ArticleDiabetologia2015
Protein kinase Cδ regulates nuclear export of FOXO1 through phosphorylation of the chaperone 14-3-3ζ.
Article in Diabetologia, 2015. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 37 citations in OpenAlex.
- 14-3-3 proteins: Regulators of cardiac excitation-contraction coupling and stress responses.The Journal of physiology · 2026Review
- Proteomic Analysis on Human Islets Suggests Nucleocytoplasmic Transport as a Mechanism of PERK Attenuation Effects in Diabetes.Molecular & cellular proteomics : MCP · 2026Article
- YWHAZ downregulated innate immune responses to RNA viruses by inhibiting the IRF3 signaling pathway.mSphere · 2026Article
- Exploring 14-3-3ζ: insights into its role in cancer mechanisms and future therapeutic applications.Hereditas · 2026Review
- Characterization of multiple binding sites on microtubule associated protein 2c recognized by dimeric and monomeric 14-3-3ζ.The FEBS journal · 2025Article
- Endothelial Foxo1 Phosphorylation Inhibition via Aptamer-Liposome Alleviates OPN-Induced Pathological Vascular Remodeling Following Spinal Cord Injury.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2024Article
- Acetylation of FOXO1 activates Bim expression involved in CVB3 induced cardiomyocyte apoptosis.Apoptosis : an international journal on programmed cell death · 2024Article
- STK3 kinase activation inhibits tumor proliferation through FOXO1-TP53INP1/P21 pathway in esophageal squamous cell carcinoma.Cellular oncology (Dordrecht, Netherlands) · 2024Article
- Autonomous Synthesis of Functional, Permanently Phosphorylated Proteins for Defining the Interactome of Monomeric 14-3-3ζ.ACS central science · 2023Article
- Structural insights into the functional roles of 14-3-3 proteins.Frontiers in molecular biosciences · 2022Review
- Plasma miR-193b-3p Is Elevated in Type 2 Diabetes and Could Impair Glucose Metabolism.Frontiers in endocrinology · 2022Article
- Phosphorylated and Phosphomimicking Variants May Differ-A Case Study of 14-3-3 Protein.Frontiers in chemistry · 2022Article
- Article
- Role of FoxO1 in regulating autophagy in type 2 diabetes mellitus (Review).Experimental and therapeutic medicine · 2021Review
- Protein Kinases Signaling in Pancreatic Beta-cells Death and Type 2 Diabetes.Advances in experimental medicine and biology · 2021Article
- Persulfidation of transcription factor FOXO1 at cysteine 457: A novel mechanism by which HJournal of advanced research · 2021Review
- Diacylglycerol-evoked activation of PKC and PKD isoforms in regulation of glucose and lipid metabolism: a review.Lipids in health and disease · 2020Review
- Phosphorylation of 14-3-3ζ links YAP transcriptional activation to hypoxic glycolysis for tumorigenesis.Oncogenesis · 2019Article
- Targeting Protein Kinases to Enhance the Response to anti-PD-1/PD-L1 Immunotherapy.International journal of molecular sciences · 2019Review
- Article
Corrections and comments
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Authors and funding
11 authors at 6 institutions in 2 countries.
Funding
No grant is acknowledged in the PubMed record.
Abstract
aims/hypothesisForkhead box protein O1 (FOXO1) is a transcription factor essential for beta cell fate. Protein kinase B-dependent phosphorylation of FOXO1 at S256 (P-FOXO1) enables its binding to 14-3-3 dimers and nuclear export. Dephosphorylated FOXO1 enters nuclei and activates pro-apoptotic genes. Since our previous observations suggest that protein kinase C delta (PKCδ) induces nuclear accumulation of FOXO1, the underlying mechanism was examined.
methodsIn human islets, genetically modified mice and INS-1E cells apoptosis was assessed by TUNEL staining. Subcellular translocation of proteins was examined by confocal microscopy and signalling pathways were analysed by western blotting and overlay assay.
resultsIn PKCδ-overexpressing (PKCδ-tg) mouse islet cells and INS-1E cells FOXO1 accumulated in nuclei, surprisingly, as P-FOXO1. PKCδ-tg decelerated IGF-1-dependent stimulation of nuclear export, indicating that changes in export caused nuclear retention of P-FOXO1. Nuclear accumulation of P-FOXO1 was accompanied by increased phosphorylation of 14-3-3ζ at S58 and reduced dimerisation of 14-3-3ζ. Palmitic acid further augmented phosphorylation of 14-3-3ζ and triggered nuclear accumulation of FOXO1 in both INS-1E and human islet cells. Furthermore, the overexpression of a phosphomimicking mutant of 14-3-3ζ (S58D) enhanced nuclear FOXO1. In accordance with the nuclear accumulation of P-FOXO1, PKCδ overexpression alone did not increase apoptotic cell death. Additionally, insulin secretion and glucose homeostasis in PKCδ-overexpressing mice remained unaffected. CONCLUSIONS/
interpretationThese results suggest that PKCδ-mediated phosphorylation of 14-3-3ζ contributes to the nuclear retention of FOXO1, even when FOXO1 is phosphorylated as under non-stress conditions. P-FOXO1 does not induce pro-apoptotic genes, but may rather exert beneficial effects on beta cells.
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