ArticlePloS one2015
The Identification of Novel Protein-Protein Interactions in Liver that Affect Glucagon Receptor Activity.
Article in PloS one, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 14 papers.
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Who cites it
14 citing papers in PubMed, 29 citations in OpenAlex.
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- Study of the role of transmembrane emp24 domain-containing protein 2 in oral squamous cell carcinoma.Journal of applied oral science : revista FOB · 2025Article
- Proximity extracellular protein-protein interaction analysis of EGFR using AirID-conjugated fragment of antigen binding.Nature communications · 2023Article
- Hepatocyte cholesterol content modulates glucagon receptor signalling.Molecular metabolism · 2022Article
- CF-PPiD technology based on cell-free protein array and proximity biotinylation enzyme for in vitro direct interactome analysis.Scientific reports · 2022Article
- Glucagon signaling via supraphysiologic GCGR can reduce cell viability without stimulating gluconeogenic gene expression in liver cancer cells.Cancer & metabolism · 2022Article
- Subcutaneous adipose tissue splice quantitative trait loci reveal differences in isoform usage associated with cardiometabolic traits.American journal of human genetics · 2022Article
- Synthesis and anti-diabetic activity of novel biphenylsulfonamides as glucagon receptor antagonists.Chemical biology & drug design · 2021Article
- Extracellular calcium alters calcium-sensing receptor network integrating intracellular calcium-signaling and related key pathway.Scientific reports · 2021Article
- AirID, a novel proximity biotinylation enzyme, for analysis of protein-protein interactions.eLife · 2020Article
- Expression and Importance of TMED2 in Multiple Myeloma Cells.Cancer management and research · 2020Article
- Transmembrane emp24 domain proteins in development and disease.Genetics research · 2019Review
- Identification of Proteins Interacting with Cytoplasmic High-Mobility Group Box 1 during the Hepatocellular Response to Ischemia Reperfusion Injury.International journal of molecular sciences · 2017Article
- Predicting diabetes mellitus genes via protein-protein interaction and protein subcellular localization information.BMC genomics · 2016Article
Corrections and comments
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Authors and funding
11 authors at 2 institutions in 2 countries.
Funding
Abstract
Glucagon regulates glucose homeostasis by controlling glycogenolysis and gluconeogenesis in the liver. Exaggerated and dysregulated glucagon secretion can exacerbate hyperglycemia contributing to type 2 diabetes (T2D). Thus, it is important to understand how glucagon receptor (GCGR) activity and signaling is controlled in hepatocytes. To better understand this, we sought to identify proteins that interact with the GCGR to affect ligand-dependent receptor activation. A Flag-tagged human GCGR was recombinantly expressed in Chinese hamster ovary (CHO) cells, and GCGR complexes were isolated by affinity purification (AP). Complexes were then analyzed by mass spectrometry (MS), and protein-GCGR interactions were validated by co-immunoprecipitation (Co-IP) and Western blot. This was followed by studies in primary hepatocytes to assess the effects of each interactor on glucagon-dependent glucose production and intracellular cAMP accumulation, and then in immortalized CHO and liver cell lines to further examine cell signaling. Thirty-three unique interactors were identified from the AP-MS screening of GCGR expressing CHO cells in both glucagon liganded and unliganded states. These studies revealed a particularly robust interaction between GCGR and 5 proteins, further validated by Co-IP, Western blot and qPCR. Overexpression of selected interactors in mouse hepatocytes indicated that two interactors, LDLR and TMED2, significantly enhanced glucagon-stimulated glucose production, while YWHAB inhibited glucose production. This was mirrored with glucagon-stimulated cAMP production, with LDLR and TMED2 enhancing and YWHAB inhibiting cAMP accumulation. To further link these interactors to glucose production, key gluconeogenic genes were assessed. Both LDLR and TMED2 stimulated while YWHAB inhibited PEPCK and G6Pase gene expression. In the present study, we have probed the GCGR interactome and found three novel GCGR interactors that control glucagon-stimulated glucose production by modulating cAMP accumulation and genes that control gluconeogenesis. These interactors may be useful targets to control glucose homeostasis in T2D.
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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.