Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR Action

Hara, Kenta; Maruki, Yoshiko; Long, Samuel; Yoshino, Koichi; Oshiro, Noriko; Sujuti, Hidayat; Tokunaga, Chiharu; Avruch, Joseph; Yonezawa, Kazuyoshi

doi:10.1016/s0092-8674(02)00833-4

Cited by 1,639 publications

(1,390 citation statements)

References 56 publications

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“…Recently, two mTOR complexes (mTOR-raptor, TORC1 and mTOR-rictor, TORC2) have been identified (Hara et al, 2002;Kim et al, 2002;Jacinto et al, 2004;Sarbassov et al, 2004). TORC1 regulates phosphorylation of S6K1 and 4E-BP1 (Hara et al, 2002;Kim et al, 2002;Jacinto et al, 2004;Sarbassov et al, 2004), and TORC2 phosphorylates Akt at S473 (Sarbassov et al, 2005).…”

Section: Rapamycin Inhibition Of Cell Motility Via S6k1 and 4e-bp1mentioning

confidence: 99%

“…The mammalian target of rapamycin (mTOR), a 289 kDa Ser/Thr kinase, lies downstream of phosphatidylinositol 3 0 -kinase (PI3K), and senses mitogenic stimuli, nutrient conditions (Hara et al, 2002;Kim et al, 2002) and ATP (Dennis et al, 2001), and regulates multiple cellular events required for cellular growth (size) and proliferation (Fingar et al, 2002;Martin and Hall, 2005), differentiation (Erbay and Chen, 2001;Shu et al, 2002), and survival (Hosoi et al, 1999;Beuvink et al, 2005). Dysregulation of PI3K-mTOR pathway generates a favorable oncogenic environment and has been seen in a variety of transformed cells and human tumors, including rhabdomyosarcoma, lung, bladder, renal, ovary, breast, prostate, gastric, pancreatic, head and neck carcinomas, lymphoma, melanoma, glioma and other brain malignancies (Huang and Houghton, 2003).…”

Section: Introductionmentioning

confidence: 99%

“…In addition, inhibition of mTOR by rapamycin inactivates S6K1, blocking translation of mRNA species containing 5 0 terminal oligopyrimidine tracts (Dennis et al, 1996;von Manteuffel et al, 1997), though this remains controversial (Tang et al, 2001;Stolovich et al, 2002). Recently, two mTOR complexes (TORC1 and TORC2) have been identified (Hara et al, 2002;Kim et al, 2002;Jacinto et al, 2004;Sarbassov et al, 2004). TORC1 consists of mTOR, mLST8 (also termed Gprotein b-subunit-like protein, GbL, a yeast homolog of LST8), and regulatory-associated protein of mTOR (raptor), and rapamycin sensitive, whereas TORC2 is composed of mTOR, mLST8, and rapamycin-insensitive companion of mTOR (rictor), and rapamycininsensitive (Jacinto et al, 2004;Sarbassov et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

“…TORC1 consists of mTOR, mLST8 (also termed Gprotein b-subunit-like protein, GbL, a yeast homolog of LST8), and regulatory-associated protein of mTOR (raptor), and rapamycin sensitive, whereas TORC2 is composed of mTOR, mLST8, and rapamycin-insensitive companion of mTOR (rictor), and rapamycininsensitive (Jacinto et al, 2004;Sarbassov et al, 2004). TORC1 regulates phosphorylation of S6K1 and 4E-BP1 (Hara et al, 2002;Kim et al, 2002;Jacinto et al, 2004;Sarbassov et al, 2004) and controls translation initiation, ribosome biogenesis and other growth-related events. TORC2 phosphorylates Akt at S473 (Sarbassov et al, 2005), and regulates actin cytoskeleton (Loewith et al, 2002;Jacinto et al, 2004;Sarbassov et al, 2004).…”

