TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms

Autor: Søren T. Christensen, Lotte B. Pedersen, Lisbeth Birk Møller, Lasse Jonsgaard Larsen, Thomas Rosengren
Rok vydání: 2017
Předmět:
0301 basic medicine
Cell signaling
congenital
hereditary
and neonatal diseases and abnormalities
Hedgehog signaling
mTORC1
Zinc Finger Protein Gli2
TGF-β signaling
Tuberous Sclerosis Complex 1 Protein
03 medical and health sciences
Cellular and Molecular Neuroscience
Primary cilia
GLI1
Tuberous Sclerosis Complex 2 Protein
Autophagy
Animals
Hedgehog Proteins
Cilia
WNT5a
Molecular Biology
Hedgehog
PI3K/AKT/mTOR pathway
Cells
Cultured
TSC
Pharmacology
Mice
Knockout
biology
Chemistry
Tumor Suppressor Proteins
Wnt signaling pathway
Cell Biology
Fibroblasts
Embryo
Mammalian
Smoothened Receptor
Hedgehog signaling pathway
Cell biology
030104 developmental biology
Gene Expression Regulation
biology.protein
mTOR
Molecular Medicine
RNA Interference
Original Article
LC3b
Smoothened
Signal Transduction
Zdroj: Cellular and Molecular Life Sciences
Rosengren, T, Larsen, L J, Pedersen, L B, Christensen, S T & Møller, L B 2018, ' TSC1 and TSC2 regulate cilia length and canonical Hedgehog signaling via different mechanisms ', Cellular and Molecular Life Sciences, vol. 75, no. 14, pp. 2663-2680 . https://doi.org/10.1007/s00018-018-2761-8
ISSN: 1420-9071
DOI: 10.1007/s00018-018-2761-8
Popis: Primary cilia are sensory organelles that coordinate multiple cellular signaling pathways, including Hedgehog (HH), Wingless/Int (WNT) and Transforming Growth Factor-β (TGF-β) signaling. Similarly, primary cilia have been implicated in regulation of mTOR signaling, in which Tuberous Sclerosis Complex proteins 1 and 2 (TSC1/2) negatively regulate protein synthesis by inactivating the mTOR complex 1 (mTORC1) at energy limiting states. Here we report that TSC1 and TSC2 regulate Smoothened (SMO)-dependent HH signaling in mouse embryonic fibroblasts (MEFs). Reduced SMO-dependent expression of Gli1 was demonstrated in both Tsc1−/− and Tsc2−/− cells, and we found that Tsc1 is required for TGF-β induced phosphorylation of SMAD2/3 and subsequent expression of the HH signaling effector and transcription factor GLI2. Hedgehog signaling was restored in Tsc1−/− cells after exogenous expression of Gli2, whereas rapamycin restored HH signaling in Tsc2−/− cells. Furthermore, we observed that Tsc1−/− MEFs display significantly elongated cilia, whereas cilia in Tsc2−/− MEFs were shorter than normal. The elongated cilium phenotype of Tsc1−/− MEFs is likely due to increased mTORC1-dependent autophagic flux observed in these cells, as both the autophagic flux and the cilia length phenotype was restored by rapamycin. In addition, ciliary length control in Tsc1−/− MEFs was also influenced by reduced expression of Gli2, which compromised expression of Wnt5a that normally promotes cilia disassembly. In summary, our results support distinct functions of Tsc1 and Tsc2 in cellular signaling as the two genes affect ciliary length control and HH signaling via different mechanisms. Electronic supplementary material The online version of this article (10.1007/s00018-018-2761-8) contains supplementary material, which is available to authorized users.
Databáze: OpenAIRE
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