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mTORC1 hampers Hedgehog signaling in Tsc2 deficient cells.
- Source :
-
Life science alliance [Life Sci Alliance] 2024 Aug 26; Vol. 7 (11). Date of Electronic Publication: 2024 Aug 26 (Print Publication: 2024). - Publication Year :
- 2024
-
Abstract
- 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 Tsc2 <superscript> -/- </superscript> 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, Gli1 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.<br /> (© 2024 Larsen et al.)
- Subjects :
- Animals
Mice
Cell Membrane metabolism
Cilia metabolism
Fibroblasts metabolism
Kruppel-Like Transcription Factors metabolism
Kruppel-Like Transcription Factors genetics
Mice, Knockout
Zinc Finger Protein GLI1 metabolism
Zinc Finger Protein GLI1 genetics
Hedgehog Proteins metabolism
Hedgehog Proteins genetics
Mechanistic Target of Rapamycin Complex 1 metabolism
Signal Transduction
Smoothened Receptor metabolism
Smoothened Receptor genetics
Tuberous Sclerosis Complex 2 Protein metabolism
Tuberous Sclerosis Complex 2 Protein genetics
Tumor Suppressor Proteins metabolism
Tumor Suppressor Proteins genetics
Zinc Finger Protein Gli2 metabolism
Zinc Finger Protein Gli2 genetics
Subjects
Details
- Language :
- English
- ISSN :
- 2575-1077
- Volume :
- 7
- Issue :
- 11
- Database :
- MEDLINE
- Journal :
- Life science alliance
- Publication Type :
- Academic Journal
- Accession number :
- 39187374
- Full Text :
- https://doi.org/10.26508/lsa.202302419