mTOR信号通路在疾病中的作用与调控机制
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摘要
mTOR是一种丝氨酸/苏氨酸蛋白激酶,与不同的蛋白质结合形成mTORC1和mTORC2两种复合物,体现了结构和功能上的差异。mTOR信号通路参与多种生理和病理过程,不仅可以调节细胞生长、代谢、血管生成、内环境稳定、自噬和衰老等生理过程,还与多种恶性肿瘤、自身免疫性疾病、心脑血管疾病等一系列的疾病发生及肿瘤抗药性相关。该文综述了mTOR信号通路在疾病发生中的作用及调控机制,为疾病治疗提供参考。
mTOR is a conserved serine/threonine kinase that is known to be part of two different protein complexes: mTORC1 and mTORC2, which differ in some components and in upstream and downstream signaling. mTOR signaling pathway was associated with multiple physiological and pathological processes, and it not only plays a significant role in cell growth, metabolism, homeostasis, autophagy and aging, but also is involved in human diseases including cancer, autoimmune diseases, cardiovascular diseases and cancer resistance. The role of mTOR signaling pathway in the occurrence of diseases was reviewed, aiming to provide references for disease therapy.
mTOR is a conserved serine/threonine kinase that is known to be part of two different protein complexes: mTORC1 and mTORC2, which differ in some components and in upstream and downstream signaling. mTOR signaling pathway was associated with multiple physiological and pathological processes, and it not only plays a significant role in cell growth, metabolism, homeostasis, autophagy and aging, but also is involved in human diseases including cancer, autoimmune diseases, cardiovascular diseases and cancer resistance. The role of mTOR signaling pathway in the occurrence of diseases was reviewed, aiming to provide references for disease therapy.
引文
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[46]Nagao M,Toh R,Irino Y,et al.High-density lipoprotein protects cardiomyocytes from oxidative stress via the PI3K/mTOR signaling pathway.FEBS Open Bio,2017,7:1402-9
[47]Frias MA,James RW,Gerberwicht C,et al.Native and reconstituted HDL activate Stat3 in ventricular cardiomyocytes via ERK1/2:role of sphingosine-1-phosphate.Cardiovasc Res,2009,82:313-23
[48]Means CK,Xiao CY,Li Z,et al.Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol,2007,292:2944-51
[49]Shende P,Xu L,Morandi C,et al.Cardiac mTOR complex2 preserves ventricular function in pressure overload hypertrophy.Cardiovasc Res,2015,109:103-14
[2]Kim LC,Cook RS,Chen J.mTORC1 and mTORC2 in cancer and the tumor microenvironment.Oncogene,2017,36:2191-201
[3]Saxton RA,Sabatini DM.mTOR signaling in growth,metabolism,and disease.Cell,2017,168:960-76
[4]Kim YC,Guan KL.mTOR:a pharmacologic target for autophagy regulation.J Clin Invest,2015,125:25-32
[5]Laplante M,Sabatini DM.mTOR signaling in growth control and disease.Cell,2012,149:274-93
[6]Shimobayashi M,Hall MN.Multiple amino acid sensing inputs to mTORC1.Cell Res,2016,26:689-97
[7]Chen J,Bai M,Ning C,et al.Gankyrin facilitates folliclestimulating hormone-driven ovarian cancer cell proliferation through the PI3K/AKT/HIF-1α/cyclin D1pathway.Oncogene,2015,35:2506-17
[8]Guri Y,Colombi M,Dazert E,et al.mTORC2 promotes tumorigenesis via lipid synthesis.Cancer Cell,2017,32:807-23
[9]Lee HK,Kwon B,Lemere CA,et al.mTORC2(Rictor)in Alzheimer's disease and reversal of amyloid-βexpressioninduced insulin resistance and toxicity in rat primary cortical neurons.J Alzheimers Dis,2016,56:1015-36
[10]Grier MD,West KL,Kelm ND,et al.Loss of mTORC2signaling in oligodendrocyte precursor cells delays myelination.PLoS One,2017,12:e0188417
[11]Xie J,Wang X,Proud CG.mTOR inhibitors in cancer therapy.F1000Res,2016,5:F1000 Faculty Rev-2078
[12]Chresta CM,Davies BR,Hickson I,et al.AZD8055 is a potent,selective,and orally bioavailable ATP-competitive mammalian target of rapamycin kinase inhibitor with in vitro and in vivo antitumor activity.Cancer Res,2010,70:288-98
[13]Jain P,Silva A,Han HJ,et al.Overcoming resistance to single-agent therapy for oncogenic BRAF gene fusions via combinatorial targeting of MAPK and PI3K/mTORsignaling pathways.Oncotarget,2017,8:84697-713
[14]Yang G,Murashige D,Humphrey S,et al.A positive feedback loop between Akt and mTORC2 via SIN1phosphorylation.Cell Rep,2015,12:937-43
[15]Yu CC,Hung SK,Lin HY,et al.Targeting the PI3K/AKT/m TOR signaling pathway as an effectively radiosensitizing strategy for treating human oral squamous cell carcinoma in vitro and in vivo.Oncotarget,2017,8:68641-53
[16]Travers JG,Kamal FA,Robbins J,et al.Cardiac fibrosis:the fibroblast awakens.Circ Res,2016,118:1021-40
[17]Sung MM,Zordoky BN,Bujak AL,et al.AMPKdeficiency in cardiac muscle results in dilated cardiomyopathy in the absence of changes in energy metabolism.Cardiovasc Res,2015,107:235-45
