The Experts below are selected from a list of 360 Experts worldwide ranked by ideXlab platform
Michael N Hall - One of the best experts on this subject based on the ideXlab platform.
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tor signaling in growth and metabolism
Cell, 2006Co-Authors: Stephan Wullschleger, Robbie Loewith, Michael N HallAbstract:The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
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molecular organization of target of rapamycin complex 2
Journal of Biological Chemistry, 2005Co-Authors: Stephan Wullschleger, Wolfgang Oppliger, Robbie Loewith, Michael N HallAbstract:The target of rapamycin (TOR), a highly conserved serine/threonine kinase, plays a central role in the control of eukaryotic cell growth. TOR exists in two functionally and structurally distinct complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). TORC1 controls cell growth via a rapamycin-sensitive signaling branch regulating translation, transcription, nutrient uptake, ribosome biogenesis, and autophagy. TORC2 controls the organization of the actin cytoskeleton through a rapamycin-insensitive signaling branch and in yeast consists of the six proteins AVO1, AVO2, AVO3, BIT61, LST8, and TOR2. Here we have focused on the characterization of TORC2. Our studies suggest that TORC2 is oligomeric, likely a TORC2-TORC2 dimer. AVO1 and AVO3 bind cooperatively to the N-terminal HEAT repeat region in TOR2 and are required for TORC2 integrity. AVO2 is a nonessential peripheral protein associated with AVO1 and AVO3. LST8 binds separately to the C-terminal kinase domain region in TOR2 and appears to modulate both the integrity and kinase activity of TORC2. TORC2 autophosphorylates sites in AVO1 and AVO3, but TORC2 kinase activity is not required for TORC2 integrity. We have demonstrated that mammalian TOR is also oligomeric. The architecture of TORC2 is discussed in the context of TORC2 assembly and regulation.
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Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive
Nature Cell Biology, 2004Co-Authors: Estela Jacinto, Shuo Lin, Robbie Loewith, Markus A Ruegg, Alan Hall, Anja Schmidt, Michael N HallAbstract:The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
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Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control
Molecular Cell, 2002Co-Authors: Robbie Loewith, Estela Jacinto, Anja Lorberg, Wolfgang Oppliger, Paul Jenoe, Debora Bonenfant, José L. Crespo, Stephan Wullschleger, Michael N HallAbstract:The target of rapamycin (TOR) proteins in Saccharomyces cerevisiae, TOR1 and TOR2, redundantly regulate growth in a rapamycin-sensitive manner. TOR2 additionally regulates polarization of the actin cytoskeleton in a rapamycin-insensitive manner. We describe two functionally distinct TOR complexes. TOR Complex 1 (TORC1) contains TOR1 or TOR2, KOG1 (YHR186c), and LST8. TORC2 contains TOR2, AVO1 (YOL078w), AVO2 (YMR068w), AVO3 (YER093c), and LST8. FKBP-rapamycin binds TORC1, and TORC1 disruption mimics rapamycin treatment, suggesting that TORC1 mediates the rapamycin-sensitive, TOR-shared pathway. FKBP-rapamycin fails to bind TORC2, and TORC2 disruption causes an actin defect, suggesting that TORC2 mediates the rapamycin-insensitive, TOR2-unique pathway. Thus, the distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling. TORC1 and possibly TORC2 are conserved from yeast to man.
Jonathan D Powell - One of the best experts on this subject based on the ideXlab platform.
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the mtor kinase differentially regulates effector and regulatory t cell lineage commitment
Immunity, 2009Co-Authors: Greg M Delgoffe, Thomas P Kole, Paul E Zarek, Krystal L Matthews, Sara C. Kozma, Yan Zheng, Bo Xiao, Paul F Worley, Jonathan D PowellAbstract:Summary Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3 + regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-β. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.
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the mtor kinase differentially regulates effector and regulatory t cell lineage commitment
Immunity, 2009Co-Authors: Greg M Delgoffe, Thomas P Kole, Paul E Zarek, Krystal L Matthews, Sara C. Kozma, Yan Zheng, Bo Xiao, Paul F Worley, Jonathan D PowellAbstract:Effector T cell differentiation requires the simultaneous integration of multiple, and sometimes opposing, cytokine signals. We demonstrated mTOR's role in dictating the outcome of T cell fate. mTOR-deficient T cells displayed normal activation and IL-2 production upon initial stimulation. However, such cells failed to differentiate into T helper 1 (Th1), Th2, or Th17 effector cells. The inability to differentiate was associated with decreased STAT transcription factor activation and failure to upregulate lineage-specific transcription factors. Under normally activating conditions, T cells lacking mTOR differentiated into Foxp3(+) regulatory T cells. This was associated with hyperactive Smad3 activation in the absence of exogenous TGF-beta. Surprisingly, T cells selectively deficient in TORC1 do not divert to a regulatory T cell pathway, implicating both TORC1 and TORC2 in preventing the generation of regulatory T cells. Overall, our studies suggest that mTOR kinase signaling regulates decisions between effector and regulatory T cell lineage commitment.
