Identification of a Conserved Motif Required for mTOR Signaling
Authors: Stefanie S Schalm
John Blenis
Journal: Current Biology (2002)
Discipline: BIOLOGY & BIOCHEMISTRY
Keywords: mammalian target of rapamycin (mTOR); S6 kinases; 4E-BP; TOS motif; phosphorylation

Abstract:  Background: The mammalian target of rapamycin (mTOR) controls the translation machinery via activation of S6 kinases 1 and 2 (S6K1/2) and inhibition of the eukaryotic initiation factor 4E (eIF4E) binding proteins 1, 2, and 3 (4E-BP1/2/3). S6K1 and 4E-BP1 are regulated by nutrient-sensing and mitogen-activated pathways. The molecular basis of mTOR regulation of S6K1 and 4E-BP1 remains controversial. Results: We have identified a conserved TOR signaling (TOS) motif in the N terminus of all known S6 kinases and in the C terminus of the 4E-BPs that is crucial for phosphorylation and regulation S6K1 and 4E-BP1 activities. Deletion or mutations within the TOS motif significantly inhibit S6K1 activation and the phosphorylation of its hydrophobic motif, Thr389. In addition, this sequence is required to suppress an inhibitory activity mediated by the S6K1 C terminus. The TOS motif is essential for S6K1 activation by mTOR, as mutations in this motif mimic the effect of rapamycin on S6K1 phosphorylation, and render S6K1 insensitive to changes in amino acids. Furthermore, only overexpression of S6K1 with an intact TOS motif prevents 4E-BP1 phosphorylation by a common mTOR-regulated modulator of S6K1 and 4E-BP1. Conclusions: S6K1 and 4E-BP1 contain a conserved five amino acid sequence (TOS motif) that is crucial for their regulation by the mTOR pathway. mTOR seems to regulate S6K1 by two distinct mechanisms. The TOS motif appears to function as a docking site for either mTOR itself or a common upstream activator of S6K1 and 4E-BP1. 

