Balancing Akt with S6K

Proper regulation of the phosphoinositide 3-kinase–Akt pathway is critical for the prevention of both insulin resistance and tumorigenesis. Many recent studies have characterized a negative feedback loop in which components of one downstream branch of this pathway, composed of the mammalian target of rapamycin and ribosomal S6 kinase, block further activation of the pathway through inhibition of insulin receptor substrate function. These findings form a novel basis for improved understanding of the pathophysiology of metabolic diseases (e.g., diabetes and obesity), tumor syndromes (e.g., tuberous sclerosis complex and Peutz-Jegher's syndrome), and human cancers.

• Publication year

  2004

• Venue

  Journal of Cell Biology

• Publication date

  2004-11-08

• Fields of study

  Biology, Medicine

• Identifiers
  DOI 10.1083/jcb.200408161PMID 15533996PMCID 2172491
• External record

  Open on Semantic Scholar

• Source metadata

  Semantic Scholar, PubMed

• No claims are published for this paper.

• No concepts are published for this paper.

• Target of rapamycin (TOR): an integrator of nutrient and growth factor signals and coordinator of cell growth and cell cycle progression

  2004cited by this paper
• The TSC1-2 tumor suppressor controls insulin–PI3K signaling via regulation of IRS proteins

  2004influential reference
• Nutrient-dependent and Insulin-stimulated Phosphorylation of Insulin Receptor Substrate-1 on Serine 302 Correlates with Increased Insulin Signaling*

  2004cited by this paper
• The translation factor eIF-4E promotes tumor formation and cooperates with c-Myc in lymphomagenesis

  2004cited by this paper
• The LKB1 tumor suppressor negatively regulates mTOR signaling.

  2004cited by this paper
• Modulation of human insulin receptor substrate-1 tyrosine phosphorylation by protein kinase Cdelta.

  2004cited by this paper
• Insulin Resistance Due to Phosphorylation of Insulin Receptor Substrate-1 at Serine 302*

  2004cited by this paper
• Absence of S6K1 protects against age- and diet-induced obesity while enhancing insulin sensitivity

  2004influential reference
• Survival signalling by Akt and eIF4E in oncogenesis and cancer therapy

  2004cited by this paper
• Inappropriate activation of the TSC/Rheb/mTOR/S6K cassette induces IRS1/2 depletion, insulin resistance, and cell survival deficiencies.

  2004influential reference
• eIF4E – from translation to transformation

  2004cited by this paper
• Mammalian target of rapamycin regulates IRS-1 serine 307 phosphorylation.

  2004cited by this paper
• Mutation in TSC2 and activation of mammalian target of rapamycin signalling pathway in renal angiomyolipoma.

  2003cited by this paper
• TSC2 mediates cellular energy response to control cell growth and survival.

  2003cited by this paper
• Loss of Tsc1 or Tsc2 induces vascular endothelial growth factor production through mammalian target of rapamycin.

  2003cited by this paper
• Rheb fills a GAP between TSC and TOR.

  2003cited by this paper
• Loss of Tsc1/Tsc2 activates mTOR and disrupts PI3K-Akt signaling through downregulation of PDGFR.

  2003influential reference
• Modulation of Insulin-stimulated Degradation of Human Insulin Receptor Substrate-1 by Serine 312 Phosphorylation*

  2003influential reference
• Tuberous Sclerosis: from Tubers to mTOR

  2003cited by this paper
• Tuberin Regulates p70 S6 Kinase Activation and Ribosomal Protein S6 Phosphorylation

  2002influential reference
• A central role for JNK in obesity and insulin resistance

  2002influential reference
• Tuberous sclerosis complex tumor suppressor–mediated S6 kinase inhibition by phosphatidylinositide-3-OH kinase is mTOR independent

  2002cited by this paper
• TSC2 is phosphorylated and inhibited by Akt and suppresses mTOR signalling

  2002cited by this paper
• Identification of the tuberous sclerosis complex-2 tumor suppressor gene product tuberin as a target of the phosphoinositide 3-kinase/akt pathway.

