SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity

Jacinto, Estela; Facchinetti, Valeria; Liu, Dou; Soto, Nelyn; Wei, Shiniu; Jung, Sung Yun; Huang, Qiuyuan; Qin, Jun; Su, Bing

doi:10.1016/j.cell.2006.08.033

Cited by 1,234 publications

(1,194 citation statements)

References 69 publications

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“…16,19,35 Little is known, however, about the physiological stimuli that regulate fission yeast TORC2, whereas insulin and growth factors activate mammalian TORC2 (mTORC2) in a PI3K-dependent manner. 7,8,[36][37][38] In this report, we show that TORC2 in fission yeast is responsive to glucose and that the functional TORC2-Gad8 pathway is essential for cell proliferation in glucose-limited environment. Our mutational analysis indicated that the glucose regulation of fission yeast TORC2 is not dependent on the cAMP pathway, a signaling mechanism known to be responsive to extracellular glucose.…”

Section: Introductionmentioning

confidence: 95%

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

et al. 2015

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The Target Of Rapamycin (TOR) is an evolutionarily conserved protein kinase that forms 2 distinct protein complexes referred to as TOR complex 1 (TORC1) and 2 (TORC2). Recent extensive studies have demonstrated that TORC1 is under the control of the small GTPases Rheb and Rag that funnel multiple input signals including those derived from nutritional sources; however, information is scarce as to the regulation of TORC2. A previous study using the model system provided by the fission yeast Schizosaccharomyces pombe identified Ryh1, a Rab-family GTPase, as an activator of TORC2. Here, we show that the nucleotide-binding state of Ryh1 is regulated in response to glucose, mediating this major nutrient signal to TORC2. In glucose-rich growth media, the GTP-bound form of Ryh1 induces TORC2-dependent phosphorylation of Gad8, a downstream target of TORC2 in fission yeast. Upon glucose deprivation, Ryh1 becomes inactive, which turns off the TORC2-Gad8 pathway. During glucose starvation, however, Gad8 phosphorylation by TORC2 gradually recovers independently of Ryh1, implying an additional TORC2 activator that is regulated negatively by glucose. The paired positive and negative regulatory mechanisms may allow fine-tuning of the TORC2-Gad8 pathway, which is essential for growth under glucose-limited environment.

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Section: Introductionmentioning

confidence: 95%

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

et al. 2015

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“…Among the residues that are phosphorylated over the course of Akt kinase activation is Ser473 in the C-terminal portion of the protein 40,41 . Depletion of Ofd1 or Bbs4 reproducibly results in reduced phospho-Akt (pSer473) after insulin stimulation (5 mU ml À 1 , 15 min) in MIN6m9 cells (Fig.…”

Section: Disruption Of Basal Body Integrity Impairs Insulin Secretionmentioning

confidence: 99%

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

Christou-Savina²,

et al. 2014

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Type 2 diabetes mellitus is affecting more than 382 million people worldwide. Although much progress has been made, a comprehensive understanding of the underlying disease mechanism is still lacking. Here we report a role for the b-cell primary cilium in type 2 diabetes susceptibility. We find impaired glucose handling in young Bbs4 À / À mice before the onset of obesity. Basal body/ciliary perturbation in murine pancreatic islets leads to impaired first phase insulin release ex and in vivo. Insulin receptor is recruited to the cilium of stimulated b-cells and ciliary/basal body integrity is required for activation of downstream targets of insulin signalling. We also observe a reduction in the number of ciliated b-cells along with misregulated ciliary/basal body gene expression in pancreatic islets in a diabetic rat model. We suggest that ciliary function is implicated in insulin secretion and insulin signalling in the b-cell and that ciliary dysfunction could contribute to type 2 diabetes susceptibility.

