Stefania Battaglioni 2Don Benjamin 2Matthias Wälchli Timm Maier Michael N. Hall
Published:May 16, 2022DOI:https://doi.org/10.1016/j.cell.2022.04.013
30年前发现的雷帕霉素靶点(TOR)是一种高度保守的丝氨酸/苏氨酸蛋白激酶,在调节细胞生长和代谢中发挥着核心作用。它被营养物质、生长因子和细胞能量所激活。TOR形成两个结构和功能不同的复合物,TORC1和TORC2。TOR信号通过刺激合成代谢而抑制分解代谢过程来激活细胞生长,定义为生物量的增加。以哺乳动物TOR(mTOR)为重点,我们全面回顾了文献并确定了所有报道的直接底物。在最近的结构信息方面,我们讨论了mTORC1和mTORC2尽管有一个共同的催化亚基,但如何磷酸化不同的底物。我们的结论是,这两个复合体招募不同的底物来磷酸化一个共同的、最小的主题。
雷帕霉素是由一种细菌产生的次级代谢物,这种细菌最初于1965年从复活节岛(拉帕努伊)收集的土壤样本中分离出来。最初被确定为一种抗真菌剂,后来发现它具有免疫抑制和抗癌活性(Sehgal等人,1975;Vézina等人,1975)。由此对雷帕霉素的兴趣导致了对其细胞靶点的追寻。雷帕霉素的靶点(TOR)首先在酵母中被描述(Cafferkey等人,1993;Heitman等人,1991;Helliwell等人,1994;Kunz等人,1993),然后在哺乳动物细胞中被描述(Brown等人,1994;Chiu等人,1994;Sabatini等人,1994;Sabers等人,1995)。该领域的第二个里程碑是在20世纪90年代末认识到TOR是细胞生长的中心控制器(Schmelzle和Hall,2000)。第三个里程碑是在21世纪初发现TOR存在于两个结构和功能不同的复合物中,这些复合物和TOR本身一样,从酵母到人类都是保守的(Hara等人,2002;Kim等人,2002;Loewith等人,2002)(图1)。多年来,mTOR的失调已与重大疾病如糖尿病、癌症和神经系统疾病有关。鉴于其在基础生物学和医学中的重要性,对mTOR的研究已经成为一个庞大而复杂的研究领域。
mTORC1和mTORC2
mTOR是磷脂酰肌醇(PI)激酶相关激酶(PIKK)家族非典型蛋白激酶的成员(Hunter, 2014; Keith, and Schreiber, 1995)。尽管与PI激酶有共同的血统,但mTOR和其他PIKKs没有已知的脂质激酶活性,而是具有丝氨酸/苏氨酸蛋白激酶活性。mTOR的N端含有多个HEAT重复序列,mTOR的中间部分有一个FRAP/ATM/TRRAP(FAT)结构域,后面是FKBP-rapamycin结合(FRB)结构域。C端包含激酶结构域(图2)。
mTORC1的直接底物和信号
Substrate | Uniprot ID | Phosphorylated site(s) | Phosphorylated site(s) and adjacent residues | TOS motif | Purpose of phosphorylation | Function | Remarks | Reference |
---|---|---|---|---|---|---|---|---|
4E-BP1a | Q13541 | T37,T46 | GDYSTTPGGTLFSTTPGGTR | FEMDI | Inhibitory | Translation regulation | Rapamycin insensitive | Burnett et al. (1998) |
S65,T70 | MECRNSPVTKTPPRDL | – | Inhibitory | Rapamycin sensitive | Mothe-Satney et al. (2000) | |||
ACINUS | Q9UKV3 | S240,S243 | RAAKLSEGSQPAEE | – | Unknown significance | EJC, splicing | – | Schwarz et al. (2015) |
AMBRA1 | Q9C0C7 | S52 | VELPDSPRSTF | – | Inhibitory | Autophagy | – | Nazio et al. (2013) |
AMPKα1 | Q13131 | S356b | FYLATSPPDSF | – | Inhibitory | Signaling | – | Ling et al. (2020) |
AMPKα2 | P54646 | S345 | FYLASSPPSGS | – | Inhibitory | Signaling | – | Ling et al. (2020) |
S377 | PLIADSPKARC | – | Specific activation | Glucose uptake | – | Needham et al. (2022) | ||
AR | P10275 | S96 | QGEDGSPQAHR | – | Activating | Signaling | – | Ren et al. (2022) |
AS160 | O60343 | S666 | AQGVRSPLLRQ | FEMDI | Unknown | Signaling | Sensitive to TOS mutation and rapamycin | Geraghty et al. (2007) |
ATG13 | O75143 | S259c | TSFSTSPPSQL | – | Inhibitory | Autophagy | – | Puente et al. (2016) |
ATG14 | Q6ZNE5 | S3 | MASPSGKG | – | Inhibitory | Autophagy | – | Yuan et al. (2013) |
S223,T233 | PADVSSESDSAMTSSTVSKLA | |||||||
S383 | LMYLVSPSSEH | |||||||
S440 | WENLPSPRFCD | |||||||
BACH2 | Q9BYV9 | S510d | KVCPRSPPLET | – | Inhibitory | Transcriptional regulator | – | Ando et al. (2016) |
S536d | DGSGGSPCSLP | |||||||
CLIP1 | P30622 | Multiple sites | – | – | Activating | Microtubule organization | – | Choi et al. (2002) |
CRTC2 | Q53ET0 | S136 | SPAYLSPPPES | – | Inhibitory | SREBP1 processing | – | Han et al. (2015) |
DAP1 | P51397 | S3 | MSSPPEGK | – | Inhibitory | Autophagy | – | Koren et al. (2010) |