  2002cited by this paper
• A mouse model of TSC1 reveals sex-dependent lethality from liver hemangiomas, and up-regulation of p70S6 kinase activity in Tsc1 null cells.

  2002cited by this paper
• IRS proteins and the common path to diabetes.

  2002influential reference
• Tuberous sclerosis complex-1 and -2 gene products function together to inhibit mammalian target of rapamycin (mTOR)-mediated downstream signaling

  2002cited by this paper
• Akt regulates growth by directly phosphorylating Tsc2

  2002cited by this paper
• Activated mammalian target of rapamycin pathway in the pathogenesis of tuberous sclerosis complex renal tumors.

  2002cited by this paper
• Lethality of Drosophila lacking TSC tumor suppressor function rescued by reducing dS6K signaling.

  2002influential reference
• Tsc tumour suppressor proteins antagonize amino-acid–TOR signalling

  2002influential reference
• Mammalian Target of Rapamycin Pathway Regulates Insulin Signaling via Subcellular Redistribution of Insulin Receptor Substrate 1 and Integrates Nutritional Signals and Metabolic Signals of Insulin

  2001cited by this paper
• A phosphatidylinositol 3-kinase/Akt/mTOR pathway mediates and PTEN antagonizes tumor necrosis factor inhibition of insulin signaling through insulin receptor substrate-1

  2001influential reference
• Insulin signalling and the regulation of glucose and lipid metabolism

  2001cited by this paper
• Insulin/IGF-1 and TNF-alpha stimulate phosphorylation of IRS-1 at inhibitory Ser307 via distinct pathways.

  2001influential reference
• Amino acid and insulin signaling via the mTOR/p70 S6 kinase pathway. A negative feedback mechanism leading to insulin resistance in skeletal muscle cells.

  2001cited by this paper
• Enhanced sensitivity of PTEN-deficient tumors to inhibition of FRAP/mTOR

  2001influential reference
• A rapamycin-sensitive pathway down-regulates insulin signaling via phosphorylation and proteasomal degradation of insulin receptor substrate-1.

  2000cited by this paper
• The c-Jun NH2-terminal Kinase Promotes Insulin Resistance during Association with Insulin Receptor Substrate-1 and Phosphorylation of Ser307 *

  2000cited by this paper
• TOR, a central controller of cell growth.

  2000cited by this paper
• New insights into tumor suppression: PTEN suppresses tumor formation by restraining the phosphoinositide 3-kinase/AKT pathway.

  1999cited by this paper
• Modulation of Insulin Receptor Substrate-1 Tyrosine Phosphorylation by an Akt/Phosphatidylinositol 3-Kinase Pathway*

  1999influential reference
• Amino Acid Sufficiency and mTOR Regulate p70 S6 Kinase and eIF-4E BP1 through a Common Effector Mechanism*

  1998cited by this paper
• IRS-1-Mediated Inhibition of Insulin Receptor Tyrosine Kinase Activity in TNF-α- and Obesity-Induced Insulin Resistance

  1996cited by this paper
• Molecular basis for the substrate specificity of protein kinase B; comparison with MAPKAP kinase‐1 and p70 S6 kinase

  1996cited by this paper
• Wortmannin and LY294002 inhibit the insulin-induced down-regulation of IRS-1 in 3T3-L1 adipocytes.

  1995cited by this paper

• Effect of dietary patterns and nutritional supplementation in the management of endometriosis: a review

  2025cites this paper
• Muscle Cell Palmitate-Induced Insulin Resistance, JNK, IKK/NF-κB and STAT3 Activation are Attenuated by Carnosic and Rosmarinic Acid.

  2025cites this paper
• Polyethylene terephthalate microplastics promote pulmonary fibrosis via AKT1, PIK3CD, and PIM1: A network toxicology and multi-omics analysis.

  2025cites this paper
• Acyl-CoA binding protein (ACBP) in Siberian sturgeon (Acipenser baerii Brandt): Characterization, synthesis and orexigenic function.

  2025cites this paper
• AKT-mediated phosphorylation of TSC2 controls stimulus- and tissue-specific mTORC1 signaling and organ growth.

