Cellular response to starvation

Stable Identifier
Homo sapiens
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Deprivation of nutrients triggers diverse short- and long terms adaptations in cells. Here we have annotated two aspects of cellular responses to amino acid deprivation, ones mediated by EIF2AK4 and ones mediated by mTORC.

EIF2AK4 (GCN2) senses amino acid deficiency by binding uncharged tRNAs near the ribosome, and phosphorylating EIF2S1 (reviewed in Chaveroux et al. 2010, Castilho et al. 2014, Gallinetti et al. 2013, Bröer and Bröer 2017, Wek 2018). This reduces translation of most mRNAs but increases translation of mRNAs, notably ATF4, that mediate stress responses (reviewed in Kilberg et al. 2012, Wortel et al. 2017; Dever and Hinnebusch 2005).

The mTORC1 complex acts as an integrator that regulates translation, lipid synthesis, autophagy, and cell growth in response to multiple inputs, notably glucose, oxygen, amino acids, and growth factors such as insulin (reviewed in Sabatini 2017, Meng et al. 2018, Kim and Guan 2019).

MTOR, the kinase subunit of mTORC1, is activated by interaction with RHEB:GTP at the cytosolic face of lysosomal membrane (Long et al. 2005, Tee et al. 2005, Long et al. 2007, Yang et al. 2017). This process is regulated by various individual amino acids (reviewed in Zhuang et al. 2019, Wolfson and Sabatini 2017, Yao et al. 2017) and is reversed in response to the removal of amino acids, through the action of TSC1 (Demetriades et al. 2014).
Literature References
PubMed ID Title Journal Year
17470430 The Rheb switch 2 segment is critical for signaling to target of rapamycin complex 1

Busch, S, Lin, Y, Long, X, Avruch, J, Ortiz-Vega, S

J. Biol. Chem. 2007
24529380 Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2

Demetriades, C, Teleman, AA, Doumpas, N

Cell 2014
29078414 Twenty-five years of mTOR: Uncovering the link from nutrients to growth

Sabatini, DM

Proc. Natl. Acad. Sci. U.S.A. 2017
28768171 The Dawn of the Age of Amino Acid Sensors for the mTORC1 Pathway

Sabatini, DM, Wolfson, RL

Cell Metab. 2017
29236692 Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40

Yang, A, Yang, HJ, Jiang, X, Li, B, Pavletich, NP, Yang, H, Dhar, A, Miller, M

Nature 2017
24732012 Keeping the eIF2 alpha kinase Gcn2 in check

Shanmugam, R, Himme, BM, Sattlegger, E, Silva, RC, Ramesh, R, Castilho, BA

Biochim. Biophys. Acta 2014
23216249 Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR

Mitchell, JR, Gallinetti, J, Harputlugil, E

Biochem. J. 2013
29311260 mTOR signaling in stem and progenitor cells

Frank, AR, Meng, D, Jewell, JL

Development 2018
28797581 Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells

Kilberg, MS, van der Meer, LT, Wortel, IMN, van Leeuwen, FN

Trends Endocrinol. Metab. 2017
28686218 Lysosomal Regulation of mTORC1 by Amino Acids in Mammalian Cells

Inoki, K, Yao, Y, Jones, E

Biomolecules 2017
30602761 mTOR as a central hub of nutrient signalling and cell growth

Guan, KL, Kim, J

Nat. Cell Biol. 2019
20188139 Molecular mechanisms involved in the adaptation to amino acid limitation in mammals

Bruhat, A, Cherasse, Y, Fafournoux, P, Carraro, V, Lambert-Langlais, S, Chaveroux, C, Jousse, C, Averous, J, Maurin, AC, Parry, L

Biochimie 2010
28546457 Amino acid homeostasis and signalling in mammalian cells and organisms

Bröer, A, Broer, S

Biochem. J. 2017
15878852 Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency

Lin, Y, Long, X, Avruch, J, Ortiz-Vega, S

J. Biol. Chem. 2005
22585903 The transcription factor network associated with the amino acid response in mammalian cells

Kilberg, MS, Balasubramanian, M, Shan, J, Fu, L

Adv Nutr 2012
29440070 Role of eIF2α Kinases in Translational Control and Adaptation to Cellular Stress

Wek, RC

Cold Spring Harb Perspect Biol 2018
15837415 GCN2 whets the appetite for amino acids

Dever, TE, Hinnebusch, AG

Mol. Cell 2005
30844724 Recent advances in understanding of amino acid signaling to mTORC1 activation

Wang, XX, Zhuang, Y, Yin, Y, He, J, He, S

Front Biosci (Landmark Ed) 2019
15854902 Rheb binds and regulates the mTOR kinase

Yonezawa, K, Ortiz-Vega, S, Avruch, J, Lin, Y, Long, X

Curr Biol 2005
16098514 Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1

Proud, CG, Blenis, J, Tee, AR

FEBS Lett. 2005
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