Robbie Loewith - One of the best experts on this subject based on the ideXlab platform.
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tor signaling in growth and metabolism
Cell, 2006Co-Authors: Stephan Wullschleger, Robbie Loewith, Michael N HallAbstract:The target of rapamycin (TOR) is a conserved Ser/Thr kinase that regulates cell growth and metabolism in response to environmental cues. Here, highlighting contributions from studies in model organisms, we review mammalian TOR complexes and the signaling branches they mediate. TOR is part of two distinct multiprotein complexes, TOR complex 1 (TORC1), which is sensitive to rapamycin, and TORC2, which is not. The physiological consequences of mammalian TORC1 dysregulation suggest that inhibitors of mammalian TOR may be useful in the treatment of cancer, cardiovascular disease, autoimmunity, and metabolic disorders.
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molecular organization of target of rapamycin complex 2
Journal of Biological Chemistry, 2005Co-Authors: Stephan Wullschleger, Wolfgang Oppliger, Robbie Loewith, Michael N HallAbstract:The target of rapamycin (TOR), a highly conserved serine/threonine kinase, plays a central role in the control of eukaryotic cell growth. TOR exists in two functionally and structurally distinct complexes, TOR complex 1 (TORC1) and TOR complex 2 (TORC2). TORC1 controls cell growth via a rapamycin-sensitive signaling branch regulating translation, transcription, nutrient uptake, ribosome biogenesis, and autophagy. TORC2 controls the organization of the actin cytoskeleton through a rapamycin-insensitive signaling branch and in yeast consists of the six proteins AVO1, AVO2, AVO3, BIT61, LST8, and TOR2. Here we have focused on the characterization of TORC2. Our studies suggest that TORC2 is oligomeric, likely a TORC2-TORC2 dimer. AVO1 and AVO3 bind cooperatively to the N-terminal HEAT repeat region in TOR2 and are required for TORC2 integrity. AVO2 is a nonessential peripheral protein associated with AVO1 and AVO3. LST8 binds separately to the C-terminal kinase domain region in TOR2 and appears to modulate both the integrity and kinase activity of TORC2. TORC2 autophosphorylates sites in AVO1 and AVO3, but TORC2 kinase activity is not required for TORC2 integrity. We have demonstrated that mammalian TOR is also oligomeric. The architecture of TORC2 is discussed in the context of TORC2 assembly and regulation.
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Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive
Nature Cell Biology, 2004Co-Authors: Estela Jacinto, Shuo Lin, Robbie Loewith, Markus A Ruegg, Alan Hall, Anja Schmidt, Michael N HallAbstract:The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
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Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control
Molecular Cell, 2002Co-Authors: Robbie Loewith, Estela Jacinto, Anja Lorberg, Wolfgang Oppliger, Paul Jenoe, Debora Bonenfant, José L. Crespo, Stephan Wullschleger, Michael N HallAbstract:The target of rapamycin (TOR) proteins in Saccharomyces cerevisiae, TOR1 and TOR2, redundantly regulate growth in a rapamycin-sensitive manner. TOR2 additionally regulates polarization of the actin cytoskeleton in a rapamycin-insensitive manner. We describe two functionally distinct TOR complexes. TOR Complex 1 (TORC1) contains TOR1 or TOR2, KOG1 (YHR186c), and LST8. TORC2 contains TOR2, AVO1 (YOL078w), AVO2 (YMR068w), AVO3 (YER093c), and LST8. FKBP-rapamycin binds TORC1, and TORC1 disruption mimics rapamycin treatment, suggesting that TORC1 mediates the rapamycin-sensitive, TOR-shared pathway. FKBP-rapamycin fails to bind TORC2, and TORC2 disruption causes an actin defect, suggesting that TORC2 mediates the rapamycin-insensitive, TOR2-unique pathway. Thus, the distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling. TORC1 and possibly TORC2 are conserved from yeast to man.
Chojiro Kojima - One of the best experts on this subject based on the ideXlab platform.