S51 | EWESPSPPKPT | – | – | |||||
DEPTOR | Q8TB45 | S293, T295, S299 | GYFSSSPTLSSSPPVLC | – | Degradation | Signaling | mTORC1 regulation | Duan et al. (2011), Gao et al. (2011) |
eEF2K | O00418 | S78 | GSPANSFHFKE | – | Inhibitory | Translation regulation | – | Wang et al. (2014) |
S396 | DSLPSSPSSAT | – | – | |||||
eIF2B | P20042 | S2 | MSGDEMI | FDIDE | Activating | Translation regulation | – | Gandin et al. (2016) |
S67 | RKKDASDDLDD | – | – | |||||
eIF4E | P06730 | S209 | ATKSGSTTKNR | – | Activating | Translation regulation | TPTPNPP Raptor-binding motif | Batool et al. (2020) |
ERα | P03372 | S104,S106 | PLNSVSPSPLMLL | FPATV | Activating | Signaling | – | Alayev et al. (2016) |
GRASP55 | Q9H8Y8 | Undetermined | – | – | Localization | Protein transport | – | Nüchel et al. (2021) |
GRB10 | Q13322-1 | S474,S476e | MNILGSQSPLHPS | – | Protein stabilization | Signaling | – | Hsu et al. (2011), Yu et al. (2011) |
HSF1 | Q00613 | S326 | VDTLLSPTALI | – | Activating | Transcription | – | Chou et al. (2012) |
IMP2 | Q9Y6M1 | S162,S164 | DEEVSSPSPPQRA | – | Activating | Translation regulation | – | Dai et al. (2011) |
IRS1 | P35568-1 | S422,S423 | DGGFISSDEYGS | – | Protein degradation | Signaling | – | Yoneyama et al. (2018) |
S636,S639 | DYMPMSPKSVSAPQ | – | Protein degradation | Signaling | SAIN domain binding to Raptor | Tzatsos (2009), Tzatsos and Kandror (2006) | ||
ISCU | Q9H1K1 | S14 | LRRAASALLLR | – | Protein stabilization | Protein folding | – | La et al. (2013) |
JMJD1C | Q15652 | T505 | VSRPPTPKCVI | – | Activating | Histone demethylase | – | Viscarra et al. (2020) |
KAP1 | Q13263 | S824 | GAGLSSQELSG | – | Inhibitory | Transcriptional repressor | – | Rauwel et al. (2015) |
LARP1 | Q6PKG0 | 26 S/T residues | – | – | Activating | TOP mRNA translation | – | Hong et al. (2017), Jia et al. (2021) |
LIPIN1 | Q14693-3 | S106 | MHLATSPILSE | – | Localization | Lipid metabolism | Rapamycin sensitive | Peterson et al. (2011) |
S470f | RSANQSPQSVG | – | Rapamycin insensitive | |||||
MAF1 | Q9H063 | S60,S68,S75 | VLEALSPPQTSGLSPSRLSKSQGGEE | – | Inhibitory | RNA polIII repressor | – | Michels et al. (2010) |
MFN2 | O95140 | S200 | LVLMDSPGIDV | – | Activating | Mitochondrial fusion | – | Li et al. (2019) |
OTUD5 | Q96G74-5 | S323,S332 | EPIRVSYHRNIHYNSVVNPN | – | Protein stabilization | Deubiquitination | mTORC1 and | Cho et al. (2021) |
S503 | ADRATSPLVSL | – | Activation | – | mTORC2 regulation | |||
NRBF2 | Q96F24 | S113,S120 | DAEGQSPLSQKYSPSTEK | – | Inhibitory | Autophagy | – | Ma et al. (2017) |
p300 | Q09472 | S2271,S2279 | QQQMGSPVQPNPMSPQQHM | – | Activating | Protein acetylation | – | Wan et al. (2017) |
S2291 | PNQAQSPHLQG | – | – | |||||
S2315 | PQPVPSPRPQS | – | – | |||||
p53 | P04637 | S15 | VEPPLSQETFS | – | Protein stabilization | Tumor suppressor | mTORC1 & mTORC2 dependent | Jung et al. (2019) |
p62 | Q13501-1 | S349g | KEVDPSTGELQ | – | Inhibitory | Autophagy | – | Ichimura et al. (2013) |
PACER | Q9H714 | S157 | GILATSPYPET | – | Inhibitory | Autophagy | – | Cheng et al. (2019) |
