ArticleProceedings of the National Academy of Sciences of the United States of America2003
Insulin-induced phosphorylation of FKHR (Foxo1) targets to proteasomal degradation.
Article in Proceedings of the National Academy of Sciences of the United States of America, 2003. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 251 papers.
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Who cites it
251 citing papers in PubMed, 537 citations in OpenAlex.
- USP7 inhibits FOXO1 activity in chronic lymphocytic leukaemia cells enhancing cell survival.Molecular oncology · 2026Article
- Berberine attenuates diabetic kidney injury via FOXO1/SP1-associated regulation of renal SGLT-2 expression.Chinese medicine · 2026Article
- Non-enzymatic hepatic ABHD6 interacts with Akt-FoxO1 axis to regulate metabolic health.Nature communications · 2026Article
- Non-enzymatic ABHD6 interacts with Akt-FoxO1 axis to regulate selective hepatic insulin resistance.bioRxiv : the preprint server for biology · 2026Article
- Studies of Foxo1 over the Past 25 Years: Mechanisms of Insulin Resistance and Glucose Dysregulation.Cells · 2026Review
- Dual-specificity phosphatase 6 interferes with the repressive activity of forkhead box O1 towards CYP4A11 that mediates lipid accumulation in the liver.Scientific reports · 2026Article
- The metabolic role of corticotropin-releasing hormone receptor 2 and its UCN peptides: emerging therapeutic potential.Skeletal muscle · 2025Review
- Elevated PEDF promotes the occurrence of diabetes mellitus via suppressing GSIS by downregulating the SNARE complex.Communications biology · 2025Article
- MDMX reprograms glycolysis of hepatocellular carcinoma via 14-3-3γ/FOXO1.Cell death discovery · 2025Article
- Obeticholic acid prevents cyclophosphamide-induced placental injury via SIRT1 and TLR4/NF-κB pathways.BMC pharmacology & toxicology · 2025Article
- Hepatic ASPG-mediated lysophosphatidylinositol catabolism impairs insulin signal transduction.The EMBO journal · 2025Article
- Osteocalcin induces phosphorylation of FOXO1 in human beta-cells and restores insulin expression under hyperglycemic conditions.Research square · 2025Article
- Insights of direct and indirect regulation of PXR through phosphorylation in fatty liver disease.Molecular pharmacology · 2025Review
- Comparative analysis of acute eccentric contraction-induced changes to the skeletal muscle transcriptome in young and aged mice and humans.American journal of physiology. Regulatory, integrative and comparative physiology · 2025Article
- The post-translational modification O-GlcNAc is a sensor and regulator of metabolism.Open biology · 2024Review
- Targeting PI3K family with small-molecule inhibitors in cancer therapy: current clinical status and future directions.Molecular cancer · 2024Review
- Muscle-specific lack of Gfpt1 triggers ER stress to alleviate misfolded protein accumulation.Disease models & mechanisms · 2024Article
- Mst1-mediated phosphorylation of FoxO1 and C/EBP-β stimulates cell-protective mechanisms in cardiomyocytes.Nature communications · 2024Article
- Parental experiences orchestrate locust egg hatching synchrony by regulating nuclear export of precursor miRNA.Nature communications · 2024Article
- O-GlcNAcylation mediates HActa pharmacologica Sinica · 2024Article
191 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
5 authors at 3 institutions in 1 country.
Funding
No grant is acknowledged in the PubMed record.
Abstract
Forkhead transcription factor FKHR (Foxo1) is a key regulator of glucose homeostasis, cell-cycle progression, and apoptosis. It has been shown that FKHR is phosphorylated via insulin or growth factor signaling cascades, resulting in its cytoplasmic retention and the repression of target gene expression. Here, we investigate the fate of FKHR after cells are stimulated by insulin. We show that insulin treatment decreases endogenous FKHR proteins in HepG2 cells, which is inhibited by proteasome inhibitors. FKHR is ubiquitinated in vivo and in vitro, and insulin enhances the ubiquitination in the cells. In addition, the signal to FKHR degradation from insulin is mediated by the phosphatidylinositol 3-kinase pathway, and the mutation of FKHR at the serine or threonine residues phosphorylated by protein kinase B, a downstream target of phosphatidylinositol 3-kinase, inhibits the ubiquitination in vivo and in vitro. Finally, efficient ubiquitination of FKHR requires both phosphorylation and cytoplasmic retention in the cells. These results demonstrate that the insulin-induced phosphorylation of FKHR leads to the multistep negative regulation, not only by the nuclear exclusion but also the ubiquitination-mediated degradation.
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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.