G protein-coupled receptor kinase 2 promotes high-level Hedgehog signaling by regulating the active state of Smo through kinase-dependent and kinase-independent mechanisms in Drosophila

Yongbin Chen, Shuang Li, Chao Tong, Yun Zhao, Bing Wang, Yajuan Liu, Jianhang Jia, Jin Jiang

Research output: Contribution to journalArticle

69 Scopus citations

Abstract

G protein-coupled receptor kinase 2 (Gprk2/GRK2) plays a conserved role in modulating Hedgehog (Hh) pathway activity, but its mechanism of action remains unknown. Here we provide evidence that Gprk2 promotes high-level Hh signaling by regulating Smoothened (Smo) conformation through both kinase-dependent and kinase-independent mechanisms. Gprk2 promotes Smo activation by phosphorylating Smo C-terminal tail (C-tail) at Ser741/Thr742, which is facilitated by PKA and CK1 phosphorylation at adjacent Ser residues. In addition, Gprk2 forms a dimer/oligomer and binds Smo C-tail in a kinase activity-independent manner to stabilize the active Smo conformation, and promotes dimerization/oligomerization of Smo C-tail. Gprk2 expression is induced by Hh signaling, and Gprk2/Smo interaction is facilitated by PKA/CK1-mediated phosphorylation of Smo C-tail. Thus, Gprk2 forms a positive feedback loop and acts downstream from PKA and CK1 to facilitate high-level Hh signaling by promoting the active state of Smo through direct phosphorylation and molecular scaffolding.

Original languageEnglish (US)
Pages (from-to)2054-2067
Number of pages14
JournalGenes and Development
Volume24
Issue number18
DOIs
StatePublished - Sep 15 2010

Keywords

  • Conformation
  • GPCR
  • Gprk2/GRK2
  • Hedgehog
  • Phosphorylation
  • Smo

ASJC Scopus subject areas

  • Genetics
  • Developmental Biology

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