Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling
| Autor: | Christian Siebold, Giovanni Luchetti, Rajat Rohatgi, Andreas Sagner, Sigrid Nachtergaele, Jennifer H. Kong, Ria Sircar, Eamon F. X. Byrne, Douglas F. Covey |
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| Jazyk: | angličtina |
| Rok vydání: | 2016 |
| Předmět: |
0301 basic medicine
QH301-705.5 Science Cell Biology General Biochemistry Genetics and Molecular Biology Cell membrane 03 medical and health sciences 0302 clinical medicine medicine Biology (General) Hedgehog G protein-coupled receptor Regulation of gene expression General Immunology and Microbiology General Neuroscience cholesterol General Medicine hedgehog signaling Hedgehog signaling pathway 3. Good health Cell biology 030104 developmental biology medicine.anatomical_structure Biochemistry G-protein coupled receptor Medicine lipids (amino acids peptides and proteins) Stem cell Smoothened 030217 neurology & neurosurgery |
| Zdroj: | eLife, Vol 5 (2016) eLife Luchetti, G, Sircar, R, Kong, J H, Nachtergaele, S, Sagner, A, Byrne, E F, Covey, D F, Siebold, C & Rohatgi, R 2016, ' Cholesterol activates the G-protein coupled receptor Smoothened to promote Hedgehog signaling ', eLife, vol. 5, e20304 . https://doi.org/10.7554/eLife.20304 |
| DOI: | 10.7554/eLife.20304 |
| Popis: | Cells must communicate with each other to coordinate the development of most tissues and organs. Damage to these communication systems is often seen in degenerative disorders and in cancer. The Hedgehog signaling pathway is one of a handful of these critical systems. Reduced Hedgehog signals can lead to birth defects, while excessive Hedgehog signals can lead to skin and brain cancers. Cells transmit the Hedgehog signal by releasing a protein into their surroundings, where it can influence neighboring cells. Despite years of study, it is not understood how the Hedgehog signal is transmitted from the outside to the inside of a receiving cell. Studies first done in flies and subsequently confirmed in humans have shown that a protein called Smoothened is needed to transmit the Hedgehog signal across the membrane of receiving cells. But it was not known how Smoothened carries out this critical signaling step to influence gene activation inside the cell and consequently to change cell behavior. Now, Luchetti, Sircar et al. find that cholesterol, an important component of the cell membrane, directly binds to Smoothened and changes its shape so that it can activate Hedgehog signaling components inside cells. The experiments made use of mouse cells, and the discovery shows that cholesterol may play a previously underappreciated role in cell-to-cell communication. This newly discovered role for cholesterol has implications for diseases, including a unique set of developmental disorders caused by abnormalities in pathways that produce cholesterol in human cells. Furthermore, this unexpected insight into Smoothened’s activity may be clinically important, because Smoothened can cause cancer when mutated and is the target of anti-cancer drugs that are being used in the clinic. Following on from these findings, a major step will be to uncover if and how Hedgehog signals regulate cholesterol to allow Smoothened to transmit these signals across the cell membrane. |
| Databáze: | OpenAIRE |
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