Retracted: No

PubPeer comments:
 Who had  Bizarrely inappropriate references in their Bingo card?  Cysteine proteases, (Gingipains), are P. gingivalisu2019 main factors of virulence, which have vital significant function in the regulating the synthesis of extracellular membrane proteins, biofilm formation as well as evasion of the cell host defense [4]. - [4]. S. Guo, R. Chen, H. Li, T. Zhang, and Y. Liu (2019). Int. J. Softw. Eng. Knowl. 29, 139. ** Identify Severity Bug Report with Distribution Imbalance by CR-SMOTE and ELM **  Cysteine proteases are coded by two different kinds of genes in the bacteria, one is arginine-specific regulated by rgp and another is lysine-specific coded by kgp [5]. - [5]. D. Yuan, C. Zhang, S. Tang, X. Li, J. Tang, Y. Rao, Z. Wang, and Q. Zhang (2019). Water Res. 163, 114861. ** Enhancing CaO2 fenton-like process by Fe(II)-oxalic acid complexation for organic wastewater treatment ** , 
 This is one of a large number of coordination-chemistry papers that appear to have all been written according to a template. - Most draw on two papers by Y. Feng et al. and one by C.-W. Duan et al to illustrate the broad range of applications and properties of MOFs. Notably, these are not papers about MOFs. - - Y. Feng, H. Fan, Z. Zhong, H. Wang, D. Qiu, Inorg. Chem. 2016, 55, 11987u201311992.  Cd3(MoO4)(TeO3)2: A Polar 3D Compound Containing d10-d0 SCALP-Effect Cations - - Y. Feng, M. Li, H. Fan, Q. Huang, D. Qiu, H. Shi, Dalton Trans. 2015, 44, 894u2013897.  A Novel Open-Framework Copper Borophosphate Containing 1-D Borophosphate Anion with 10-MR Windows and 12-MR Channels - - C. W. Duan, L. X. Hu, J. L. Ma, J. Mater. Chem. A 2018, 6, 6309u20136318  Ionic liquids as an efficient medium for the mechanochemical synthesis of u03b1-AlH3 nano-composites - The cluster is sometimes accompanied by less relevant references and clusters of references. Frequently co-occuring papers include - - Duan CW, Cao YZ, Hu LX, Fu D, Ma JL (2019)  Synergistic effect of TiF3 on the dehydriding property of a-AlH3 nano-composite . - - K. Wang, J. Pang, L. Li, S. Zhou, Y. Li, T. Zhang, Front. Chem. Sci. Eng. 2018, 12, 376u2013382.  Synthesis of hydrophobic carbon nanotubes reduced graphene oxide composite films by flash light irradiation - - K. Wu, K. Du, G. Hu, J. Mater. Chem. A 2018, 6, 1057u20131066  Red-blood-cell-like (NH4) [Fe2(OH)(PO4)2]u00b72H2O particles: Fabrication and application in high-performance LiFePO4 cathode materials - - Yin K, Chu DK, Dong XR, Wang C, Duan JA, He J (2017)  Femtosecond laser induced robust periodic nanoripples structured mesh for highly efficient oil-water separation . Nanoscale 9:14229u201314235. - - Davila-Manzanilla SG, Figueroa-de-Paz Y, Mejia C, Ruiz-Azuara L (2017)  Synergistic effects between a copper-based metal Casiopeu00edna III-Ia and cisplatin . Eur J Med Chem 129:266u2013274 - The vast majority of email identities for corresponding authors were formed by taking an underscore-separated name and appending **666** or 66 . I am advised that these are auspicious numbers with positive associations. So one possibility is that the authors all decided independently to generate email accounts with this format. The alternative is that *some outside contractor* handled the task of negotiating with journals (generating these disposable accounts in the process) - perhaps also the task of writing the manuscripts, using a single Bibliography file to save time. The complete list [is here] . , 
  In short, the *P. gingivalis* was cultured in **rain heart infusion (BHI)** broth added with hemin and menadione (HM) the anaerobic chamber (CO2 of 10%, H2 of 10% as well as N2 of 80%), then we inoculated bacterial suspension into 96-well plates (3595, Corning, New York, NY). The misspelling of  Brain Heart Infusion as  Rain Heart Infusion is largely confined to this literature of medical applications for coordinate polymers. It is possible that the similarity of wording in the various manifestations of the term are merely coincidental. Alternatively, they could all be [products of a papermill] .  Two coordination polymers: treatment activity on the bacterial infection in the hemodialysis patients via inhibiting Staphylococcus aureus survival ([Zhang et al 2020] : -  Briefly, [S. aureus] was incubated in rain heart infusion (BHI) broth at an 37 C, 5% CO2, then the CFU bacterial cells of 1 x 10^4 were collected and inoculated into plates of 96-well. After that, treatment with 1 or 2 took place for 24 h incubation.  TWO NEW Co(II)-BASED COORDINATION POLYMERS: CRYSTAL STRUCTURES AND TREATMENT ACTIVITY ON ACUTE BACTERIAL SINUSITIS BY INHIBITING MRSA BACTERIAL GROWTH ([Zhu et al 2020] ): -  In brief, the MRSA cells in the logarithmic growth phase were collected and incubated in the rain heart infusion (BHI) broth. All the bacterial cells were cultured at 37 C, then 1u00b710 4 CFU MRSA bacterial cells were seeded into 96-well plates (3595, Corning, New York, NY) and u2026  Two new Zn(II) and Ni(II) coordination polymers: treatment effect on acute bacterial sinusitis by inhibiting the methicillin resistant Staphylococcus aureus growth ([Li et al 2021] ): -  Briefly, the MRSA was incubated in rain heart infusion (BHI) broth at an 37 C condition, then 1 u00d7 10 4 CFU bacterial cells were seeded into 96-well plates (3595, Corning, New York, NY) with 5 mg mL of compound 1 or 2 for 24 incubation.  A new porous Co(II)u2010coordination polymer for the chemical fixation of CO 2 and treatment effect against tuberculosis by reducing the pckA expression in Mycobacterium tuberculosis ([Yan et al 2020] ): -  In sum, *M. tuberculosis* ATCC 25177 was incubated in rain heart infusion (BHI) broth at 37 C. After M.TB entered the logarithmic growth phase, 1 u00d7 104 CFU M.TB were inoculated into 96-well plates (3595, Corning, NY, USA) and treated with compounds of the indicated concentration for 1 day.  A fluorescent Zn(II)-containing coordination polymer for antibiotic sensing and treatment activity on periodontal tissue inflammation after orthodontics by inhibiting the growth of Porphyromonas gingivalis ([Niu et al 2020] ): -  In brief, the *P. gingivalis* ATCC 33277 was incubated in rain heart infusion (BHI) broth at an anaerobic condition (80% N2, 10% H2, and 10% CO2). 1 u00d7 10^4 CFU bacterial cells were seeded into 96-well plates (3595, Corning, New York, NY) with indication concentration of compound for 24 treatment. ,