Format

Send to

Choose Destination
PLoS Biol. 2016 Feb 10;14(2):e1002375. doi: 10.1371/journal.pbio.1002375. eCollection 2016 Feb.

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

Author information

1
Markey Cancer Center, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
2
Department of Pediatrics, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
3
Department of Surgery, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.
4
Department of Molecular and Cellular Biochemistry, University of Kentucky College of Medicine, Lexington, Kentucky, United States of America.

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.

PMID:
26863604
PMCID:
PMC4749301
DOI:
10.1371/journal.pbio.1002375
[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Public Library of Science Icon for PubMed Central
Loading ...
Support Center