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Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis.

Manning BD - J. Cell Biol. (2004)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA. bmanning@hsph.harvard.edu

ABSTRACT
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.

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Model of the PI3K–Akt–TSC–TOR pathway and feedback regulation of insulin/IGF-I signaling. (A) Under normal conditions, insulin/IGF-I engagement of the insulin or IGF-I receptor (IR) leads to Tyr phosphorylation of IRS proteins and subsequent recruitment and activation of PI3K. PI3K activity leads to activation of Akt, which phosphorylates and inhibits many downstream substrates, including BAD, FOXO transcription factors, GSK3, and tuberin (TSC2). Through these and other targets, Akt activity stimulates glucose uptake and cell growth and proliferation, and inhibits apoptosis. Akt-directed phosphorylation of tuberin relieves its inhibition of TOR, via activation of the small G protein Rheb (not depicted). TOR activation by this pathway requires the presence of nutrients and results in activation of S6K and inhibition of 4E-BP1. S6K phosphorylates the ribosomal S6 protein (not depicted) and can feedback and inhibit IRS proteins (see S6K1: closing the loop section for details). Inhibition of 4E-BP1 relieves its inhibition of the translation initiation factor eIF4E. (B) Under atypical conditions of constitutive TOR activation, arising from chronic insulin/IGF-I exposure, excess nutrients (e.g., amino acids [AAs] and free fatty acids [FFAs]), inflammatory cytokines, or genetic loss of specific tumor suppressor genes, such as TSC2 (encoding tuberin), aberrantly high S6K activity shuts down insulin/IGF-I signaling. Therefore, although this unregulated TOR activity leads to constitutive eIF4E activation, it leads to insulin/IGF-I resistance through down-regulation of IRS protein function. This feedback inhibition prevents Akt-mediated glucose uptake and regulation of its downstream substrates. Dashed versus solid lines represent hypothetical signal strength.
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fig1: Model of the PI3K–Akt–TSC–TOR pathway and feedback regulation of insulin/IGF-I signaling. (A) Under normal conditions, insulin/IGF-I engagement of the insulin or IGF-I receptor (IR) leads to Tyr phosphorylation of IRS proteins and subsequent recruitment and activation of PI3K. PI3K activity leads to activation of Akt, which phosphorylates and inhibits many downstream substrates, including BAD, FOXO transcription factors, GSK3, and tuberin (TSC2). Through these and other targets, Akt activity stimulates glucose uptake and cell growth and proliferation, and inhibits apoptosis. Akt-directed phosphorylation of tuberin relieves its inhibition of TOR, via activation of the small G protein Rheb (not depicted). TOR activation by this pathway requires the presence of nutrients and results in activation of S6K and inhibition of 4E-BP1. S6K phosphorylates the ribosomal S6 protein (not depicted) and can feedback and inhibit IRS proteins (see S6K1: closing the loop section for details). Inhibition of 4E-BP1 relieves its inhibition of the translation initiation factor eIF4E. (B) Under atypical conditions of constitutive TOR activation, arising from chronic insulin/IGF-I exposure, excess nutrients (e.g., amino acids [AAs] and free fatty acids [FFAs]), inflammatory cytokines, or genetic loss of specific tumor suppressor genes, such as TSC2 (encoding tuberin), aberrantly high S6K activity shuts down insulin/IGF-I signaling. Therefore, although this unregulated TOR activity leads to constitutive eIF4E activation, it leads to insulin/IGF-I resistance through down-regulation of IRS protein function. This feedback inhibition prevents Akt-mediated glucose uptake and regulation of its downstream substrates. Dashed versus solid lines represent hypothetical signal strength.

Mentions: The hamartin and tuberin proteins form a complex that has recently been found to act within the pathway leading from PI3K–Akt activation to mTOR signaling (for review see Manning and Cantley, 2003). The tuberin–hamartin complex potently inhibits TOR-dependent signaling in both flies and mammals (Gao et al., 2002; Goncharova et al., 2002; Kwiatkowski et al., 2002; Tee et al., 2002), and this inhibition is relieved by Akt-directed phosphorylation of tuberin (Inoki et al., 2002; Manning et al., 2002; Potter et al., 2002). Therefore, in response to growth factors such as insulin, the PI3K–Akt pathway activates mTOR signaling through phosphorylation and inhibition of tuberin (Fig. 1 A). Interestingly, the responsiveness of TOR proteins to other signals, such as nutrient and energy availability, also appears to be dependent on the TSC genes (Gao et al., 2002; Inoki et al., 2003, Shaw et al., 2004). Therefore, homozygous loss of TSC1 or TSC2 leads to high constitutive activation of mTOR signaling, as detected in mouse embryonic fibroblasts (MEFs; Jaeschke et al., 2002; Kwiatkowski et al., 2002; Zhang et al., 2003), in the tumors of rodent models of TSC (Kenerson et al., 2002; El-Hashemite et al., 2003a), and in human TSC cells and tumors (Goncharova et al., 2002; El-Hashemite et al., 2003b).


Balancing Akt with S6K: implications for both metabolic diseases and tumorigenesis.