[18]Kang JI,Hong JY,Lee HJ,et al.Anti-tumor activity of Yuanhuacine by regulating AMPK/mTOR signaling pathway and actin cytoskeleton organization in non-small cell lung cancer cells.PLoS One,2015,10:e0144368
[19]Wang B,Jie Z,Joo D,et al.TRAF2 and OTUD7B govern a ubiquitin-dependent switch that regulates mTORC2,signalling.Nature,2017,545:365-9
[20]Liu P,Gan W,Inuzuka H,et al.Sin1 phosphorylation impairs mTORC2 complex integrity and inhibits downstream Akt signaling to suppress tumorigenesis.Nat Cell Biol,2013,15:1340-50
[21]Eiden AM,Zhang S,Gary JM,et al.Molecular pathways:increased susceptibility to infection is a complication of mTOR inhibitor use in cancer therapy.Clin Cancer Res,2015,22:277-83
[22]Guri Y,Hall MN.mTOR signaling confers resistance to targeted cancer drugs.Trends Cancer,2016,12:688-97
[23]Romeo Y,Zhang X,Roux PP.Regulation and function of the RSK family of protein kinases.Biochem J,2012,441:553-69
[24]She QB,Halilovic E,Ye Q,et al.4E-BP1 is a key effector of the oncogenic activation of the AKT and ERK signaling pathways that integrates their function in tumors.Cancer Cell,2010,18:39-51
[25]Baquero P,Jimnezmora E,Santos A,et al.TGFβinduces epithelial-mesenchymal transition of thyroid cancer cells by both the BRAF/MEK/ERK and Src/FAK pathways.Mol Carcinog,2016,55:1639-54
[26]Canino C,Mori F,Cambria A,et al.SASP mediates chemoresistance and tumor-initiating-activity of mesothelioma cells.Oncogene,2012,31:3148-63
[27]Herranz N,Gallage S,Mellone M,et al.mTOR regulates MAPKAPK2 translation to control the senescenceassociated secretory phenotype.Nat Cell Biol,2015,17:1205-17
[28]Lee E,Decker AM,Cackowski FC,et al.Growth arrestspecific 6(GAS6)promotes prostate cancer survival by G1 arrest/S phase delay and inhibition of apoptosis during chemotherapy in bone marrow.J Cell Biochem,2016,117:2815-24
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[31]Pennell LM,Fish EN.Interferon-βregulates dendritic cell activation and migration in experimental autoimmune encephalomyelitis.Immunology,2017,152:439-50
[32]Russo CD,Lisi L,Feinstein DL,et al.mTOR kinase,a key player in the regulation of glial functions:relevance for the therapy of multiple sclerosis.Glia,2013,61:301-11
[33]Esposito M,Ruffini F,Bellone M,et al.Rapamycin inhibits relapsing experimental autoimmune encephalomyelitis by both effector and regulatory T cells modulation.JNeuroimmunol,2010,220:52-63
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[35]Szabo SJ,Kim ST,Costa GL,et al.A novel transcription factor,T-bet,directs Th1 lineage commitment.Cell,2000,100:655-69
[36]Wu X,Dou Y,Yang Y,et al.Arctigenin exerts anti-colitis efficacy through inhibiting the differentiation of Th1 and Th17 cells via an mTORC1-dependent pathway.Biochem Pharmacol,2015,96:323-36
[37]Hou H,Miao J,Cao R,et al.Rapamycin ameliorates experimental autoimmune encephalomyelitis by suppressing the mTOR-STAT3 pathway.Neurochem Res,2017,42:2831-40
[38]Liang Z,Zhang L,Su H,et al.MTOR signaling is essential for the development of thymic epithelial cells and the induction of central immune tolerance.Autophagy,2018,14:505-7
[39]Takada K,Ohigashi I,Kasai M,et al.Development and function of cortical thymic epithelial cells.Curr Top Microbiol Immunol,2013,373:1-17
[40]Zhang S,Readinger JA,Dubois W,et al.Constitutive reductions in mTOR alter cell size,immune cell development,and antibody production.Blood,2011,117:1228-38
[41]Wang HX,Cheng JS,Chu S,et al.mTORC2 in thymic epithelial cells controls thymopoiesis and T cell development.J Immunol,2016,197:141-50
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[45]Frias MA,Pedretti S,Hacking D,et al.HDL protects against ischemia reperfusion injury by preserving mitochondrial integrity.Atherosclerosis,2013,228:110-6
[46]Nagao M,Toh R,Irino Y,et al.High-density lipoprotein protects cardiomyocytes from oxidative stress via the PI3K/mTOR signaling pathway.FEBS Open Bio,2017,7:1402-9
[47]Frias MA,James RW,Gerberwicht C,et al.Native and reconstituted HDL activate Stat3 in ventricular cardiomyocytes via ERK1/2:role of sphingosine-1-phosphate.Cardiovasc Res,2009,82:313-23
[48]Means CK,Xiao CY,Li Z,et al.Sphingosine 1-phosphate S1P2 and S1P3 receptor-mediated Akt activation protects against in vivo myocardial ischemia-reperfusion injury.Am J Physiol Heart Circ Physiol,2007,292:2944-51
[49]Shende P,Xu L,Morandi C,et al.Cardiac mTOR complex2 preserves ventricular function in pressure overload hypertrophy.Cardiovasc Res,2015,109:103-14