title: PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail.
abstract: In Hedgehog (Hh) signaling, binding of Hh to the Patched-Interference Hh (Ptc-Ihog) receptor complex relieves Ptc inhibition on Smoothened (Smo). A longstanding question is how Ptc inhibits Smo and how such inhibition is relieved by Hh stimulation. In this study, we found that Hh elevates production of phosphatidylinositol 4-phosphate (PI(4)P). Increased levels of PI(4)P promote, whereas decreased levels of PI(4)P inhibit, Hh signaling activity. We further found that PI(4)P directly binds Smo through an arginine motif, which then triggers Smo phosphorylation and activation. Moreover, we identified the pleckstrin homology (PH) domain of G protein-coupled receptor kinase 2 (Gprk2) as an essential component for enriching PI(4)P and facilitating Smo activation. PI(4)P also binds mouse Smo (mSmo) and promotes its phosphorylation and ciliary accumulation. Finally, Hh treatment increases the interaction between Smo and PI(4)P but decreases the interaction between Ptc and PI(4)P, indicating that, in addition to promoting PI(4)P production, Hh regulates the pool of PI(4)P associated with Ptc and Smo.
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: Kai
authors: K
authors: Jiang
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: Yajuan
authors: Y
authors: Liu
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: Junkai
authors: J
authors: Fan
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: Jie
authors: J
authors: Zhang
authors: Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: Xiang-An
authors: XA
authors: Li
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.|Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: B Mark
authors: BM
authors: Evers
authors: Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: Haining
authors: H
authors: Zhu
authors: Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.|Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
authors: Jianhang
authors: J
authors: Jia
mesh_terms: D000818:Animals; D002923:Cilia / Q000378:metabolism; D004330:Drosophila; D029721:Drosophila Proteins / Q000378:metabolism*; D054769:G-Protein-Coupled Receptor Kinase 2 / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism*; D051379:Mice; D041681:NIH 3T3 Cells; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D018129:Phosphatidylinositol Phosphates / Q000378:metabolism*; D010766:Phosphorylation; D011956:Receptors, Cell Surface / Q000378:metabolism; D043562:Receptors, G-Protein-Coupled / Q000378:metabolism*; D000072086:Smoothened Receptor
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D000072079:Patched Receptors; D000072081:Patched-1 Receptor; D018129:Phosphatidylinositol Phosphates; C000606240:Ptch1 protein, mouse; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; C037178:phosphatidylinositol 4-phosphate; C100664:smo protein, Drosophila; C077245:hh protein, Drosophila; D054769:G-Protein-Coupled Receptor Kinase 2; C496574:Gprk2 protein, Drosophila