Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling
- Stanford University School of Medicine, United States
- The Francis Crick Institute, United Kingdom
- University of Oxford, United Kingdom
- Washington University School of Medicine, United States
Abstract
Cholesterol is necessary for the function of many G-protein coupled receptors (GPCRs). We find that cholesterol is not just necessary but also sufficient to activate signaling by the Hedgehog (Hh) pathway, a prominent cell-cell communication system in development. Cholesterol influences Hh signaling by directly activating Smoothened (SMO), an orphan GPCR that transmits the Hh signal across the membrane in all animals. Unlike most GPCRs, which are regulated by cholesterol through their heptahelical transmembrane domains, SMO is activated by cholesterol through its extracellular cysteine-rich domain (CRD). Residues shown to mediate cholesterol binding to the CRD in a recent structural analysis also dictate SMO activation, both in response to cholesterol and to native Hh ligands. Our results show that cholesterol can initiate signaling from the cell surface by engaging the extracellular domain of a GPCR and suggest that SMO activity may be regulated by local changes in cholesterol abundance or accessibility.
Article and author information
Author details
Funding
National Institutes of Health (GM106078, HL067773)
- Douglas F Covey
- Rajat Rohatgi
Cancer Research UK (C20724/A14414)
- Christian Siebold
Taylor Family institute for Psychiatric Research
- Douglas F Covey
Ford Foundation
- Giovanni Luchetti
National Science Foundation
- Sigrid Nachtergaele
Nuffield Department of Medicine, Oxford University
- Eamon FX Byrne
EMBO LTF (1438-2013)
- Andreas Sagner
HFSP LTF (LT000401/2014-L)
- Andreas Sagner
People Programme of the EU's Seventh Framework Programme (FP7-2013)
- Andreas Sagner
The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.
Copyright
© 2016, Luchetti et al.
This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.
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Cholesterol activates the G-protein coupled receptor Smoothened to promote morphogenetic signaling
eLife 5:e20304.
https://doi.org/10.7554/eLife.20304
Further reading
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- Biochemistry and Chemical Biology
- Developmental Biology
Cholesterol can regulate the Hedgehog signalling pathway by directly binding to a receptor on the cell surface.
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- Biochemistry and Chemical Biology
In healthy cells, cyclin D1 is expressed during the G1 phase of the cell cycle, where it activates CDK4 and CDK6. Its dysregulation is a well-established oncogenic driver in numerous human cancers. The cancer-related function of cyclin D1 has been primarily studied by focusing on the phosphorylation of the retinoblastoma (RB) gene product. Here, using an integrative approach combining bioinformatic analyses and biochemical experiments, we show that GTSE1 (G-Two and S phases expressed protein 1), a protein positively regulating cell cycle progression, is a previously unrecognized substrate of cyclin D1–CDK4/6 in tumor cells overexpressing cyclin D1 during G1 and subsequent phases. The phosphorylation of GTSE1 mediated by cyclin D1–CDK4/6 inhibits GTSE1 degradation, leading to high levels of GTSE1 across all cell cycle phases. Functionally, the phosphorylation of GTSE1 promotes cellular proliferation and is associated with poor prognosis within a pan-cancer cohort. Our findings provide insights into cyclin D1’s role in cell cycle control and oncogenesis beyond RB phosphorylation.
