Modulation of ß-catenin signaling by glucagon receptor activation.
PLoS One
; 7(3): e33676, 2012.
Article
en En
| MEDLINE
| ID: mdl-22438981
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 ß-catenin stabilization and activated ß-catenin-mediated transcription. Activation of ß-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 ß-catenin signaling, we examined the role of Lrp5 in glucagon-induced ß-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced ß-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 ß-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 ß-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations.
Texto completo:
1
Colección:
01-internacional
Base de datos:
MEDLINE
Asunto principal:
Receptores de Glucagón
/
Beta Catenina
Límite:
Animals
/
Humans
Idioma:
En
Revista:
PLoS One
Asunto de la revista:
CIENCIA
/
MEDICINA
Año:
2012
Tipo del documento:
Article
País de afiliación:
Estados Unidos