J, Zhang, C, Harikumar, KG, Zylstra-Diegel, CR, Wang, L, Mowry, LE, Miller, LJ, Williams, BO & Xu, HE 2012, 'Modulation of β-catenin signaling by glucagon receptor activation', PLoS One, vol. 7, no. 3, e33676. https://doi.org/10.1371/journal.pone.0033676
Ke J, Zhang C, Harikumar KG, Zylstra-Diegel CR, Wang L, Mowry LE et al. Modulation of β-catenin signaling by glucagon receptor activation. PLoS One. 2012 Mar 16;7(3). e33676. https://doi.org/10.1371/journal.pone.0033676
Ke, Jiyuan ; Zhang, Chenghai ; Harikumar, Kaleeckal G. ; Zylstra-Diegel, Cassandra R. ; Wang, Liren ; Mowry, Laura E. ; Miller, Laurence J ; Williams, Bart O. ; Xu, H. Eric. / Modulation of β-catenin signaling by glucagon receptor activation. In: PLoS One. 2012 ; Vol. 7, No. 3.
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