Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase

CORC > 昆明动物研究所 > 昆明动物研究所 > 动物模型与人类重大疾病机理重点实验室 > 肿瘤信号转导

	Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase
	Li SX 1,2; Li S 1,2; Han YH 1,2; Tong C 2; Wang B 1,2; Chen YB 2,3; Jiang J[*]1,2,4
刊名	PLOS BIOLOGY
	2016
卷号	14 期号:6 页码:e1002481
通讯作者	jin.jiang@utsouthwestern.edu
英文摘要	Hedgehog (Hh) signaling controls embryonic development and adult tissue homeostasis through the G protein coupled receptor (GPCR)-family protein Smoothened (Smo). Upon stimulation, Smo accumulates on the cell surface in Drosophila or primary cilia in vertebrates, which is thought to be essential for its activation and function, but the underlying mechanisms remain poorly understood. Here we show that Hh stimulates the binding of Smo to a plasma membrane-associated kinase Gilgamesh (Gish)/CK1γ and that Gish fine-tunes Hh pathway activity by phosphorylating a Ser/Thr cluster (CL-II) in the juxtamembrane region of Smo carboxyl-terminal intracellular tail (C-tail). We find that CL-II phosphorylation is promoted by protein kinase A (PKA)-mediated phosphorylation of Smo C-tail and depends on cell surface localization of both Gish and Smo. Consistent with CL-II being critical for high-threshold Hh target gene expression, its phosphorylation appears to require higher levels of Hh or longer exposure to the same level of Hh than PKA-site phosphorylation on Smo. Furthermore, we find that vertebrate CK1γ is localized at the primary cilium to promote Smo phosphorylation and Sonic hedgehog (Shh) pathway activation. Our study reveals a conserved mechanism whereby Hh induces a change in Smo subcellular localization to promote its association with and activation by a plasma membrane localized kinase, and provides new insight into how Hh morphogen progressively activates Smo.
收录类别	其他
资助信息	Jin Jiang received grants from the National Institute of General Medicine Sciences (GM061269, GM067045, GM118063) and the Welch Foundation (I-1603), and YC received grants from the National Natural Science Foundation of China (31328017, 81322030, and 31271579).
语种	英语
内容类型	期刊论文
源URL	[http://159.226.149.26:8080/handle/152453/10029]
专题	昆明动物研究所_肿瘤信号转导
作者单位	1.Department of Molecular Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America 2.Department of Developmental Biology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America 3.Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan, China 4.Department of Pharmacology, University of Texas Southwestern Medical Center at Dallas, Dallas, Texas, United States of America
推荐引用方式 GB/T 7714	Li SX,Li S,Han YH,et al. Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase[J]. PLOS BIOLOGY,2016,14(6):e1002481.
APA	Li SX.,Li S.,Han YH.,Tong C.,Wang B.,...&Jiang J[*].(2016).Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase.PLOS BIOLOGY,14(6),e1002481.
MLA	Li SX,et al."Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase".PLOS BIOLOGY 14.6(2016):e1002481.