期刊
PLOS ONE
卷 7, 期 3, 页码 -出版社
PUBLIC LIBRARY SCIENCE
DOI: 10.1371/journal.pone.0033676
关键词
-
资金
- National Institutes of Health (NIH) [R21RR024887, R01DK46577, 5R01GM087413]
- Jay and Betty Van Andel Foundation
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 beta-catenin stabilization and activated beta-catenin-mediated transcription. Activation of beta-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 beta-catenin signaling, we examined the role of Lrp5 in glucagon-induced beta-catenin signaling. Cotransfection with Lrp5 enhanced the glucagon-induced beta-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 beta-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 beta-catenin signaling, and may help to explain the metabolic phenotypes of Lrp5/6 mutations.
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