  2025cites this paper
• The impact of whey protein on plasma branched-chain amino acids and glycaemic control in humans. A narrative review.

  2025cites this paper
• Surveying the Therapeutic Potentials of Isoliquiritigenin (ISL): A Comprehensive Review

  2025cites this paper
• Phosphoproteomic analysis reveals the diversity of signaling behind ErbB‐inhibitor‐induced phenotypes

  2024cites this paper
• Tryptophan supplements in high-carbohydrate diets by improving insulin response and glucose transport through PI3K-AKT-GLUT2 pathways in blunt snout bream (Megalobrama amblycephala).

  2024cites this paper
• The rapid proximity labeling system PhastID identifies ATP6AP1 as an unconventional GEF for Rheb

  2024cites this paper
• Integrative modeling uncovers p21-driven drug resistance and prioritizes therapies for PIK3CA-mutant breast cancer

  2024cites this paper
• Poststroke hyperglycemia dysregulates cap-dependent translation in neural cells.

  2024cites this paper
• mTOR in the Development of Hypoxic Pulmonary Hypertension Associated with Cardiometabolic Risk Factors

  2024cites this paper
• mTORC1 restricts TFE3 activity by auto-regulating its presence on lysosomes.

  2024cites this paper
• Evaluation of the Combination of Metformin and Rapamycin in an MPP+-Treated SH-SY5Y Model of Parkinson's Disease

  2023cites this paper
• Time‐restricted eating for chronodisruption‐related chronic diseases

  2023cites this paper
• Targeted suppression of mTORC2 reduces seizures across models of epilepsy

  2023cites this paper
• Melatonin suppresses Akt/mTOR/S6K activity, induces cell apoptosis, and synergistically inhibits cell growth with sunitinib in renal carcinoma cells via reversing Warburg effect

  2023influential citation
• Intervertebral disc cell fate during aging and degeneration: apoptosis, senescence, and autophagy.

  2023cites this paper
• Health risks of neonicotinoids chronic exposure and its association with glucose metabolism: A case-control study in rural China.

  2023cites this paper
• Targeting mTOR to overcome resistance to hormone and CDK4/6 inhibitors in ER-positive breast cancer models

  2023cites this paper
• Muscle Cell Insulin Resistance Is Attenuated by Rosmarinic Acid: Elucidating the Mechanisms Involved

  2023cites this paper
• DEPTOR loss impairs brown adipocyte development in vitro but has limited impacts in mice

  2022cites this paper
• Expression Profiles of Exosomal MicroRNAs Derived from Cerebrospinal Fluid in Patients with Congenital Hydrocephalus Determined by MicroRNA Sequencing

  2022cites this paper
• Targeting mTOR Signaling in Type 2 Diabetes Mellitus and Diabetes Complications.

  2022cites this paper
• Physiological significance of bistable circuit design in metabolic homeostasis: role of integrated insulin-glucagon signalling network

  2022cites this paper
• Real-Time Analysis of AKT Signaling Activities at Single-Cell Resolution Using Cyclic Peptide-Based Probes.

  2022cites this paper
• Isoliquiritigenin alleviates diabetic symptoms via activating AMPK and inhibiting mTORC1 signaling in diet-induced diabetic mice.

  2022cites this paper
• Recent advances and limitations of mTOR inhibitors in the treatment of cancer

  2022cites this paper
• The Effect of Ryegrass Silage Feeding on Equine Fecal Microbiota and Blood Metabolite Profile

  2021cites this paper
• Expanding TOR Complex 2 Signaling: Emerging Regulators and New Connections

  2021cites this paper
• Aging and Protein Kinases.

  2021cites this paper
• Dietary berberine can ameliorate glucose metabolism disorder of Megalobrama amblycephala exposed to a high-carbohydrate diet

  2021cites this paper
• Convergent and Divergent Mechanisms of Epileptogenesis in mTORopathies

  2021influential citation
• Age-related expression of prominent regulatory elements in mouse brain: catastrophic decline of FOXO3a

  2021cites this paper
• Rosemary Extract Activates AMPK, Inhibits mTOR and Attenuates the High Glucose and High Insulin-Induced Muscle Cell Insulin Resistance.

