Interaction of FoxO1 and TSC2 Induces Insulin Resistance through Activation of the Mammalian Target of Rapamycin/p70 S6K Pathway

University of Tsukuba, Tsukuba, Ibaraki, Japan
Journal of Biological Chemistry (Impact Factor: 4.57). 01/2007; 281(52):40242-51. DOI: 10.1074/jbc.M608116200
Source: PubMed


Both TSC2 (tuberin) and forkhead transcription factor FoxO1 are phosphorylated and inhibited by Akt and play important roles in insulin signaling. However, little is known about the relationship between TSC2 and FoxO1. Here we identified TSC2 as a FoxO1-binding protein by using a yeast two-hybrid screening with a murine islet cDNA library. Among FoxOs, only FoxO1 can be associated with TSC2. The physical association between the C terminus of TSC2 (amino acids 1280-1499) and FoxO1 degrades the TSC1-TSC2 complex and inhibits GTPase-activating protein activity of TSC2 toward Rheb. Overexpression of wild type FoxO1 enhances p70 S6K phosphorylation, whereas overexpression of TSC2 can reverse these effects. Knockdown of endogenous FOXO1 in human vascular endothelial cells decreased phosphorylation of p70 S6K. Prolonged overexpression of wild type FoxO1 enhanced phosphorylation of serine 307 of IRS1 and decreased phosphorylation of Akt and FoxO1 itself even in the presence of serum. These data suggest a novel mechanism by which FoxO1 regulates the insulin signaling pathway through negative regulation of TSC2 function.

