mTOR Complex 2 Regulates Proper Turnover of Insulin Receptor Substrate-1 via the Ubiquitin Ligase Subunit Fbw8

Kim, Sung Jin; DeStefano, Michael A.; Oh, Won Zin; Wu, Chang-Chih; Vega-Cotto, Nicole M.; Finlan, Monica; Liu, Dou; Su, Bing; Jacinto, Estela

doi:10.1016/j.molcel.2012.09.029

Cited by 96 publications

(103 citation statements)

References 46 publications

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“…Recently, it was reported that mTORC2 could trigger IRS1 degradation via Fbw8 stablization [24]. However, the same study also reported that depletion of SIN1 led to insufficient activation of InsR and reduced PIP3 production [24]. Our current finding highlights the first important interaction between mTORC2 and IGF-IR/InsR, and identifies IRS1/2 as important mediators of this interaction.…”

Section: Discussionsupporting

confidence: 58%

“…Phosphorylation of IRS1/2 by mTOR and S6K1 then leads to their proteasomal degradation [38][39][40]. Recently, it was reported that mTORC2 could trigger IRS1 degradation via Fbw8 stablization [24]. However, the same study also reported that depletion of SIN1 led to insufficient activation of InsR and reduced PIP3 production [24].…”

Section: Discussionmentioning

confidence: 99%

“…In addition, mTORC2 disruption in mice leads to insulin resistance [22,23]. mTORC2 also negatively feeds back to IRS1 via Fbw8-mediated degradation [24]. Despite a handful of reports that provide support for the involvement of mTOR in IGF/insulin signaling, IGF-IR and InsR have not been considered as membrane receptors that are directly regulated by mTOR.…”

Section: Introductionmentioning

confidence: 99%

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mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR

et al. 2015

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Section: Discussionsupporting

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR

et al. 2015

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“…Previous studies already linked the proteasome-mediated degradation of IRS1 to the inhibition of insulin action in response to hyperinsulinaemia [35,36] and inflammation [37]. In this context, multiple E3-ligases, including F-box only protein 40, CBLB, and F-box/WD repeat-containing protein 8, have been linked to IRS1 degradation in response to hyperinsulinaemia, inflammation and chronic exposure to insulin-like growth factor 1 [37][38][39][40][41]. Furthermore, increased expression of Fbxo32 and Murf1 associated with reduced activation of the PI3K/Akt pathway by insulin was described in skeletal muscle of db/db mice [42].…”

Section: Discussionmentioning

confidence: 99%

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Wiza

Nascimento

et al. 2013

Diabetologia

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Aims/hypothesis The proline-rich Akt substrate of 40 kDa (PRAS40) is a component of the mammalian target of rapamycin complex 1 (mTORC1) and among the most prominent Akt substrates in skeletal muscle. Yet the cellular functions of PRAS40 are incompletely defined. This study assessed the function of PRAS40 in insulin action in primary human skeletal muscle cells (hSkMC). Methods Insulin action was examined in hSkMC following small interfering RNA-mediated silencing of PRAS40 (also known as AKT1S1) under normal conditions and following chemokine-induced insulin resistance. Results PRAS40 knockdown (PRAS40-KD) in hSkMC decreased insulin-mediated phosphorylation of Akt by 50% (p<0.05) as well as of the Akt substrates glycogen synthase kinase 3 (40%) and tuberous sclerosis complex 2 (32%) (both p<0.05). Furthermore, insulin-stimulated glucose uptake was reduced by 20% in PRAS40-KD myotubes (p<0.05). Exposing PRAS40-KD myotubes to chemokines caused no additional deterioration of insulin action. PRAS40-KD further reduced insulin-mediated phosphorylation of the mTORC1-regulated proteins p70S6 kinase (p70S6K) (47%), S6 (43%), and eukaryotic elongation 4E-binding protein 1 (100%), as well as protein levels of growth factor receptor bound protein 10 (35%) (all p<0.05). The inhibition of insulin action in PRAS40-KD myotubes was associated with a reduction in IRS1 protein levels (60%) (p<0.05), and was reversed by pharmacological proteasome inhibition. Accordingly, expression of the genes encoding E3-ligases Fbox protein 32 (also known as atrogin-1) and muscle RINGfinger protein-1 and activity of the proteasome was elevated in PRAS40-KD myotubes. Conclusions/interpretation Inhibition of insulin action in PRAS40-KD myotubes was found to associate with IRS1 degradation promoted by increased proteasome activity rather than hyperactivation of the p70S6K-negative-feedback loop. These findings identify PRAS40 as a modulator of insulin action.