  2021cites this paper
• The role of mTOR in age-related diseases

  2021cites this paper
• Time-restricted feeding regulates molecular mechanisms with involvement of circadian rhythm to prevent metabolic diseases.

  2021cites this paper
• AMPK

  2020cites this paper
• From causes of aging to death from COVID-19

  2020cites this paper
• The Role of Pi, Glutamine and the Essential Amino Acids in Modulating the Metabolism in Diabetes and Cancer

  2020cites this paper
• Granulocyte-colony stimulating factor gene therapy as a novel therapeutics for stroke in a mouse model

  2020cites this paper
• β1 integrin, ILK and mTOR regulate collagen synthesis in mechanically loaded tendon cells

  2020cites this paper
• Pharmacoproteomics reveals the mechanism of Chinese dragon's blood in regulating the RSK/TSC2/mTOR/ribosome pathway in alleviation of DSS-induced acute ulcerative colitis.

  2020cites this paper
• Investigation of the effects of rapamycin on the mTOR pathway and apoptosis in metastatic and non-metastatic human breast cancer cell lines.

  2020cites this paper
• Evaluation of an aldo-keto reductase gene signature with prognostic significance in colon cancer via activation of epithelial to mesenchymal transition and the p70S6K pathway.

  2020cites this paper
• AMPK: Central Regulator of Glucose and Lipid Metabolism and Target of Type 2 Diabetes Therapeutics

  2020cites this paper
• Autophagy and mTOR signaling during intervertebral disc aging and degeneration

  2020cites this paper
• The Circadian Protein Period2 Suppresses mTORC1 Activity via Recruiting Tsc1 to mTORC1 Complex.

  2019cites this paper
• Effects of Docosahexaenoic Acid-Rich Microalgae Supplementation on Metabolic and Inflammatory Parameters in Horses With Equine Metabolic Syndrome.

  2019cites this paper
• Minimal effects of spargel (PGC-1) overexpression in a Drosophila mitochondrial disease model

  2019cites this paper
• The Pathophysiology of Obesity and Obesity-Related Disease

  2019cites this paper
• Rapamycin for longevity: opinion article

  2019cites this paper
• Fasting and rapamycin: diabetes versus benevolent glucose intolerance

  2019cites this paper
• Phosphoethanolamine Accumulation Protects Cancer Cells under Glutamine Starvation through Downregulation of PCYT2.

  2019cites this paper
• The pancreatic β-cell zinc response to chronic stimulation and extracellular zinc depletion

  2019cites this paper
• Sirolimus and mTOR Inhibitors: A Review of Side Effects and Specific Management in Solid Organ Transplantation

  2019cites this paper
• VicTORia: a randomised phase II study to compare vinorelbine in combination with the mTOR inhibitor everolimus versus vinorelbine monotherapy for second-line chemotherapy in advanced HER2-negative breast cancer

  2019cites this paper
• Circulating microRNAs in human obesity: a systematic review

  2019cites this paper
• Combining PI3K/Akt/mTOR Inhibition With Chemotherapy

  2019cites this paper
• The subunit assembly state of the Mediator complex is nutrient-regulated and is dysregulated in a genetic model of insulin resistance and obesity

  2019cites this paper
• Role of the mTOR signalling pathway in salivary gland development

  2019cites this paper
• Brain insulin resistance and altered brain glucose are related to memory impairments in schizophrenia.

  2019cites this paper
• Inhibition of Growth of TSC2-Null Cells by a PI3K/mTOR Inhibitor but Not by a Selective MNK1/2 Inhibitor

  2019cites this paper
• FoxO transcription factors in cancer metabolism.

