{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,8,18]],"date-time":"2026-08-18T15:31:12Z","timestamp":1787067072713,"version":"build-2736575974"},"reference-count":40,"publisher":"Life Science Alliance, LLC","issue":"11","license":[{"start":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T00:00:00Z","timestamp":1724630400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Independent Research Fund Denmark","award":["12-127196 #0602-02725B"],"award-info":[{"award-number":["12-127196 #0602-02725B"]}]}],"content-domain":{"domain":["life-science-alliance.org"],"crossmark-restriction":true},"short-container-title":["Life Sci. Alliance"],"accepted":{"date-parts":[[2024,8,16]]},"published-print":{"date-parts":[[2024,11]]},"abstract":"<jats:p>\n                    The mTORC1-complex is negatively regulated by TSC1 and TSC2. Activation of Hedgehog signaling is strictly dependent on communication between Smoothened and the Hedgehog-signaling effector and transcription factor, GLI2, in the primary cilium. Details about this communication are not known, and we wanted to explore this further. Here we report that in\n                    <jats:italic>Tsc2<\/jats:italic>\n                    <jats:sup>\n                      <jats:italic>\u2212\/\u2212<\/jats:italic>\n                    <\/jats:sup>\n                    MEFs constitutively activated mTORC1 led to mis-localization of Smoothened to the plasma membrane, combined with increased concentration of GLI2 in the cilia and reduced Hedgehog signaling, measured by reduced expression of the Hedgehog target gene,\n                    <jats:italic>Gli1<\/jats:italic>\n                    . Inhibition of mTORC1 rescued the cellular localization of Smoothened to the cilia, reduced the cilia concentration of GLI2, and restored Hedgehog signaling. Our results reveal evidence for a two-step activation process of GLI2. The first step includes GLI2 stabilization and cilium localization, whereas the second step includes communication with cilia-localized Smoothened. We found that mTORC1 inhibits the second step. This is the first demonstration that mTORC1 is involved in the regulation of Hedgehog signaling.\n                  <\/jats:p>","DOI":"10.26508\/lsa.202302419","type":"journal-article","created":{"date-parts":[[2024,8,26]],"date-time":"2024-08-26T13:35:16Z","timestamp":1724679316000},"page":"e202302419","update-policy":"https:\/\/doi.org\/10.26508\/lsa.crossmarkpolicy","source":"Crossref","is-referenced-by-count":3,"title":["mTORC1 hampers Hedgehog signaling in\n                    <i>Tsc2<\/i>\n                    deficient cells"],"prefix":"10.26508","volume":"7","author":[{"given":"Lasse Jonsgaard","family":"Larsen","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03mchdq19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet","place":[", Glostrup, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elsebet","family":"\u00d8stergaard","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03mchdq19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet","place":[", Glostrup, Denmark"]},{"name":"Department of Clinical Medicine, University of Copenhagen, Copenhagen, Denmark"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9524-4301","authenticated-orcid":true,"given":"Lisbeth Birk","family":"M\u00f8ller","sequence":"additional","affiliation":[{"id":[{"id":"https:\/\/ror.org\/03mchdq19","id-type":"ROR","asserted-by":"publisher"}],"name":"Department of Genetics, Kennedy Center, Copenhagen University Hospital, Rigshospitalet","place":[", Glostrup, Denmark"]}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"12380","published-online":{"date-parts":[[2024,8,26]]},"reference":[{"key":"2024110107452952000_7.11.e202302419.1","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddn325"},{"key":"2024110107452952000_7.11.e202302419.2","doi-asserted-by":"publisher","DOI":"10.1093\/hmg\/ddi260"},{"key":"2024110107452952000_7.11.e202302419.3","doi-asserted-by":"publisher","DOI":"10.1042\/BJ20080281"},{"key":"2024110107452952000_7.11.e202302419.4","doi-asserted-by":"publisher","DOI":"10.3390\/cancers11101422"},{"key":"2024110107452952000_7.11.e202302419.5","unstructured":"Northrup H , FACMG, Koenig MK , Pearson DA , Au KS (2021) Tuberous Sclerosis Complex. 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