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“…It was shown that CRL7-induced degradation of IRS1 is part of a negative feedback loop via mechanistic target of rapamycin complex 1 (mTORC1) to restrain IRS1 downstream signaling (17,19). A more recent study suggested an mTORC2-dependent feedback inhibition of IRS1 by direct phosphorylation of Fbw8, resulting in enhanced stability of this F-box protein that promotes IRS1 degradation (20). Collectively, these studies have implicated roles for CRL7 in regulating both mTORC1 and mTORC2 signaling.…”

mentioning

confidence: 99%

Inhibition of Cullin-RING E3 ubiquitin ligase 7 by simian virus 40 large T antigen

Hartmann

Kronast

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Simian virus 40 (SV40) large tumor antigen (LT) triggers oncogenic transformation by inhibition of key tumor suppressor proteins, including p53 and members of the retinoblastoma family. In addition, SV40 transformation requires binding of LT to Cullin 7 (CUL7), a core component of Cullin-RING E3 ubiquitin ligase 7 (CRL7). However, the pathomechanistic effects of LT-CUL7 interaction are mostly unknown. Here we report both in vitro and in vivo experimental evidence that SV40 LT suppresses the ubiquitin ligase function of CRL7. We show that SV40 LT, but not a CUL7 binding-deficient mutant (LT Δ69-83 ), impaired 26S proteasomedependent proteolysis of the CRL7 target protein insulin receptor substrate 1 (IRS1), a component of the insulin and insulin-like growth factor 1 signaling pathway. SV40 LT expression resulted in the accumulation and prolonged half-life of IRS1. In vitro, purified SV40 LT reduced CRL7-dependent IRS1 ubiquitination in a concentration-dependent manner. Expression of SV40 LT, or depletion of CUL7 by RNA interference, resulted in the enhanced activation of IRS1 downstream signaling pathways phosphatidylinositol-3-kinase/AKT and Erk mitogen-activated pathway kinase, as well as up-regulation of the downstream target gene c-fos. Finally, SV40 LT-positive carcinoma of carcinoembryonic antigen 424/SV40 LT transgenic mice displayed elevated IRS1 protein levels and activation of downstream signaling. Taken together, these data suggest that SV40 LT protects IRS1 from CRL7-mediated degradation, thereby sustaining high levels of promitogenic IRS1 downstream signaling pathways. S tudies with simian virus 40 (SV40), a member of the Polyomaviridae family of tumor viruses, have led to fundamental insights into molecular processes of cell transformation and oncogenesis (1, 2). SV40 encodes the large tumor antigen (LT) with the potential to transform cells in culture and induce tumors in rodents. The tumorigenic features of SV40 have been attributed to binding and deactivation of key tumor suppressor proteins of the host cell including p53 and members of the retinoblastoma (pRB) family (1-3). In addition, SV40 LT was shown to be physically associated with Cullin 7 (CUL7; also named p185 or p193) (4, 5) as well as insulin receptor substrate 1 (IRS1) (6). It has been proposed that the association of SV40 LT with either CUL7 or IRS1 is critical to SV40 oncogenic transformation (7-9). However, the functional effect of LT interaction with CUL7/IRS1 and their pathophysiological interrelation remains mostly unknown.CUL7 is a scaffold protein responsible for assembling the multisubunit Cullin-RING E3 ubiquitin ligase 7 (CRL7) that consists of the RING-finger protein ROC1 and the Skp1-Fbw8 substrate-targeting subunit (10, 11). Genetic studies documented a pivotal growth-regulatory role of CRL7. Both cul7 (12) and fbw8 (13) null mice exhibit intrauterine growth retardation. In addition, CUL7 germ-line mutations were linked to 3-M syndrome, a hereditary disorder characterized by pre-and postnatal growth retardation in hum...

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mTOR Complex 2 Regulates Proper Turnover of Insulin Receptor Substrate-1 via the Ubiquitin Ligase Subunit Fbw8

Cited by 96 publications

References 46 publications

mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR

mTORC2 promotes type I insulin-like growth factor receptor and insulin receptor activation through the tyrosine kinase activity of mTOR

Knockdown of PRAS40 inhibits insulin action via proteasome-mediated degradation of IRS1 in primary human skeletal muscle cells

Inhibition of Cullin-RING E3 ubiquitin ligase 7 by simian virus 40 large T antigen

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