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substrate specificity of tor complex 2 is determined by a ubiquitin fold domain of the sin1 subunit
eLife, 2017Co-Authors: Hisashi Tatebe, Shinichi Murayama, Toshiya Yonekura, Tomoyuki Hatano, David Richter, Tomomi Furuya, Saori Kataoka, Kyoko Furuita, Chojiro KojimaAbstract:The target of rapamycin (TOR) protein kinase forms multi-subunit TOR complex 1 (TORC1) and TOR complex 2 (TORC2), which exhibit distinct substrate specificities. Sin1 is one of the TORC2-specific subunit essential for phosphorylation and activation of certain AGC-family kinases. Here, we show that Sin1 is dispensable for the catalytic activity of TORC2, but its conserved region in the middle (Sin1CRIM) forms a discrete domain that specifically binds the TORC2 substrate kinases. Sin1CRIM fused to a different TORC2 subunit can recruit the TORC2 substrate Gad8 for phosphorylation even in the sin1 null mutant of fission yeast. The solution structure of Sin1CRIM shows a ubiquitin-like fold with a characteristic acidic loop, which is essential for interaction with the TORC2 substrates. The specific substrate-recognition function is conserved in human Sin1CRIM, which may represent a potential target for novel anticancer drugs that prevent activation of the mTORC2 substrates such as AKT.
Estela Jacinto - One of the best experts on this subject based on the ideXlab platform.
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sin1 mip1 maintains rictor mtor complex integrity and regulates akt phosphorylation and substrate specificity
Cell, 2006Co-Authors: Estela Jacinto, Valeria Facchinetti, Nelyn Soto, Sung Yun Jung, Qiaojia Huang, Bing SuAbstract:Mammalian target of rapamycin (mTOR) controls cell growth and proliferation via the raptor-mTOR (TORC1) and rictor-mTOR (TORC2) protein complexes. Recent biochemical studies suggested that TORC2 is the elusive PDK2 for Akt/PKB Ser473 phosphorylation in the hydrophobic motif. Phosphorylation at Ser473, along with Thr308 of its activation loop, is deemed necessary for Akt function, although the regulatory mechanisms and physiological importance of each phosphorylation site remain to be fully understood. Here, we report that SIN1/MIP1 is an essential TORC2/PDK2 subunit. Genetic ablation of sin1 abolished Akt-Ser473 phosphorylation and disrupted rictor-mTOR interaction but maintained Thr308 phosphorylation. Surprisingly, defective Ser473 phosphorylation affected only a subset of Akt targets in vivo, including FoxO1/3a, while other Akt targets, TSC2 and GSK3, and the TORC1 effectors, S6K and 4E-BP1, were unaffected. Our findings reveal that the SIN1-rictor-mTOR function in Akt-Ser473 phosphorylation is required for TORC2 function in cell survival but is dispensable for TORC1 function.
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Mammalian TOR complex 2 controls the actin cytoskeleton and is rapamycin insensitive
Nature Cell Biology, 2004Co-Authors: Estela Jacinto, Shuo Lin, Robbie Loewith, Markus A Ruegg, Alan Hall, Anja Schmidt, Michael N HallAbstract:The target of rapamycin (TOR) is a highly conserved protein kinase and a central controller of cell growth. In budding yeast, TOR is found in structurally and functionally distinct protein complexes: TORC1 and TORC2. A mammalian counterpart of TORC1 (mTORC1) has been described, but it is not known whether TORC2 is conserved in mammals. Here, we report that a mammalian counterpart of TORC2 (mTORC2) also exists. mTORC2 contains mTOR, mLST8 and mAVO3, but not raptor. Like yeast TORC2, mTORC2 is rapamycin insensitive and seems to function upstream of Rho GTPases to regulate the actin cytoskeleton. mTORC2 is not upstream of the mTORC1 effector S6K. Thus, two distinct TOR complexes constitute a primordial signalling network conserved in eukaryotic evolution to control the fundamental process of cell growth.
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Two TOR complexes, only one of which is rapamycin sensitive, have distinct roles in cell growth control
Molecular Cell, 2002Co-Authors: Robbie Loewith, Estela Jacinto, Anja Lorberg, Wolfgang Oppliger, Paul Jenoe, Debora Bonenfant, José L. Crespo, Stephan Wullschleger, Michael N HallAbstract:The target of rapamycin (TOR) proteins in Saccharomyces cerevisiae, TOR1 and TOR2, redundantly regulate growth in a rapamycin-sensitive manner. TOR2 additionally regulates polarization of the actin cytoskeleton in a rapamycin-insensitive manner. We describe two functionally distinct TOR complexes. TOR Complex 1 (TORC1) contains TOR1 or TOR2, KOG1 (YHR186c), and LST8. TORC2 contains TOR2, AVO1 (YOL078w), AVO2 (YMR068w), AVO3 (YER093c), and LST8. FKBP-rapamycin binds TORC1, and TORC1 disruption mimics rapamycin treatment, suggesting that TORC1 mediates the rapamycin-sensitive, TOR-shared pathway. FKBP-rapamycin fails to bind TORC2, and TORC2 disruption causes an actin defect, suggesting that TORC2 mediates the rapamycin-insensitive, TOR2-unique pathway. Thus, the distinct TOR complexes account for the diversity, specificity, and selective rapamycin inhibition of TOR signaling. TORC1 and possibly TORC2 are conserved from yeast to man.
