{"doi":"10.1016/j.jbc.2022.102030","title":"Prolonged deprivation of arginine or leucine induces PI3K/Akt-dependent reactivation of mTORC1","abstract":"The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids, which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach. The mechanistic target of rapamycin complex 1 (mTORC1) is a serine/threonine kinase complex that promotes anabolic processes including protein, lipid, and nucleotide synthesis, while suppressing catabolic processes such as macroautophagy. mTORC1 activity is regulated by growth factors and amino acids, which signal through distinct but integrated molecular pathways: growth factors largely signal through the PI3K/Akt-dependent pathway, whereas the availabilities of amino acids leucine and arginine are communicated to mTORC1 by the Rag-GTPase pathway. While it is relatively well described how acute changes in leucine and arginine levels affect mTORC1 signaling, the effects of prolonged amino acid deprivation remain less well understood. Here, we demonstrate that prolonged deprivation of arginine and/or leucine leads to reactivation of mTORC1 activity, which reaches activation levels similar to those observed in nutrient-rich conditions. Surprisingly, we find that this reactivation is independent of the regeneration of amino acids by canonical autophagy or proteasomal degradation but is dependent on PI3K/Akt signaling. Together, our data identify a novel crosstalk between the amino acid and PI3K/Akt signaling pathways upstream of mTORC1. These observations extend our understanding of the role of mTORC1 in growth-related diseases and indicate that dietary intervention by removal of leucine and/or arginine may be an ineffective therapeutic approach. In order for cells to maintain homeostasis in an ever-changing environment, cells need to carefully balance anabolic reactions with catabolic reactions. This is largely orchestrated by the mechanistic target of rapamycin complex 1 (mTORC1), a highly evolutionarily conserved serine/threonine kinase complex that promotes growth-favoring processes, including protein translation, lipid synthesis, and nucleotide biosynthesis, under conditions of nutrient sufficiency (1Kim J. Guan K.-L. mTOR as a central hub of nutrient signalling and cell growth.Nat. Cell Biol. 2019; 21: 63-71Crossref PubMed Scopus (591) Google Scholar, 2Liu G.Y. Sabatini D.M. mTOR at the nexus of nutrition, growth, ageing and disease.Nat. Rev. Mol. Cell Biol. 2020; 21: 183-203Crossref PubMed Scopus (1203) Google Scholar, 3González A. Hall M.N. Nutrient sensing and TOR signaling in yeast and mammals.EMBO J. 2017; 36: 397-408Crossref PubMed Scopus (453) Google Scholar, 4Ben-Sahra I. Manning B.D. mTORC1 signaling and the metabolic control of cell growth.Curr. Opin. Cell Biol. 2017; 45: 72","journal":"Journal of Biological Chemistry","year":2022,"id":244545,"datarank":0.5050943744979712,"base_score":3.367295829986474,"endowment":3.367295829986474,"self_citation_contribution":0.5050943744979712,"citation_network_contribution":0.0,"self_endowment_contribution":0.5050943744979712,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":28,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9516,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2022-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":878978,"name":"Huy Q. Dang","orcid":null,"position":1,"is_corresponding":false},{"id":3257,"name":"John M. Asara","orcid":"0000-0001-7450-2589","position":2,"is_corresponding":false},{"id":85690,"name":"John Blenis","orcid":"0000-0003-3622-2337","position":3,"is_corresponding":false},{"id":295482,"name":"Anders P. Mutvei","orcid":"0000-0002-2498-5225","position":4,"is_corresponding":false},{"id":325212,"name":"Gwen R. Buel","orcid":"0000-0003-2917-3055","position":0,"is_corresponding":true}],"reference_count":42,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T00:23:30.364338Z","pmid":"35577075","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}