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    • "Furthermore, Akt-phosphorylated cytoplasmic FoxO1 binds to TSC2 and thereby dissociates the TSC1/TSC2 complex, which activates mTORC1 113. Thus, activated Akt inhibits FoxO1, FoxO3 and FoxO4 through direct phosphorylation and indirectly activates mTORC1, which in turn increases protein and lipid synthesis and induces insulin resistance 113. "
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    ABSTRACT: Acne in adolescents of developed countries is an epidemic skin disease and has currently been linked to the Western diet (WD). It is the intention of this viewpoint to discuss the possible impact of WD-mediated nutrient signalling in the pathogenesis of acne. High glycaemic load and dairy protein consumption both increase insulin/insulin-like growth factor-1 (IGF-1) signalling (IIS) that is superimposed on elevated IGF-1 signalling of puberty. The cell's nutritional status is primarily sensed by the forkhead box transcription factor O1 (FoxO1) and the serine/threonine kinase mammalian target of rapamycin complex 1 (mTORC1). Increased IIS extrudes FoxO1 into the cytoplasm, whereas nuclear FoxO1 suppresses hepatic IGF-1 synthesis and thus impairs somatic growth. FoxO1 attenuates androgen signalling, interacts with regulatory proteins important for sebaceous lipogenesis, regulates the activity of innate and adaptive immunity, antagonizes oxidative stress and most importantly functions as a rheostat of mTORC1, the master regulator of cell growth, proliferation and metabolic homoeostasis. Thus, FoxO1 links nutrient availability to mTORC1-driven processes: increased protein and lipid synthesis, cell proliferation, cell differentiation including hyperproliferation of acroinfundibular keratinocytes, sebaceous gland hyperplasia, increased sebaceous lipogenesis, insulin resistance and increased body mass index. Enhanced androgen, TNF-α and IGF-1 signalling due to genetic polymorphisms promoting the risk of acne all converge in mTORC1 activation, which is further enhanced by nutrient signalling of WD. Deeper insights into the molecular interplay of FoxO1/mTORC1-mediated nutrient signalling are thus of critical importance to understand the impact of WD on the promotion of epidemic acne and more serious mTORC1-driven diseases of civilization.
    Experimental Dermatology 05/2013; 22(5):311-5. DOI:10.1111/exd.12142 · 3.76 Impact Factor
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    • "Hyperactivation of the mTOR-mediated pathway(s) has been observed in insulin desensitizing events and insulin resistant animal models [26-31]. This can be prevented or reversed by rapamycin [30,31]. "
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    ABSTRACT: AMP-activated protein kinase (AMPK) is a fuel-sensing enzyme that is activated when cells experience energy deficiency and conversely suppressed in surfeit of energy supply. AMPK activation improves insulin sensitivity via multiple mechanisms, among which AMPK suppresses mTOR/S6K-mediated negative feedback regulation of insulin signaling. In the present study we further investigated the mechanism of AMPK-regulated insulin signaling. Our results showed that 5-aminoimidazole-4-carboxamide-1 ribonucleoside (AICAR) greatly enhanced the ability of insulin to stimulate the insulin receptor substrate-1 (IRS1)-associated PI3K activity in differentiated 3T3-F442a adipocytes, leading to increased Akt phosphorylation at S473, whereas insulin-stimulated activation of mTOR was diminished. In 3T3-F442a preadipocytes, these effects were attenuated by expression of a dominant negative mutant of AMPK alpha1 subunit. The enhancing effect of ACIAR on Akt phosphorylation was also observed when the cells were treated with EGF, suggesting that it is regulated at a step beyond IR/IRS1. Indeed, when the cells were chronically treated with AICAR in the absence of insulin, Akt phosphorylation was progressively increased. This event was associated with an increase in levels of phosphatidylinositol -3,4,5-trisphosphate (PIP3) and blocked by Wortmannin. We then expressed the dominant negative mutant of PTEN (C124S) and found that the inhibition of endogenous PTEN per se did not affect phosphorylation of Akt at basal levels or upon treatment with AICAR or insulin. Thus, this result suggests that AMPK activation of Akt is not mediated by regulating phosphatase and tensin homologue (PTEN). Our present study demonstrates that AMPK exerts dual effects on the PI3K pathway, stimulating PI3K/Akt and inhibiting mTOR/S6K.
    Journal of Molecular Signaling 02/2010; 5(1):1. DOI:10.1186/1750-2187-5-1
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    • "Erk Serine/threonine kinase Raf-MEK1/2-Erk1/2 signaling (regulation of cell growth and differentiation) Not determined co-IP 293 [46] ERM Cytoskeletal anchor protein Regulation of cell–cell adhesion Hamartin aa 881–1084 Y2H, slot blot and blotoverly assay, co-IP, co-localization HUVEC [79] FIP200 Kinase binding protein Inhibition of FAK kinase (regulation of cell size, cell cycle progression, cell migration) Hamartin aa 403–787 Y2H, GST affinity precipitation, co-IP MEF, 293T [17] FoxO1 Transcription factor Cell signaling (regulation of cell cycle, cell survival, glucose and lipid metabolism) Tuberin aa 1280–1499 Y2H, co-IP co-localization Adipocytes, HEK293, hepatocytes [60] "
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    ABSTRACT: Mutations in the tumor suppressor genes TSC1 and TSC2, encoding hamartin and tuberin, respectively, cause the tumor syndrome tuberous sclerosis with similar phenotypes. Until now, over 50 proteins have been demonstrated to interact with hamartin and/or tuberin. Besides tuberin, the proteins DOCK7, ezrin/radixin/moesin, FIP200, IKKbeta, Melted, Merlin, NADE(p75NTR), NF-L, Plk1 and TBC7 have been found to interact with hamartin. Whereas Plk1 and TBC7 have been demonstrated not to bind to tuberin, for all the other hamartin-interacting proteins the question, whether they can also bind to tuberin, has not been studied. Tuberin interacts with 14-3-3 beta,epsilon,gamma,eta,sigma,tau,zeta, Akt, AMPK, CaM, CRB3/PATJ, cyclin A, cyclins D1, D2, D3, Dsh, ERalpha, Erk, FoxO1, HERC1, HPV16 E6, HSCP-70, HSP70-1, MK2, NEK1, p27KIP1, Pam, PC1, PP2Ac, Rabaptin-5, Rheb, RxRalpha/VDR and SMAD2/3. 14-3-3 beta,epsilon,gamma,eta,sigma,tau,zeta, Akt, Dsh, FoxO1, HERC1, p27KIP1 and PP2Ac are known not to bind to hamartin. For the other tuberin-interacting proteins this question remains elusive. The proteins axin, Cdk1, cyclin B1, GADD34, GSK3, mTOR and RSK1 have been found to co-immunoprecipitate with both, hamartin and tuberin. The kinases Cdk1 and IKKbeta phosphorylate hamartin, Erk, Akt, MK2, AMPK and RSK1 phosphorylate tuberin, and GSK3 phosphorylates both, hamartin and tuberin. This detailed summary of protein interactions allows new insights into their relevance for the wide variety of different functions of hamartin and tuberin.
    Mutation Research/Fundamental and Molecular Mechanisms of Mutagenesis 03/2008; 658(3):234-46. DOI:10.1016/j.mrrev.2008.01.001 · 3.68 Impact Factor
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