气候变化领域集成服务门户(CCPortal): Mechanism and ultrasensitivity in Hedgehog signaling revealed by Patched1 disease mutations

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DOI	10.1073/pnas.2006800118
	Mechanism and ultrasensitivity in Hedgehog signaling revealed by Patched1 disease mutations
	Petrov K.; de Almeida Magalhaes T.; Salic A.
发表日期	2021
ISSN	00278424
卷号	118 期号:6
英文摘要	Hedgehog signaling is fundamental in animal embryogenesis, and its dysregulation causes cancer and birth defects. The pathway is triggered when the Hedgehog ligand inhibits the Patched1 membrane receptor, relieving repression that Patched1 exerts on the GPCR-like protein Smoothened. While it is clear how loss-of-function Patched1 mutations cause hyperactive Hedgehog signaling and cancer, how other Patched1 mutations inhibit signaling remains unknown. Here, we develop quantitative single-cell functional assays for Patched1, which, together with mathematical modeling, indicate that Patched1 inhibits Smoothened enzymatically, operating in an ultrasensitive regime. Based on this analysis, we propose that Patched1 functions in cilia, catalyzing Smoothened deactivation by removing cholesterol bound to its extracellular, cysteine-rich domain. Patched1 mutants associated with holoprosencephaly dampen signaling by three mechanisms: reduced affinity for Hedgehog ligand, elevated catalytic activity, or elevated affinity for the Smoothened substrate. Our results clarify the enigmatic mechanism of Patched1 and explain how Patched1 mutations lead to birth defects. © 2021 National Academy of Sciences. All rights reserved.
英文关键词	Hedgehog signaling; Holoprosencephaly; Mathematical modeling; Ultrasensitivity
语种	英语
来源期刊	Proceedings of the National Academy of Sciences of the United States of America
文献类型	期刊论文
条目标识符	http://gcip.llas.ac.cn/handle/2XKMVOVA/180682
作者单位	Department of Cell Biology, Harvard Medical School, Boston, MA 02115, United States
推荐引用方式 GB/T 7714	Petrov K.,de Almeida Magalhaes T.,Salic A.. Mechanism and ultrasensitivity in Hedgehog signaling revealed by Patched1 disease mutations[J],2021,118(6).
APA	Petrov K.,de Almeida Magalhaes T.,&Salic A..(2021).Mechanism and ultrasensitivity in Hedgehog signaling revealed by Patched1 disease mutations.Proceedings of the National Academy of Sciences of the United States of America,118(6).
MLA	Petrov K.,et al."Mechanism and ultrasensitivity in Hedgehog signaling revealed by Patched1 disease mutations".Proceedings of the National Academy of Sciences of the United States of America 118.6(2021).