AMPK/mTOR信号通路的研究进展
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摘要
mTOR是细胞生长和增殖的中枢调控因子。mTOR形成2个不同的复合物mTORC1和mTORC2。mTORC1受多种信号调节,如生长因子、氨基酸和细胞能量,同时,mTORC1调节许多重要的细胞过程,包括翻译、转录和自噬。AMPK作为一种关键的生理能量传感器,是细胞和有机体能量平衡的主要调节因子,协调多种代谢途径,平衡能量的供应和需求,最终调节细胞和器官的生长。能量代谢平衡调控是由多个与之相关的信号通路所介导,其中AMPK/mTOR信号通路在细胞内共同构成一个合成代谢和分解代谢过程的开关。此外,AMPK/mTOR信号通路还是一个自噬的重要调控途径。本文着重于目前对AMPK和mTOR信号传导之间关系的了解,讨论了AMPK/mTOR在细胞和有机体能量稳态中的作用。
mTOR is a central controller of cell growth and proliferation. mTOR forms two distinct complexes, mTORC1 and mTORC2. mTORC1 is regulated by multiple signals such as growth factors, amino acids, and cellular energy and regulates numerous essential cellular processes including translation, transcription, and autophagy. As a key physiological energy sensor, AMPK is the main regulator of cell and organism energy balance, coordinates multiple metabolic pathways, balances energy supply and demand, and ultimately regulates the growth of cells and organs. The regulation of energy metabolism balance is mediated by a number of related signaling pathways, in which the AMPK/mTOR signaling pathway together constitute a switch for anabolic and catabolic processes. Furthermore, the AMPK/mTOR signaling pathway is an important regulatory pathway for autophagy. This review focuses on current understanding the relationship between AMPK and mTOR signaling and discusses their roles in cellular and organism energy homeostasis.
mTOR is a central controller of cell growth and proliferation. mTOR forms two distinct complexes, mTORC1 and mTORC2. mTORC1 is regulated by multiple signals such as growth factors, amino acids, and cellular energy and regulates numerous essential cellular processes including translation, transcription, and autophagy. As a key physiological energy sensor, AMPK is the main regulator of cell and organism energy balance, coordinates multiple metabolic pathways, balances energy supply and demand, and ultimately regulates the growth of cells and organs. The regulation of energy metabolism balance is mediated by a number of related signaling pathways, in which the AMPK/mTOR signaling pathway together constitute a switch for anabolic and catabolic processes. Furthermore, the AMPK/mTOR signaling pathway is an important regulatory pathway for autophagy. This review focuses on current understanding the relationship between AMPK and mTOR signaling and discusses their roles in cellular and organism energy homeostasis.
引文
[1]Daniel Garcia,Reuben J Shaw.AMPK:Mechanisms of Cellular Energy Sensing and Restoration of Metabolic Balance[J].Molecular Cell,2017,66(6),66:789-800.
[2]Ross FA,Mac Kintosh C,Hardie DG.AMP-activated protein kinase:a cellular energy sensor that comes in 12 flavours[J].FEBS,2016,283:2987-3001.
[3]Jensen TE,Ross FA,Kleinert M,et al.PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle,but activates all threeγsubunit complexes in cultured human cells by inhibiting the respiratory chain[J].Biochem,2015,467:461-472.
[4]Rajamohan F,Reyes AR,Frisbie RK,et al.Probing the enzyme kinetics,allosteric modulation and activation ofα1-andα2-subunit-containing AMP-activated protein kinase(AMPK)heterotrimeric complexes by pharmacological and physiological activators[J].Biochem,2016,473:581-592.
[5]Zhang YL,Guo Hl,Zhang CS,et al.AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation[J].Cell Metab,2013,18:546-555.
[6]Zhang CS,Jiang B,Li M,et al.The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and m TORC1,acting as a switch between catabolism and anabolism[J].Cell Metab,2014,20:526-540.
[7]Zhang CS,Hawley S,Zong Y,et al Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK.[J]Nature,2017,548:112-116.
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[14]Cool B,Zinker B,Chiou W,et al.Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome[J].Cell Metab,2006,3:403-416.
[15]Xiao B.Sanders MJ,Carmena D,et al.Structural basis of AMPK regulation by small molecule activators[J].Nat,Commun,2013,4:3017.
