ArticleiScience2018
GPRC5B-Mediated Sphingomyelin Synthase 2 Phosphorylation Plays a Critical Role in Insulin Resistance.
Article in iScience, 2018. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 31 papers.
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Who cites it
31 citing papers in PubMed, 57 citations in OpenAlex.
- Small molecule inhibitor of orphan GPCR dimerization improves host defense and blood pressure control in mice.The Journal of clinical investigation · 2026Article
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- Orphan Receptor GPRC5B Controls Adult Hippocampal Neurogenesis and Affects Retinoic Acid-Mediated Behaviors.Molecular neurobiology · 2025Article
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- Reelin Increases the Sphingomyelin Content of the Plasma Membrane and Affects the Surface Expression of GPI-Anchored Proteins in Hippocampal Neurons.Journal of neurochemistry · 2025Article
- Fyn Kinase: A Potential Target in Glucolipid Metabolism and Diabetes Mellitus.Current issues in molecular biology · 2025Review
- Sphingomyelin synthase inhibitors from edible mushrooms prevent overweight and improve vitamin D homeostasis in a mouse model of diet-induced obesity.Frontiers in nutrition · 2025Article
- Discovery of a novel thiophene carboxamide analogue as a highly potent and selective sphingomyelin synthase 2 inhibitor for dry eye disease therapy.Acta pharmaceutica Sinica. B · 2025Article
- Proteomic analysis identifies novel biological pathways that may link dietary quality to type 2 diabetes risk: evidence from African American and Asian cohorts.The American journal of clinical nutrition · 2025Article
- Identification of porcine fast/slow myogenic exosomes and their regulatory effects on lipid accumulation in intramuscular adipocytes.Journal of animal science and biotechnology · 2024Article
- Maternal Age at Menarche Genes Determines Fetal Growth Restriction Risk.International journal of molecular sciences · 2024Article
- Glucose dysregulation in antipsychotic-naive first-episode psychosis: in silico exploration of gene expression signatures.Translational psychiatry · 2024Article
- Aquaporin-4 and GPRC5B: old and new players in controlling brain oedema.Brain : a journal of neurology · 2023Article
- Acylphenols and Dimeric Acylphenols from the GenusPlants (Basel, Switzerland) · 2023Review
- Sphingolipid metabolism in brain insulin resistance and neurological diseases.Frontiers in endocrinology · 2023Review
- Pathogenic variants of sphingomyelin synthase SMS2 disrupt lipid landscapes in the secretory pathway.eLife · 2022Article
- Review
- Comprehensive Spatial Profile of the Orphan G Protein Coupled Receptor GPRC5B Expression in Mouse Brain.Frontiers in neuroscience · 2022Article
- Drug Development in the Field of Sphinogolipid Metabolism.Advances in experimental medicine and biology · 2022Article
- Sphingomyelin Synthase Family and Phospholipase Cs.Advances in experimental medicine and biology · 2022Article
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
GPRC5B recruitment of Src family kinases has been implicated in diet-induced insulin resistance. However, the mechanism of this action is not fully understood. Here, we report that GPRC5B-mediated phosphorylation of sphingomyelin synthase 2 (SMS2) by Fyn is a crucial step in the development of insulin resistance. Lipid-induced metabolic stress augments SMS2 phosphorylation by facilitating the interaction of GPRC5B and SMS2. SMS2 phosphorylation reduces its ubiquitination, and consequently increases SMS2 protein abundance. Although ceramide and diacylglycerol (DAG) have been known to be central mediators of lipid-induced insulin resistance, the accumulation of these lipids fails to impair insulin signaling in SMS2 knockout mouse embryonic fibroblasts (MEFs). Conversely, exogenous expression of a phosphomimetic SMS2 impairs insulin action in SMS2 knockout MEFs under metabolic stress conditions. We demonstrate that SMS2-generated DAG in sphingomyelin synthesis inhibits insulin signaling through JNK activation. Thus, GPRC5B links sphingolipid metabolism to diet-induced insulin resistance via SMS2-dependent DAG production.
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Registered trials
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.