ArticleThe Journal of biological chemistry2012
Insulin and insulin-like growth factor II differentially regulate endocytic sorting and stability of insulin receptor isoform A.
Article in The Journal of biological chemistry, 2012. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 58 papers.
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Who cites it
58 citing papers in PubMed, 84 citations in OpenAlex.
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- An engineered insulin analog with dual insulin and IGF-1 receptor agonism and distinct signaling.Science advances · 2026Article
- Viral insulin/IGF-like peptides inhibit IGF-1 receptor signaling to enhance viral replication.Cell reports · 2025Article
- Insulin receptor alternative splicing in breast and prostate cancer.Cancer cell international · 2024Review
- A viral insulin-like peptide inhibits IGF-1 receptor phosphorylation and regulates IGF1R gene expression.Molecular metabolism · 2024Article
- The final walk with preptin.PloS one · 2024Article
- Insulin Receptor Isoforms and Insulin Growth Factor-like Receptors: Implications in Cell Signaling, Carcinogenesis, and Chemoresistance.International journal of molecular sciences · 2023Review
- Non-glycosylated IGF2 prohormones are more mitogenic than native IGF2.Communications biology · 2023Article
- Progranulin and EGFR modulate receptor-like tyrosine kinase sorting and stability in mesothelioma cells.American journal of physiology. Cell physiology · 2023Article
- Modulation of the antagonistic properties of an insulin mimetic peptide by disulfide bridge modifications.Journal of peptide science : an official publication of the European Peptide Society · 2023Article
- IGF2: A Role in Metastasis and Tumor Evasion from Immune Surveillance?Biomedicines · 2023Review
- Hepatocyte Deletion of IGF2 Prevents DNA Damage and Tumor Formation in Hepatocellular Carcinoma.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2022Article
- Subventricular zone adult mouse neural stem cells require insulin receptor for self-renewal.Stem cell reports · 2022Article
- Insulin-like growth factor role in determining the anti-cancer effect of metformin: RCT in prostate cancer patients.Endocrine connections · 2022Article
- Article
- Adipocyte CAMK2 deficiency improves obesity-associated glucose intolerance.Molecular metabolism · 2021Article
- A radioligand receptor binding assay for measuring of insulin secreted by MIN6 cells after stimulation with glucose, arginine, ornithine, dopamine, and serotonin.Analytical and bioanalytical chemistry · 2021Article
- Isoform- and Paralog-Switching in IR-Signaling: When Diabetes Opens the Gates to Cancer.Biomolecules · 2020Review
- Progranulin/EphA2 axis: A novel oncogenic mechanism in bladder cancer.Matrix biology : journal of the International Society for Matrix Biology · 2020Article
- Discoidin Domain Receptor 1 functionally interacts with the IGF-I system in bladder cancer.Matrix biology plus · 2020Article
Corrections and comments
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Authors and funding
9 authors at 7 institutions in 4 countries.
Funding
Abstract
The insulin receptor isoform A (IR-A) binds both insulin and insulin-like growth factor (IGF)-II, although the affinity for IGF-II is 3-10-fold lower than insulin depending on a cell and tissue context. Notably, in mouse embryonic fibroblasts lacking the IGF-IR and expressing solely the IR-A (R-/IR-A), IGF-II is a more potent mitogen than insulin. As receptor endocytosis and degradation provide spatial and temporal regulation of signaling events, we hypothesized that insulin and IGF-II could affect IR-A biological responses by differentially regulating IR-A trafficking. Using R-/IR-A cells, we discovered that insulin evoked significant IR-A internalization, a process modestly affected by IGF-II. However, the differential internalization was not due to IR-A ubiquitination. Notably, prolonged stimulation of R-/IR-A cells with insulin, but not with IGF-II, targeted the receptor to a degradative pathway. Similarly, the docking protein insulin receptor substrate 1 (IRS-1) was down-regulated after prolonged insulin but not IGF-II exposure. Similar results were also obtained in experiments using [NMeTyr(B26)]-insulin, an insulin analog with IR-A binding affinity similar to IGF-II. Finally, we discovered that IR-A was internalized through clathrin-dependent and -independent pathways, which differentially regulated the activation of downstream effectors. Collectively, our results suggest that a lower affinity of IGF-II for the IR-A promotes lower IR-A phosphorylation and activation of early downstream effectors vis à vis insulin but may protect IR-A and IRS-1 from down-regulation thereby evoking sustained and robust mitogenic stimuli.
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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.