ArticlePloS one2011
Regulation of AKT phosphorylation at Ser473 and Thr308 by endoplasmic reticulum stress modulates substrate specificity in a severity dependent manner.
Article in PloS one, 2011. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 98 papers, 1 of them a synthesis that pooled it.
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Who cites it
98 citing papers in PubMed, 1 synthesis or guideline pooled it, 153 citations in OpenAlex.
- Pathophysiology and targets for treatment in hereditary galactosemia: A systematic review of animal and cellular models.Journal of inherited metabolic disease · 2020Pooled it
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- Regulation of autophagy by the p53 family and the implications for cancer therapies.Discover oncology · 2026Review
- Structural and mechanistic basis of mTORC2 activation of protein kinase AKT/PKB.The Biochemical journal · 2026Review
- The investigational anti-B7-H3 antibody-drug conjugate vobramitamab duocarmazine exerts anti-tumor activity in vitro and in vivo in pediatric sarcoma preclinical models.Cell death & disease · 2026Article
- Review
- Intricacies of PKB/Akt Activity after Sciatic Nerve Damage: A Comprehensive Review.Current protein & peptide science · 2026Review
- The Bordetella type III secretion system effector BteA targets host eosinophil-epithelial signaling to promote IL-1Ra expression and persistence.Communications biology · 2025Article
- Degraded Polysaccharides fromFoods (Basel, Switzerland) · 2025Article
- Autophagy induction by piplartine ameliorates axonal degeneration caused by mutant HSPB1 and HSPB8 in Charcot-Marie-Tooth type 2 neuropathies.Autophagy · 2025Article
- Fructose induces inflammatory activation in macrophages and microglia through the nutrient-sensing ghrelin receptor.FASEB journal : official publication of the Federation of American Societies for Experimental Biology · 2025Article
- Delivery of US28 by incoming HCMV particles rapidly attenuates Akt activity to suppress HCMV lytic replication in monocytes.Science signaling · 2024Article
- Complex Role of Regulatory T Cells (Tregs) in the Tumor Microenvironment: Their Molecular Mechanisms and Bidirectional Effects on Cancer Progression.International journal of molecular sciences · 2024Review
- A systems biology-based mathematical model demonstrates the potential anti-stress effectiveness of a multi-nutrient botanical formulation.Scientific reports · 2024Article
- Human cytomegalovirus modulates mTORC1 to redirect mRNA translation within quiescently infected monocytes.Journal of virology · 2024Article
- Inhibition of SIRT2 promotes death of human cytomegalovirus-infected peripheral blood monocytes via apoptosis and necroptosis.Antiviral research · 2023Article
- Targeting unfolded protein response reverts ER stress and ER CaJournal of translational medicine · 2023Article
- Venlafaxine antagonizes the noradrenaline-promoted colon cancer progression by inhibiting the norepinephrine transporter.Cell death discovery · 2023Article
- The hypergonadotropic hypogonadism conundrum of classic galactosemia.Human reproduction update · 2023Article
- The Interplay Between Autophagy and Regulated Necrosis.Antioxidants & redox signaling · 2023Review
38 more citing papers are in PubMed but not listed here.
Corrections and comments
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Authors and funding
3 authors at 2 institutions in 1 country.
Funding
Abstract
Endoplasmic reticulum (ER) stress is a common factor in the pathophysiology of diverse human diseases that are characterised by contrasting cellular behaviours, from proliferation in cancer to apoptosis in neurodegenerative disorders. Coincidently, dysregulation of AKT/PKB activity, which is the central regulator of cell growth, proliferation and survival, is often associated with the same diseases. Here, we demonstrate that ER stress modulates AKT substrate specificity in a severity-dependent manner, as shown by phospho-specific antibodies against known AKT targets. ER stress also reduces both total and phosphorylated AKT in a severity-dependent manner, without affecting activity of the upstream kinase PDK1. Normalisation to total AKT revealed that under ER stress phosphorylation of Thr308 is suppressed while that of Ser473 is increased. ER stress induces GRP78, and siRNA-mediated knock-down of GRP78 enhances phosphorylation at Ser473 by 3.6 fold, but not at Thr308. Substrate specificity is again altered. An in-situ proximity ligation assay revealed a physical interaction between GRP78 and AKT at the plasma membrane of cells following induction of ER stress. Staining was weak in cells with normal nuclear morphology but stronger in those displaying rounded, condensed nuclei. Co-immunoprecipitation of GRP78 and P-AKT(Ser473) confirmed the immuno-complex consists of non-phosphorylated AKT (Ser473 and Thr308). The interaction is likely specific as AKT did not bind to all molecular chaperones, and GRP78 did not bind to p70 S6 kinase. These findings provide one mechanistic explanation for how ER stress contributes to human pathologies demonstrating contrasting cell fates via modulation of AKT signalling.
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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.