PASK | Q96RG2 | T640,T642 | GLSFGTPTLDEPW | – | Activating | Signaling | – | Kikani et al. (2019) |
S949,S953,S956 | RLFLASLPGSTHSTAAEL | – | – | |||||
PIP4kγ | Q8TBX8 | S324,S328 | PALVGSYGTSPEGIG | – | Inhibitory | Signaling | mTORC1 regulation | Mackey et al. (2014) |
PRAS40 | Q96B36 | S183 | QQYAKSLPVSV | FVMDE | Substrate competition | Signaling | mTORC1 regulator | Oshiro et al. (2007) |
S212,S221 | NGPPSSPDLDRIAASMRALV | – | Inhibitory | Signaling | S212 rapamycin insensitive | Wang et al. (2008) | ||
RAG-C | Q9HB90 | S21 | YGAADSFPKDF | – | mTORC1 destabilization | Signaling | Rapamycin insensitive | Yang et al. (2019) |
RAPTOR | Q8N122 | S859,S863 | SSLTQSAPASPTNKG | – | Activating | Signaling | mTORC1 core component | Foster et al. (2010), Wang et al. (2009) |
S6K1 | P23443-2h | S371 | QTPVDSPDDST | FDIDL | Priming | Signaling, translation | – | Saitoh et al. (2002) |
T389 | VFLGFTYVAPS | – | Activating | – | Burnett et al. (1998) | |||
SENP3 | Q9H4L4 | S25,S26 | IPPAYSSPRRER | – | Nucleolar localization | Ribosome biogenesis | – | Raman et al. (2014) |
S141,T142,T145 | LLYSKSTSLTFHWKL | – | – | – | – | |||
SIRT1 | Q96EB6 | S47 | PGLERSPGEPG | FDVEL | Inhibitory | Protein deacetylation | – | Back et al. (2011) |
SOD1 | P00441 | T40 | SIKGLTEGLHG | – | Inhibitory | ROS detoxification | – | Tsang et al. (2018) |
STAT3 | P40763 | S727 | IDLPMSPRTLD | – | Activating | Signaling | – | Dodd et al. (2015), Yokogami et al. (2000) |
TAU | P10636-8i | S214 | RSRTPSLPTPP | – | Aggregation | Microtubule organization | – | Tang et al. (2013) |
T231 | VAVVRTPPKSP | – | – | |||||
S356 | QSKIGSLDNIT | – | – | |||||
TFEB | P19484 | S122 | PPPAASPGVRA | – | Localization | Transcription factor | – | Vega-Rubin-de-Celis et al. (2017) |
S142 | NSAPNSPMAML | – | Rapamycin insensitive | Settembre et al. (2012) | ||||
S211 | GVTSSSCPADL | – | – | Martina et al. (2012), Roczniak-Ferguson et al. (2012) | ||||
TFE3 | P19532 | S321j | ITVSNSCPAEL | – | Inhibitory | Transcription factor | – | Martina et al. (2014) |
TRPML1 | Q9GZU1 | S572,S576 | CGRDPSEEHSLLVN | – | Inhibitory | Autophagy | – | Onyenwoke et al. (2015) |
ULK1 | O75385 | S757 | VFTVGSPPSGS | – | Inhibitory | Autophagy | – | Kim et al. (2011) |
USP20 | Q9Y2K6 | S132,S134 | ADEGESESEDDDL | – | Activating | Deubiquitination | – | Lu et al. (2020) |
UVRAG | Q9P2Y5 | S498 | SGGIPSPDKGH | – | Repressor activation | Autophagy | – | Kim et al. (2015) |
S550 | TSLSSSLDTSL | – | Activating | Autophagy | – | Munson et al. (2015) | ||
S571 | EDLVGSLNGGH | – | – | |||||
VAMP8 | Q9BV40 | T48 | HLRNKTEDLEA | – | Inhibitory | Autophagy | – | Huang et al. (2021) |
WIPI2 | Q9Y4P8-4 | S395 | TYVPSSPTRLA | – | Degradation | Autophagy | – | Wan et al. (2018) |
ZNRF2 | Q8NHG8 | S145 | RLVIGSLPAHL | – | Translocation | Signaling | mTORC1 regulation | Hoxhaj et al. (2016) |
a 有三种4EBP异构体,它们都被mTORC1在相应的部位磷酸化。
b 参考文献中的Ser347。
c 参考文献中的Ser258。
d 参考文献中的Ser509和Ser535。
e 在典范的异构体3中的位置。
f 参考文献中的Ser472位置。
g 参考文献中的Ser351。
h 阿尔法II型。
i TAU-F同源型。
j 与TFEB Ser211同源,没有体外证据表明被mTORC1直接磷酸化。
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