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The nodules arise by metastasis of cells that exhibit features of neural crest and smooth muscle lineage (LAM cells). Their aberrant growth is attributed to increased activity of mechanistic target of rapamycin complex 1 (mTORC1), an anabolic protein kinase that is normally suppressed by the TSC1-TSC2 protein complex. The mTORC1 inhibitor rapamycin slows the progression of LAM but fails to eradicate disease, indicating a role for mTORC1-independent mechanisms in LAM pathogenesis. Our previous studies revealed G protein\u2013coupled urotensin-II receptor (UT) signaling as a candidate mechanism, but how it promotes oncogenic signaling in TSC2-deficient cells remained unknown. Using a human pluripotent stem cell\u2013derived in vitro model of LAM, we now show hyperactivation of UT, which was required for their enhanced migration and proneoplastic signaling in a rapamycin-insensitive mechanism that required heterotrimeric G\u03b1q\/11 (G\u03b1q). Bioluminescence resonance energy transfer assays in HEK 293T cells lacking TSC2 demonstrated selective and enhanced activation of G\u03b1q and its RhoA-associated effectors compared with wild-type control cells. By immunoprecipitation, recombinant UT was physically associated with G\u03b1q and TSC2. The augmented G\u03b1q signaling in TSC2-deleted cells was independent of mTOR activity and associated with increased endosomal targeting of p63RhoGEF, a known RhoA-activating effector of G\u03b1q. These studies identify potential mTORC1-independent proneoplastic mechanisms that can be targeted for prevention or eradication of pulmonary and extrapulmonary LAM tumors.<\/jats:p>","DOI":"10.1165\/rcmb.2024-0111oc","type":"journal-article","created":{"date-parts":[[2024,11,8]],"date-time":"2024-11-08T12:48:59Z","timestamp":1731070139000},"page":"578-590","update-policy":"https:\/\/doi.org\/10.1164\/crossmarkpolicies","source":"Crossref","is-referenced-by-count":4,"title":["Enhanced G\u03b1q Signaling in\n                    <i>TSC2<\/i>\n                    -Deficient Cells Is Required for Their Neoplastic Behavior"],"prefix":"10.1093","volume":"72","author":[{"given":"Aur\u00e9lie","family":"Tr\u00e9fier","sequence":"first","affiliation":[{"name":"Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nihad","family":"Tousson-Abouelazm","sequence":"additional","affiliation":[{"name":"Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program"},{"name":"Department of Clinical Pharmacology, Faculty of Medicine, Alexandria University, Alexandria, Egypt"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lama","family":"Yamani","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Sajida","family":"Ibrahim","sequence":"additional","affiliation":[{"name":"Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Kwang-bo","family":"Joung","sequence":"additional","affiliation":[{"name":"Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam","family":"Pietrobon","sequence":"additional","affiliation":[{"name":"The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada"},{"name":"Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada"},{"name":"Ottawa Institute of Systems Biology, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julien","family":"Yockell-Lelievre","sequence":"additional","affiliation":[{"name":"The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada"},{"name":"Ottawa Institute of Systems Biology, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Terence E.","family":"H\u00e9bert","sequence":"additional","affiliation":[{"name":"Department of Pharmacology and Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Reese J.","family":"Ladak","sequence":"additional","affiliation":[{"name":"Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Tomoko","family":"Takano","sequence":"additional","affiliation":[{"name":"Metabolic Disorders and Complications Program, Research Institute of the McGill University Health Centre, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Mark","family":"Nellist","sequence":"additional","affiliation":[{"name":"Department of Clinical Genetics, Erasmus MC, Rotterdam, the Netherlands; and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Yoon","family":"Namkung","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"David","family":"Chatenet","sequence":"additional","affiliation":[{"name":"Institut National de la Recherche Scientifique, Centre Armand-Frappier Sant\u00e9 Biotechnologie, Groupe de Recherche en Ing\u00e9nierie des Peptides et en Pharmacoth\u00e9rapie (GRIPP), Universit\u00e9 du Qu\u00e9bec, Laval, Qu\u00e9bec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"William L.","family":"Stanford","sequence":"additional","affiliation":[{"name":"The Sprott Centre for Stem Cell Research, Regenerative Medicine Program, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada"},{"name":"Department of Cellular and Molecular Medicine, University of Ottawa, Ottawa, Ontario, Canada"},{"name":"Ottawa Institute of Systems Biology, Ottawa, Ontario, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Stephane A.","family":"Laporte","sequence":"additional","affiliation":[{"name":"Department of Medicine, and"},{"name":"Department of Pharmacology and Therapeutics"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2980-8540","authenticated-orcid":false,"given":"Arnold S.","family":"Kristof","sequence":"additional","affiliation":[{"name":"Meakins-Christie Laboratories and Translational Research in Respiratory Diseases Program"},{"name":"Department of Medicine, and"},{"name":"Respiratory Division, Department of Medicine, and"},{"name":"Department of Critical Care Medicine, Faculty of Medicine, McGill University, Montreal, Quebec, Canada"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"286","published-online":{"date-parts":[[2025,5,1]]},"reference":[{"key":"2026012204172691800_bib1","doi-asserted-by":"crossref","first-page":"16035","DOI":"10.1038\/nrdp.2016.35","article-title":"Tuberous sclerosis complex","volume":"2","author":"Henske","year":"2016","journal-title":"Nat Rev Dis Primers"},{"key":"2026012204172691800_bib2","doi-asserted-by":"crossref","first-page":"813","DOI":"10.1016\/B978-0-444-64076-5.00052-1","article-title":"Tuberous sclerosis complex","volume":"148","author":"Hasbani","year":"2018","journal-title":"Handb Clin Neurol"},{"key":"2026012204172691800_bib3","doi-asserted-by":"crossref","first-page":"1259","DOI":"10.1016\/S0960-9822(03)00506-2","article-title":"Tuberous sclerosis complex gene products, Tuberin and Hamartin, control mTOR signaling by acting as a GTPase-activating protein complex toward Rheb","volume":"13","author":"Tee","year":"2003","journal-title":"Curr Biol"},{"key":"2026012204172691800_bib4","doi-asserted-by":"crossref","first-page":"30958","DOI":"10.1074\/jbc.M202678200","article-title":"Tuberin regulates p70 S6 kinase activation and ribosomal protein S6 phosphorylation. 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