Section: Introductionmentioning

confidence: 99%

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Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

et al. 2006

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Rapamycin, an inhibitor of the mammalian target of rapamycin (mTOR), inhibits tumor cell motility. However, the underlying mechanism is poorly understood. Here, we show that rapamycin inhibited type I insulin-like growth factor (IGF-I)-stimulated motility of a panel of cell lines. Expression of a rapamycin-resistant mutant of mTOR (mTORrr) prevented rapamycin inhibition of cell motility. However, cells expressing a kinase-dead mTORrr remained sensitive to rapamycin. Downregulation of raptor or rictor by RNA interference (RNAi) decreased cell motility. However, only downregulation of raptor mimicked the effect of rapamycin, inhibiting phosphorylation of S6 kinase 1 (S6K1) and 4E-BP1. Cells infected with an adenovirus expressing constitutively active and rapamycin-resistant mutant of p70 S6K1, but not with an adenovirus expressing wild-type S6K1, or a control virus, conferred to resistance to rapamycin. Further, IGF-I failed to stimulate motility of the cells, in which S6K1 was downregulated by RNAi. Moreover, downregulation of eukaryotic initiation factor 4E (eIF4E)-binding protein 1 (4E-BP1) by RNAi-attenuated rapamycin inhibition of cell motility. In contrast, expression of constitutively active 4E-BP1 dramatically inhibited IGF-I-stimulated cell motility. The results indicate that both S6K1 and 4E-BP1 pathways, regulated by TORC1, are required for cell motility. Rapamycin inhibits IGF-I-stimulated cell motility, through suppression of both S6K1 and 4E-BP1/eIF4E-signaling pathways, as a consequence of inhibition of mTOR kinase activity.

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Section: Rapamycin Inhibition Of Cell Motility Via S6k1 and 4e-bp1mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

et al. 2006

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“…substrates (14,15). PRAS40 interacts with raptor in insulin-deprived cells and inhibits the activation of mTORC1 pathway (16).…”

Section: Introductionmentioning

confidence: 99%

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

Espona-Fiedler

Soto‐Cerrato

Hosseini

et al. 2012

Biochemical Pharmacology

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The PI3K/AKT/mTOR signaling pathway regulates cell proliferation, survival and angiogenesis. The mammalian target of rapamycin (mTOR) is a protein kinase ubiquitously expressed within cells that regulates cell growth and survival by integrating nutrient and hormonal signals. mTOR exists in two complexes, mTORC1 and mTORC2. Hyperactivation of the mTOR protein has been linked to development of cancer, raising mTOR as an attractive target for cancer therapy. Prodigiosin (PG) and Obatoclax (OBX), two members of the prodiginines family, are small molecules with anticancer properties which are currently under clinical trials. In the present paper, we demonstrate that mTOR is a molecular target of both prodiginines in melanoma, a highly drug-resistant cancer model. The inhibition of mTORC1 and mTORC2 complexes by PG or OBX resulted in a loss of AKT phosphorylation at S473, preventing its full activation, with no significant effect on T308. The strongest activity inhibition (89%) was induced by PG on mTORC2. Binding assays using Surface Plasmon Resonance (SPR) provide kinetic and affinity data of the interaction of these small molecules with mTOR. In addition, in silico modelling produced a detailed atomic description of the binding modes. These results provide new data to understand the mechanism of action of these molecules, and provide new structural data that will allow the development of more specific mTOR inhibitors for cancer treatment.3

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The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways

et al. 2021

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The lysosome is a cellular signalling hub at the point of convergence of endocytic and autophagic pathways, where the contents are degraded and recycled. Pleckstrin homology domain‐containing family member 1 (PLEKHM1) acts as an adaptor to facilitate the fusion of endocytic and autophagic vesicles with the lysosome. However, it is unclear how PLEKHM1 function at the lysosome is controlled. Herein, we show that PLEKHM1 coprecipitates with, and is directly phosphorylated by, mTOR. Using a phosphospecific antibody against Ser432/S435 of PLEKHM1, we show that the same motif is a direct target for ERK2‐mediated phosphorylation in a growth factor‐dependent manner. This dual regulation of PLEKHM1 at a highly conserved region points to a convergence of both growth factor‐ and amino acid‐sensing pathways, placing PLEKHM1 at a critical juncture of cellular metabolism.

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Raptor, a Binding Partner of Target of Rapamycin (TOR), Mediates TOR Action

Cited by 1,639 publications

References 56 publications

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

Rapamycin inhibits cell motility by suppression of mTOR-mediated S6K1 and 4E-BP1 pathways

Identification of dual mTORC1 and mTORC2 inhibitors in melanoma cells: Prodigiosin vs. obatoclax

The endolysosomal adaptor PLEKHM1 is a direct target for both mTOR and MAPK pathways

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