  2018cites this paper
• Interactions between dietary carbohydrate and metformin: Implications on energy sensing, insulin signaling pathway, glycolipid metabolism and glucose tolerance in blunt snout bream Megalobrama amblycephala

  2018cites this paper
• Combination of melatonin and rapamycin for head and neck cancer therapy: Suppression of AKT/mTOR pathway activation, and activation of mitophagy and apoptosis via mitochondrial function regulation

  2018cites this paper
• Dynamic modelling of the mTOR signalling network reveals complex emergent behaviours conferred by DEPTOR

  2018cites this paper
• Intracellular lipid metabolism impairs &bgr; cell compensation during diet-induced obesity

  2018cites this paper
• Intestinal epithelial cell-specific Raptor is essential for high fat diet-induced weight gain in mice.

  2018cites this paper
• Multifaceted Nucleolin Protein and Its Molecular Partners in Oncogenesis.

  2018cites this paper
• ER Stress Activates the TOR Pathway through Atf6

  2018cites this paper
• Attenuation of Free Fatty Acid-Induced Muscle Insulin Resistance by Rosemary Extract

  2018influential citation
• Tuberous sclerosis complex is required for tumor maintenance in MYC‐driven Burkitt's lymphoma

  2018influential citation
• Emerging role of branched chain amino acids in metabolic disorders: A mechanistic review

  2018cites this paper
• Functional significance of co-occurring mutations in PIK3CA and MAP3K1 in breast cancer

  2018cites this paper
• Oxidative and nitrosative stress in myeloproliferative neoplasms: the impact on the AKT / mTOR signaling pathway.

  2018cites this paper
• Drosophila melanogaster as a Model for Diabetes Type 2 Progression

  2018cites this paper
• The structure of mTOR complexes at a glance

  2018cites this paper
• Mammalian Targets of Rapamycin Inhibitors: Temsirolimus and Everolimus

  2017cites this paper
• Functional Maturation of Engineered Myocardium for Studies of Development and Regeneration

  2017cites this paper
• AKT/PKB Signaling: Navigating the Network.

  2017cites this paper
• mTORC2 Regulates Amino Acid Metabolism in Cancer by Phosphorylation of the Cystine-Glutamate Antiporter xCT.

  2017cites this paper
• Ablation of PI3K blocks BCR-ABL leukemogenesis in mice, and a dual PI3K/mTOR inhibitor prevents expansion of human BCR-ABL+ leukemia cells.

  2017cites this paper
• Diurnal regulation of RNA polymerase III transcription is under the control of both the feeding–fasting response and the circadian clock

  2017cites this paper
• mTOR Inhibition Subdues Milk Disorder Caused by Maternal VLDLR Loss.

  2017cites this paper
• Amino Acid Sensing via General Control Nonderepressible-2 Kinase and Immunological Programming

  2017cites this paper
• Inhibition of p70S6K does not mimic the enhancement of Akt phosphorylation by rapamycin

  2017cites this paper
• Metabolic Regulation of T Cell Immunity.

  2017cites this paper
• Adipose tissue inflammation in insulin resistance: review of mechanisms mediating anti-inflammatory effects of omega-3 polyunsaturated fatty acids

  2017cites this paper
• Modified lingguizhugan decoction incorporated with dietary restriction and exercise ameliorates hyperglycemia, hyperlipidemia and hypertension in a rat model of the metabolic syndrome

  2017cites this paper
• Influences of manganese on pubertal development.

  2017cites this paper
• Cancer and mTOR Inhibitors in Transplant Recipients.

  2017cites this paper
• MicroRNA-99a inhibits insulin-induced proliferation, migration, dedifferentiation, and rapamycin resistance of vascular smooth muscle cells by inhibiting insulin-like growth factor-1 receptor and mammalian target of rapamycin.

  2017cites this paper
• Regulation of Ras signaling and function by plasma membrane microdomains.

  2017cites this paper
• Mangiferin protects mitochondrial function by preserving mitochondrial hexokinase-II in vessel endothelial cells.

  2017cites this paper
• Fetal Requirements and Placental Transfer of Nitrogenous Compounds

  2017cites this paper
• Interleukin-6-dependent growth in a newly established plasmablastic lymphoma cell line and its therapeutic targets

  2017cites this paper
• Current Status of mTOR Inhibitors as Novel Therapeutic Agents

  2017cites this paper
• Maximising the potential of AKT inhibitors as anti‐cancer treatments

  2017cites this paper