[16]Cokorinos EC,Delmore J,Reyes AR,et al.Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice[J].Cell Metab,2017,25:1147-1159.
[17]Myers RW,Guan HP,Eharhart J,et al.Systemic pan-AMPKactivator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy[J].Science,2017,357:507-511.
[18]Budanov AV,Karin M.p53 target genes sestrin1 and sestrin2connect genotoxic stress and m TOR signaling[J].Cell,2008,134(3):451-460.
[19]Mizushima N.The role of the Atg1/ULK1 complex in autophagy regulation[J].Curr.Opin.Cell Biol,2010,22:132-139.
[20]Kim J,Kundu M,Viollet B,et al.AMPK and m TOR regulate autophagy through direct phosphorylation of Ulk1[J].Nat.Cell Biol,2011,13:132-141.
[21]Wolff NC,Vega-Rubin-de-Celis S,Xie XJ,et al.Cell typedependent regulation of m TORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia[J].Mol.Cell.Biol,2011,31(9):1870-1884.
[22]Ken Inoki,Joungmok Kim,Kun-Liang Guan.AMPK and m TOR in Cellular Energy Homeostasis and Drug Targets[J].Toxicol,2012,52:381-400.
[23]Lee CH,Inoki K,Karbowniczek M,et al.Constitutive m TORactivation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53[J].EMBO,2007,26:4812-4823.
[24]Choo AY,Kim SG,Vander Heiden MG,et al.Glucose addiction of TSC null cells is caused by failed m TORC1-dependent balancing of metabolic demand with supply[J].Mol.Cell,2010,38:487-499.
[25]Cokorinos EC,Delmore J,Reyes AR,et al.Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice[J].Cell Metab,2017,25:1147-1159.
[26]Mishra P Chan,DC.Metabolic regulation of mitochondrial dynamics[J].Cell Biol,2016,212:379-387.
[27]Zibrova D,Vandermoere F,G¨oransson O,et al.GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis[J].Biochem,2017,474:983-1001.
[28]Choo AY,Kim SG,Vander Heiden MG,et al.Glucose addiction of TSC null cells is caused by failed m TORC1-dependent balancing of metabolic demand with supply[J].Mol.Cell,2010,38:487-499.
[29]Gwinn DM,Shackelford DB,Egan DF,et al.AMPK phosphorylation of raptor mediates a metabolic checkpoint[J].Mol.Cell,2008,30:214-226.
[30]Zheng M,Wang YH,Wu XN,et al.Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of m TORC1[J].Nat.Cell Biol,2011,13:263-272.
[31]Hardie DG.AMPK:a target for drugs and natural products with effects on both diabetes and cancer[J].Diabetes,2013,62:2164-2172.
[32]Wu N,Zheng B,Shaywitz A,et al.AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1[J].Mol.Cell,2013,49,1167-1175.
[33]Hoppe S,Bierhoff H,Cado I,et al.AMP-activated protein kinase adapts r RNA synthesis to cellular energy supply[J].Proc.Natl.Acad.Sci.USA,2009,106:17781-17786.
[34]Leprivier G,Remke M,Rotblat B,et al.The e EF2 kinase confers resistance to nutrient deprivation by blocking translation elongation[J].Cell,2013,153:1064-1079.
[35]Faller WJ,Jackson TJ,Knight JRP,et al.m TORC1-mediated translational elongation limits intestinal tumour initiation and growth[J].Nature,2015,517:497-500.
[36]Leprivier G,Remke M,Rotblat B,et al.The e EF2 kinase confers resistance to nutrient deprivation by blocking translation elongation[J].Cell,2013,153:1064-1079.
[37]Egan DF,Shackelford DB,Mihaylova MM,et al.Phosphorylation of ULK1(h ATG1)by AMP-activated protein kinase connects energy sensing to mitophagy[J].Science,2011,331:456-461.
[38]Kim SJ,Tang T,Abbott M,et al.AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue[J].Mol.Cell.Biol,2016,36:1961-1976.
[39]Mack HID,Zheng B,Asara JM,et al.AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization[J].Autophagy,2012,8:1197-1214.
[40]Kim J,Kim YC,Fang C,et al.Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy[J].Cell,2013,152:290-303.
[41]Young NP,Kamireddy A,Van Nostrand,et al.AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes[J].Genes Dev,2016,30:535-552.