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“…The two TOR complexes were initially identified in yeast and subsequently were also characterized in Drosophila and mammalian cells. TORC1 contains mTOR, mLST8, PRAS40, and Raptor, whereas TORC2 contains mTOR, mLST8, Rictor, and Sin1 (5)(6)(7)(8)(9)(10)(11)(12). TORC1 is responsible for phosphorylation of Thr 389 of S6K1 (ribosomal protein S6 kinase) and 4EBP1 (eukaryote initiation factor 4E-binding protein), two important regulators in protein synthesis (1).…”

mentioning

confidence: 99%

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

Wang²,

Kim

et al. 2007

Journal of Biological Chemistry

235

196

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The mammalian target of rapamycin (mTOR) is a central controller of cell growth, and it regulates translation, cell size, cell viability, and cell morphology. mTOR integrates a wide range of extracellular and intracellular signals, including growth factors, nutrients, energy levels, and stress conditions. Rheb, a Ras-related small GTPase, is a key upstream activator of mTOR. In this study, we found that Bnip3, a hypoxia-inducible Bcl-2 homology 3 domain-containing protein, directly binds Rheb and inhibits the mTOR pathway. Bnip3 decreases Rheb GTP levels in a manner depending on the binding to Rheb and the presence of the N-terminal domain. Both knockdown and overexpression experiments show that Bnip3 plays an important role in mTOR inactivation in response to hypoxia. Moreover, Bnip3 inhibits cell growth in vivo by suppressing the mTOR pathway. These observations demonstrate that Bnip3 mediates the inhibition of the mTOR pathway in response to hypoxia.Target of rapamycin (TOR), 2 is an evolutionarily conserved serine/threonine kinase that plays a central role in cell growth (1-3). TOR regulates many processes, including protein translation, ribosome biogenesis, autophagy, and metabolism. TOR functions to integrate a wide range of extracellular and intracellular signals to produce a concerted cellular response, such as to stimulate cell growth. For example, mammalian target of rapamycin (mTOR) is activated by growth factor and nutrient availability. In contrast, mTOR is inhibited by cellular energy starvation and various stress conditions, including osmotic stress and hypoxia. These observations established a fundamental importance of mTOR in signal integration in regulation of cell growth.Recent studies have demonstrated that TOR exists in two functionally distinct protein complexes, termed TOR complex 1 (TORC1) and TOR complex 2 (TORC2) (3, 4). The two TOR complexes were initially identified in yeast and subsequently were also characterized in Drosophila and mammalian cells. TORC1 contains mTOR, mLST8, PRAS40, and Raptor, whereas TORC2 contains mTOR, mLST8, Rictor, and Sin1 (5-12). TORC1 is responsible for phosphorylation of Thr 389 of S6K1 (ribosomal protein S6 kinase) and 4EBP1 (eukaryote initiation factor 4E-binding protein), two important regulators in protein synthesis (1). In contrast, TORC2 has different substrates and is responsible for phosphorylation of the hydrophobic sites in both AKT and PKC (9, 13). Interestingly, TORC1 but not TORC2 is inhibited by rapamycin (6,8,9). These observations clearly demonstrate that the two TOR complexes have different physiological functions in vivo.Much progress has been made regarding the mechanisms of TORC1 regulation. Tuberous sclerosis complex (TSC) is a genetic disease characterized by benign hamartomas in various tissues (14). Mutations in either the TSC1 or TSC2 tumor suppressor gene are responsible for TSC development. TORC1 is highly activated in TSC tumors or cells with mutation of either TSC1 or TSC2. Both genetic and biochemical data have demonstrated th...

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SIN1/MIP1 Maintains rictor-mTOR Complex Integrity and Regulates Akt Phosphorylation and Substrate Specificity

Cited by 1,234 publications

References 69 publications

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

Fission yeast Ryh1 GTPase activates TOR Complex 2 in response to glucose

Ciliary dysfunction impairs beta-cell insulin secretion and promotes development of type 2 diabetes in rodents

Bnip3 Mediates the Hypoxia-induced Inhibition on Mammalian Target of Rapamycin by Interacting with Rheb

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