PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail

Kai Jiang, Yajuan Liu, Junkai Fan, Jie Zhang, Xiang An Li, B. Mark Evers, Haining Zhu, Jianhang Jia

Research output: Contribution to journalArticlepeer-review

42 Scopus citations

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.

Original languageEnglish
Article numbere1002375
JournalPLoS Biology
Volume14
Issue number2
DOIs
StatePublished - Feb 10 2016

Bibliographical note

Publisher Copyright:
© 2016 Jiang et al.

ASJC Scopus subject areas

  • Neuroscience (all)
  • Biochemistry, Genetics and Molecular Biology (all)
  • Immunology and Microbiology (all)
  • Agricultural and Biological Sciences (all)

Fingerprint

Dive into the research topics of 'PI(4)P Promotes Phosphorylation and Conformational Change of Smoothened through Interaction with Its C-terminal Tail'. Together they form a unique fingerprint.

Cite this