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Emerging evidence suggests that mTORC1 can respond to upstream signals in a nuanced manner, enabling differential regulation of individual substrates and, consequently, specific downstream biological processes. Phosphorylation of non-canonical mTORC1 substrates, such as the lysosome biogenesis regulator transcription factor EB (TFEB), can be regulated independently of phosphorylation of canonical substrates. However, the nature of signals that determine the signaling selectivity of mTORC1 remains incompletely understood. Here, we studied mTORC1 regulation by G protein-coupled receptors (GPCRs). We found that phosphorylation of TFEB responds to GPCRs differently compared with canonical mTORC1 substrates controlling protein synthesis, such as S6K1 and 4EBP1. In particular, the muscarinic acetylcholine receptor M5 (M5R) promoted phosphorylation of S6K1 and 4EBP1 while triggering TFEB dephosphorylation. Consequently, M5R stimulated protein synthesis without inhibiting lysosome biogenesis. mTORC1 can thus separately regulate anabolic and catabolic processes under the control of M5R. The present study highlights the importance of reassessing the effects of GPCRs on mTORC1 by concurrently monitoring individual substrates, a critical consideration to be made when evaluating GPCR ligands as therapeutic agents targeting the mTORC1 pathway.<\/jats:p>","DOI":"10.1042\/bcj20260165","type":"journal-article","created":{"date-parts":[[2026,8,20]],"date-time":"2026-08-20T05:05:57Z","timestamp":1787202357000},"page":"1817-1834","update-policy":"https:\/\/doi.org\/10.1042\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Substrate-specific regulation of the mTORC1 pathway by G protein-coupled receptors"],"prefix":"10.1042","volume":"483","author":[{"given":"Samuel\u00a0J.","family":"Atkinson","sequence":"first","affiliation":[{"name":"1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Florentina","family":"Negoita","sequence":"additional","affiliation":[{"name":"2Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yuichiro","family":"Ioi","sequence":"additional","affiliation":[{"name":"3Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William\u00a0V.","family":"Ritchie","sequence":"additional","affiliation":[{"name":"1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kyle","family":"Thompson","sequence":"additional","affiliation":[{"name":"1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Max","family":"Gardner","sequence":"additional","affiliation":[{"name":"1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Peter\u00a0T.","family":"Ashdown","sequence":"additional","affiliation":[{"name":"1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kristina","family":"Hellberg","sequence":"additional","affiliation":[{"name":"2Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terunao","family":"Takahara","sequence":"additional","affiliation":[{"name":"3Graduate School of Bioagricultural Sciences, Nagoya University, Furo-cho, Chikusa-ku, Nagoya 464-8601, Japan"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kei","family":"Sakamoto","sequence":"additional","affiliation":[{"name":"2Novo Nordisk Foundation Center for Basic Metabolic Research, University of Copenhagen, Copenhagen, 2200, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Dawn","family":"Thompson","sequence":"additional","affiliation":[{"name":"1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4829-7531","authenticated-orcid":false,"given":"James\u00a0N.","family":"Hislop","sequence":"additional","affiliation":[{"name":"1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3065-6639","authenticated-orcid":false,"given":"Riko","family":"Hatakeyama","sequence":"additional","affiliation":[{"name":"1Institute of Medical Sciences, School of Medicine, Medical Sciences & Nutrition, University of Aberdeen, Foresterhill, Aberdeen AB25 2ZD, U.K."}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"288","published-online":{"date-parts":[[2026,9,3]]},"reference":[{"key":"2026090304364343800_B1","doi-asserted-by":"publisher","first-page":"155","DOI":"10.1038\/nrm3757","article-title":"Making new contacts: The mTOR network in metabolism and signalling crosstalk","volume":"15","author":"Shimobayashi","year":"2014","journal-title":"Nat. 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