Your browser doesn't support javascript.
loading
Cholesterol Modification of Smoothened Is Required for Hedgehog Signaling.
Xiao, Xu; Tang, Jing-Jie; Peng, Chao; Wang, Yan; Fu, Lin; Qiu, Zhi-Ping; Xiong, Yue; Yang, Lian-Fang; Cui, Hai-Wei; He, Xiao-Long; Yin, Lei; Qi, Wei; Wong, Catherine C L; Zhao, Yun; Li, Bo-Liang; Qiu, Wen-Wei; Song, Bao-Liang.
Affiliation
  • Xiao X; State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • Tang JJ; State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • Peng C; State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201203, China; Shanghai Science Research Center, Ch
  • Wang Y; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
  • Fu L; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • Qiu ZP; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China.
  • Xiong Y; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • Yang LF; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
  • Cui HW; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
  • He XL; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China.
  • Yin L; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China.
  • Qi W; State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • Wong CC; State Key Laboratory of Molecular Biology, National Center for Protein Science Shanghai, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 333 Haike Road, Shanghai 201203, China; Shanghai Science Research Center, Ch
  • Zhao Y; State Key Laboratory of Cell Biology, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • Li BL; State Key Laboratory of Molecular Biology, Institute of Biochemistry and Cell Biology, Shanghai Institutes for Biological Sciences, Chinese Academy of Sciences, 320 Yue-Yang Road, Shanghai 200031, China.
  • Qiu WW; Shanghai Engineering Research Center of Molecular Therapeutics and New Drug Development, School of Chemistry and Molecular Engineering, East China Normal University, Shanghai 200241, China. Electronic address: wwqiu@chem.ecnu.edu.cn.
  • Song BL; Hubei Key Laboratory of Cell Homeostasis, College of Life Sciences, the Institute for Advanced Studies, Wuhan University, Wuhan 430072, China. Electronic address: blsong@whu.edu.cn.
Mol Cell ; 66(1): 154-162.e10, 2017 Apr 06.
Article in En | MEDLINE | ID: mdl-28344083
ABSTRACT
Hedgehog (Hh) has been known as the only cholesterol-modified morphogen playing pivotal roles in development and tumorigenesis. A major unsolved question is how Hh signaling regulates the activity of Smoothened (SMO). Here, we performed an unbiased biochemical screen and identified that SMO was covalently modified by cholesterol on the Asp95 (D95) residue through an ester bond. This modification was inhibited by Patched-1 (Ptch1) but enhanced by Hh. The SMO(D95N) mutation, which could not be cholesterol modified, was refractory to Hh-stimulated ciliary localization and failed to activate downstream signaling. Furthermore, homozygous SmoD99N/D99N (the equivalent residue in mouse) knockin mice were embryonic lethal with severe cardiac defects, phenocopying the Smo-/- mice. Together, the results of our study suggest that Hh signaling transduces to SMO through modulating its cholesterylation and provides a therapeutic opportunity to treat Hh-pathway-related cancers by targeting SMO cholesterylation.
Subject(s)
Key words
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Signal Transduction / Cholesterol / Hedgehog Proteins / Smoothened Receptor Limits: Animals / Humans Language: En Year: 2017 Type: Article
Fulltext
Print
XML
PubMed Links
Search on Google

Full text: 1 Database: MEDLINE Main subject: Signal Transduction / Cholesterol / Hedgehog Proteins / Smoothened Receptor Limits: Animals / Humans Language: En Year: 2017 Type: Article