[2]Ross FA,Mac Kintosh C,Hardie DG.AMP-activated protein kinase:a cellular energy sensor that comes in 12 flavours[J].FEBS,2016,283:2987-3001.
[3]Jensen TE,Ross FA,Kleinert M,et al.PT-1 selectively activates AMPK-γ1 complexes in mouse skeletal muscle,but activates all threeγsubunit complexes in cultured human cells by inhibiting the respiratory chain[J].Biochem,2015,467:461-472.
[4]Rajamohan F,Reyes AR,Frisbie RK,et al.Probing the enzyme kinetics,allosteric modulation and activation ofα1-andα2-subunit-containing AMP-activated protein kinase(AMPK)heterotrimeric complexes by pharmacological and physiological activators[J].Biochem,2016,473:581-592.
[5]Zhang YL,Guo Hl,Zhang CS,et al.AMP as a low-energy charge signal autonomously initiates assembly of AXIN-AMPK-LKB1 complex for AMPK activation[J].Cell Metab,2013,18:546-555.
[6]Zhang CS,Jiang B,Li M,et al.The lysosomal v-ATPase-Ragulator complex is a common activator for AMPK and m TORC1,acting as a switch between catabolism and anabolism[J].Cell Metab,2014,20:526-540.
[7]Zhang CS,Hawley S,Zong Y,et al Fructose-1,6-bisphosphate and aldolase mediate glucose sensing by AMPK.[J]Nature,2017,548:112-116.
[8]Jessen N,Koh HJ,Clifford D,et al.Ablation of LKB1 in the heart leads to energy deprivation and impaired cardiac function[J].Biochim.Biophys.Acta,2010,1802:593-600.
[9]Shan T,Zhang P,Bi P,et al.Lkb1 deletion promotes ectopic lipid accumulation in muscle progenitor cells and mature muscles.J.Cell[J].Physiol,2015,230:1033-1041.
[10]Ollila S,M¨akel¨a TP.The tumor suppressor kinase LKB1:lessons from mouse models Mol[J].Cell.Biol,2011,3:330-340.
[11]Ghislat G,Patron M,Rizzuto,et al.Withdrawal of essential amino acids increases autophagy by a pathway involving Ca2+/calmodulin-dependent kinase kinase-β(CaMKK-β)[J].Biol.Chem,2012,287:38625-38636.
[12]Mungai PT,Waypa GB,Jairaman A,et al.Hypoxia triggers AMPK activation through reactive oxygen species-mediated activation of calcium release-activated calcium channels[J].Mol.Cell.Biol.,2011,31(17):3531-3545.
[13]Sallé-Lefort S,Miard S,Nolin MA,et al.Hypoxia upregulates Malat1 expression through a CaMKK/AMPK/HIF-1αaxis[J].Int.J.Oncol,2016,49:1731-1736.
[14]Cool B,Zinker B,Chiou W,et al.Identification and characterization of a small molecule AMPK activator that treats key components of type 2 diabetes and the metabolic syndrome[J].Cell Metab,2006,3:403-416.
[15]Xiao B.Sanders MJ,Carmena D,et al.Structural basis of AMPK regulation by small molecule activators[J].Nat,Commun,2013,4:3017.
[16]Cokorinos EC,Delmore J,Reyes AR,et al.Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice[J].Cell Metab,2017,25:1147-1159.
[17]Myers RW,Guan HP,Eharhart J,et al.Systemic pan-AMPKactivator MK-8722 improves glucose homeostasis but induces cardiac hypertrophy[J].Science,2017,357:507-511.
[18]Budanov AV,Karin M.p53 target genes sestrin1 and sestrin2connect genotoxic stress and m TOR signaling[J].Cell,2008,134(3):451-460.
[19]Mizushima N.The role of the Atg1/ULK1 complex in autophagy regulation[J].Curr.Opin.Cell Biol,2010,22:132-139.
[20]Kim J,Kundu M,Viollet B,et al.AMPK and m TOR regulate autophagy through direct phosphorylation of Ulk1[J].Nat.Cell Biol,2011,13:132-141.
[21]Wolff NC,Vega-Rubin-de-Celis S,Xie XJ,et al.Cell typedependent regulation of m TORC1 by REDD1 and the tumor suppressors TSC1/TSC2 and LKB1 in response to hypoxia[J].Mol.Cell.Biol,2011,31(9):1870-1884.
