ArticleMolecular & cellular proteomics : MCP2015
The last enzyme of the de novo purine synthesis pathway 5-aminoimidazole-4-carboxamide ribonucleotide formyltransferase/IMP cyclohydrolase (ATIC) plays a central role in insulin signaling and the Golgi/endosomes protein network.
Article in Molecular & cellular proteomics : MCP, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 18 papers.
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18 citing papers in PubMed, 34 citations in OpenAlex.
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- Genome-wide parallelism underlies contemporary adaptation in urban lizards.Proceedings of the National Academy of Sciences of the United States of America · 2023Article
- Purine signaling pathway dysfunction in autism spectrum disorders: Evidence from multiple omics data.Frontiers in molecular neuroscience · 2023Article
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- Combined Targeted and Untargeted Profiling of HeLa Cells Deficient in Purine De Novo Synthesis.Metabolites · 2022Article
- Insulin's Discovery: New Insights on Its Hundredth Birthday: From Insulin Action and Clearance to Sweet Networks.International journal of molecular sciences · 2021Review
- Analysis of the uterine lumen in fertility-classified heifers: II. Proteins and metabolites†.Biology of reproduction · 2020Article
- Network medicine-travelling with the insulin receptor: Encounter of the second type.EClinicalMedicine · 2019Review
- Activity-dependent neuronal Klotho enhances astrocytic aerobic glycolysis.Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism · 2019Article
- Development and External Validation of a Novel 12-Gene Signature for Prediction of Overall Survival in Muscle-Invasive Bladder Cancer.Frontiers in oncology · 2019Article
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- A type 2 diabetes disease module with a high collective influence for Cdk2 and PTPLAD1 is localized in endosomes.PloS one · 2018Article
- The Folate Cycle As a Cause of Natural Killer Cell Dysfunction and Viral Etiology in Type 1 Diabetes.Frontiers in endocrinology · 2017Article
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Authors and funding
7 authors at 1 institution in 1 country.
Funding
Abstract
Insulin is internalized with its cognate receptor into the endosomal apparatus rapidly after binding to hepatocytes. We performed a bioinformatic screen of Golgi/endosome hepatic protein fractions and found that ATIC, which is a rate-limiting enzyme in the de novo purine biosynthesis pathway, and PTPLAD1 are associated with insulin receptor (IR) internalization. The IR interactome (IRGEN) connects ATIC to AMPK within the Golgi/endosome protein network (GEN). Forty-five percent of the IR Golgi/endosome protein network have common heritable variants associated with type 2 diabetes, including ATIC and AMPK. We show that PTPLAD1 and AMPK are rapidly compartmentalized within the plasma membrane (PM) and Golgi/endosome fractions after insulin stimulation and that ATIC later accumulates in the Golgi/endosome fraction. Using an in vitro reconstitution system and siRNA-mediated partial knockdown of ATIC and PTPLAD1 in HEK293 cells, we show that both ATIC and PTPLAD1 affect IR tyrosine phosphorylation and endocytosis. We further show that insulin stimulation and ATIC knockdown readily increase the level of AMPK-Thr172 phosphorylation in IR complexes. We observed that IR internalization was markedly decreased after AMPKα2 knockdown, and treatment with the ATIC substrate AICAR, which is an allosteric activator of AMPK, increased IR endocytosis in cultured cells and in the liver. These results suggest the presence of a signaling mechanism that senses adenylate synthesis, ATP levels, and IR activation states and that acts in regulating IR autophosphorylation and endocytosis.
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