Manning BD - J. Cell Biol. (2004)

Model of the PI3K–Akt–TSC–TOR pathway and feedback regulation of insulin/IGF-I signaling. (A) Under normal conditions, insulin/IGF-I engagement of the insulin or IGF-I receptor (IR) leads to Tyr phosphorylation of IRS proteins and subsequent recruitment and activation of PI3K. PI3K activity leads to activation of Akt, which phosphorylates and inhibits many downstream substrates, including BAD, FOXO transcription factors, GSK3, and tuberin (TSC2). Through these and other targets, Akt activity stimulates glucose uptake and cell growth and proliferation, and inhibits apoptosis. Akt-directed phosphorylation of tuberin relieves its inhibition of TOR, via activation of the small G protein Rheb (not depicted). TOR activation by this pathway requires the presence of nutrients and results in activation of S6K and inhibition of 4E-BP1. S6K phosphorylates the ribosomal S6 protein (not depicted) and can feedback and inhibit IRS proteins (see S6K1: closing the loop section for details). Inhibition of 4E-BP1 relieves its inhibition of the translation initiation factor eIF4E. (B) Under atypical conditions of constitutive TOR activation, arising from chronic insulin/IGF-I exposure, excess nutrients (e.g., amino acids [AAs] and free fatty acids [FFAs]), inflammatory cytokines, or genetic loss of specific tumor suppressor genes, such as TSC2 (encoding tuberin), aberrantly high S6K activity shuts down insulin/IGF-I signaling. Therefore, although this unregulated TOR activity leads to constitutive eIF4E activation, it leads to insulin/IGF-I resistance through down-regulation of IRS protein function. This feedback inhibition prevents Akt-mediated glucose uptake and regulation of its downstream substrates. Dashed versus solid lines represent hypothetical signal strength.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2172491&req=5

fig1: Model of the PI3K–Akt–TSC–TOR pathway and feedback regulation of insulin/IGF-I signaling. (A) Under normal conditions, insulin/IGF-I engagement of the insulin or IGF-I receptor (IR) leads to Tyr phosphorylation of IRS proteins and subsequent recruitment and activation of PI3K. PI3K activity leads to activation of Akt, which phosphorylates and inhibits many downstream substrates, including BAD, FOXO transcription factors, GSK3, and tuberin (TSC2). Through these and other targets, Akt activity stimulates glucose uptake and cell growth and proliferation, and inhibits apoptosis. Akt-directed phosphorylation of tuberin relieves its inhibition of TOR, via activation of the small G protein Rheb (not depicted). TOR activation by this pathway requires the presence of nutrients and results in activation of S6K and inhibition of 4E-BP1. S6K phosphorylates the ribosomal S6 protein (not depicted) and can feedback and inhibit IRS proteins (see S6K1: closing the loop section for details). Inhibition of 4E-BP1 relieves its inhibition of the translation initiation factor eIF4E. (B) Under atypical conditions of constitutive TOR activation, arising from chronic insulin/IGF-I exposure, excess nutrients (e.g., amino acids [AAs] and free fatty acids [FFAs]), inflammatory cytokines, or genetic loss of specific tumor suppressor genes, such as TSC2 (encoding tuberin), aberrantly high S6K activity shuts down insulin/IGF-I signaling. Therefore, although this unregulated TOR activity leads to constitutive eIF4E activation, it leads to insulin/IGF-I resistance through down-regulation of IRS protein function. This feedback inhibition prevents Akt-mediated glucose uptake and regulation of its downstream substrates. Dashed versus solid lines represent hypothetical signal strength.
Mentions: The hamartin and tuberin proteins form a complex that has recently been found to act within the pathway leading from PI3K–Akt activation to mTOR signaling (for review see Manning and Cantley, 2003). The tuberin–hamartin complex potently inhibits TOR-dependent signaling in both flies and mammals (Gao et al., 2002; Goncharova et al., 2002; Kwiatkowski et al., 2002; Tee et al., 2002), and this inhibition is relieved by Akt-directed phosphorylation of tuberin (Inoki et al., 2002; Manning et al., 2002; Potter et al., 2002). Therefore, in response to growth factors such as insulin, the PI3K–Akt pathway activates mTOR signaling through phosphorylation and inhibition of tuberin (Fig. 1 A). Interestingly, the responsiveness of TOR proteins to other signals, such as nutrient and energy availability, also appears to be dependent on the TSC genes (Gao et al., 2002; Inoki et al., 2003, Shaw et al., 2004). Therefore, homozygous loss of TSC1 or TSC2 leads to high constitutive activation of mTOR signaling, as detected in mouse embryonic fibroblasts (MEFs; Jaeschke et al., 2002; Kwiatkowski et al., 2002; Zhang et al., 2003), in the tumors of rodent models of TSC (Kenerson et al., 2002; El-Hashemite et al., 2003a), and in human TSC cells and tumors (Goncharova et al., 2002; El-Hashemite et al., 2003b).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Genetics and Complex Diseases, Harvard School of Public Health, Boston, MA 02115, USA. bmanning@hsph.harvard.edu

ABSTRACT
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.

Show MeSH
Related in: MedlinePlus