[22]Ken Inoki,Joungmok Kim,Kun-Liang Guan.AMPK and m TOR in Cellular Energy Homeostasis and Drug Targets[J].Toxicol,2012,52:381-400.
[23]Lee CH,Inoki K,Karbowniczek M,et al.Constitutive m TORactivation in TSC mutants sensitizes cells to energy starvation and genomic damage via p53[J].EMBO,2007,26:4812-4823.
[24]Choo AY,Kim SG,Vander Heiden MG,et al.Glucose addiction of TSC null cells is caused by failed m TORC1-dependent balancing of metabolic demand with supply[J].Mol.Cell,2010,38:487-499.
[25]Cokorinos EC,Delmore J,Reyes AR,et al.Activation of skeletal muscle AMPK promotes glucose disposal and glucose lowering in non-human primates and mice[J].Cell Metab,2017,25:1147-1159.
[26]Mishra P Chan,DC.Metabolic regulation of mitochondrial dynamics[J].Cell Biol,2016,212:379-387.
[27]Zibrova D,Vandermoere F,G¨oransson O,et al.GFAT1 phosphorylation by AMPK promotes VEGF-induced angiogenesis[J].Biochem,2017,474:983-1001.
[28]Choo AY,Kim SG,Vander Heiden MG,et al.Glucose addiction of TSC null cells is caused by failed m TORC1-dependent balancing of metabolic demand with supply[J].Mol.Cell,2010,38:487-499.
[29]Gwinn DM,Shackelford DB,Egan DF,et al.AMPK phosphorylation of raptor mediates a metabolic checkpoint[J].Mol.Cell,2008,30:214-226.
[30]Zheng M,Wang YH,Wu XN,et al.Inactivation of Rheb by PRAK-mediated phosphorylation is essential for energy-depletion-induced suppression of m TORC1[J].Nat.Cell Biol,2011,13:263-272.
[31]Hardie DG.AMPK:a target for drugs and natural products with effects on both diabetes and cancer[J].Diabetes,2013,62:2164-2172.
[32]Wu N,Zheng B,Shaywitz A,et al.AMPK-dependent degradation of TXNIP upon energy stress leads to enhanced glucose uptake via GLUT1[J].Mol.Cell,2013,49,1167-1175.
[33]Hoppe S,Bierhoff H,Cado I,et al.AMP-activated protein kinase adapts r RNA synthesis to cellular energy supply[J].Proc.Natl.Acad.Sci.USA,2009,106:17781-17786.
[34]Leprivier G,Remke M,Rotblat B,et al.The e EF2 kinase confers resistance to nutrient deprivation by blocking translation elongation[J].Cell,2013,153:1064-1079.
[35]Faller WJ,Jackson TJ,Knight JRP,et al.m TORC1-mediated translational elongation limits intestinal tumour initiation and growth[J].Nature,2015,517:497-500.
[36]Leprivier G,Remke M,Rotblat B,et al.The e EF2 kinase confers resistance to nutrient deprivation by blocking translation elongation[J].Cell,2013,153:1064-1079.
[37]Egan DF,Shackelford DB,Mihaylova MM,et al.Phosphorylation of ULK1(h ATG1)by AMP-activated protein kinase connects energy sensing to mitophagy[J].Science,2011,331:456-461.
[38]Kim SJ,Tang T,Abbott M,et al.AMPK Phosphorylates Desnutrin/ATGL and Hormone-Sensitive Lipase To Regulate Lipolysis and Fatty Acid Oxidation within Adipose Tissue[J].Mol.Cell.Biol,2016,36:1961-1976.
[39]Mack HID,Zheng B,Asara JM,et al.AMPK-dependent phosphorylation of ULK1 regulates ATG9 localization[J].Autophagy,2012,8:1197-1214.
[40]Kim J,Kim YC,Fang C,et al.Differential regulation of distinct Vps34 complexes by AMPK in nutrient stress and autophagy[J].Cell,2013,152:290-303.
[41]Young NP,Kamireddy A,Van Nostrand,et al.AMPK governs lineage specification through Tfeb-dependent regulation of lysosomes[J].Genes Dev,2016,30:535-552.
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