Reactome | Cellular response to starvation

Cellular response to starvation

Stable Identifier

R-HSA-9711097

Type

Pathway

Species

Homo sapiens

ReviewStatus

5/5

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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 Long, X, Lin, Y, Ortiz-Vega, S, Busch, S, Avruch, J	J. Biol. Chem.	2007
24529380	Regulation of TORC1 in response to amino acid starvation via lysosomal recruitment of TSC2 Demetriades, C, Doumpas, N, Teleman, AA	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 Wolfson, RL, Sabatini, DM	Cell Metab.	2017
29236692	Mechanisms of mTORC1 activation by RHEB and inhibition by PRAS40 Yang, H, Jiang, X, Li, B, Yang, HJ, Miller, M, Yang, A, Dhar, A, Pavletich, NP	Nature	2017
24732012	Keeping the eIF2 alpha kinase Gcn2 in check Castilho, BA, Shanmugam, R, Silva, RC, Ramesh, R, Himme, BM, Sattlegger, E	Biochim. Biophys. Acta	2014
23216249	Amino acid sensing in dietary-restriction-mediated longevity: roles of signal-transducing kinases GCN2 and TOR Gallinetti, J, Harputlugil, E, Mitchell, JR	Biochem. J.	2013
29311260	mTOR signaling in stem and progenitor cells Meng, D, Frank, AR, Jewell, JL	Development	2018
28797581	Surviving Stress: Modulation of ATF4-Mediated Stress Responses in Normal and Malignant Cells Wortel, IMN, van der Meer, LT, Kilberg, MS, van Leeuwen, FN	Trends Endocrinol. Metab.	2017
28686218	Lysosomal Regulation of mTORC1 by Amino Acids in Mammalian Cells Yao, Y, Jones, E, Inoki, K	Biomolecules	2017
30602761	mTOR as a central hub of nutrient signalling and cell growth Kim, J, Guan, KL	Nat. Cell Biol.	2019
20188139	Molecular mechanisms involved in the adaptation to amino acid limitation in mammals Chaveroux, C, Lambert-Langlais, S, Cherasse, Y, Averous, J, Parry, L, Carraro, V, Jousse, C, Maurin, AC, Bruhat, A, Fafournoux, P	Biochimie	2010
28546457	Amino acid homeostasis and signalling in mammalian cells and organisms Broer, S, Bröer, A	Biochem. J.	2017
15878852	Rheb binding to mammalian target of rapamycin (mTOR) is regulated by amino acid sufficiency Long, X, Ortiz-Vega, S, Lin, Y, Avruch, J	J. Biol. Chem.	2005
22585903	The transcription factor network associated with the amino acid response in mammalian cells Kilberg, MS, Balasubramanian, M, Fu, L, Shan, J	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 Zhuang, Y, Wang, XX, He, J, He, S, Yin, Y	Front Biosci (Landmark Ed)	2019
15854902	Rheb binds and regulates the mTOR kinase Long, X, Lin, Y, Ortiz-Vega, S, Yonezawa, K, Avruch, J	Curr Biol	2005
16098514	Analysis of mTOR signaling by the small G-proteins, Rheb and RhebL1 Tee, AR, Blenis, J, Proud, CG	FEBS Lett.	2005