Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase

Shuangxi Li, Shuang Li, Yuhong Han, Chao Tong, Bing Wang, Yongbin Chen, Jin Jiang

Research output: Contribution to journalArticle

19 Citations (Scopus)

Abstract

Hedgehog (Hh) signaling controls embryonic development and adult tissue homeostasis through the G protein coupled receptor (GPCR)-family protein Smoothened (Smo). Upon stimulation, Smo accumulates on the cell surface in Drosophila or primary cilia in vertebrates, which is thought to be essential for its activation and function, but the underlying mechanisms remain poorly understood. Here we show that Hh stimulates the binding of Smo to a plasma membrane-associated kinase Gilgamesh (Gish)/CK1γ and that Gish fine-tunes Hh pathway activity by phosphorylating a Ser/Thr cluster (CL-II) in the juxtamembrane region of Smo carboxyl-terminal intracellular tail (C-tail). We find that CL-II phosphorylation is promoted by protein kinase A (PKA)-mediated phosphorylation of Smo C-tail and depends on cell surface localization of both Gish and Smo. Consistent with CL-II being critical for high-threshold Hh target gene expression, its phosphorylation appears to require higher levels of Hh or longer exposure to the same level of Hh than PKA-site phosphorylation on Smo. Furthermore, we find that vertebrate CK1γ is localized at the primary cilium to promote Smo phosphorylation and Sonic hedgehog (Shh) pathway activation. Our study reveals a conserved mechanism whereby Hh induces a change in Smo subcellular localization to promote its association with and activation by a plasma membrane localized kinase, and provides new insight into how Hh morphogen progressively activates Smo.

Original languageEnglish (US)
Article numbere1002481
JournalPLoS Biology
Volume14
Issue number6
DOIs
StatePublished - Jun 9 2016

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Phosphorylation
Hedgehogs
Erinaceidae
Cell membranes
phosphorylation
phosphotransferases (kinases)
Phosphotransferases
plasma membrane
Cell Membrane
Chemical activation
Cyclic AMP-Dependent Protein Kinases
Tissue homeostasis
Hedgehog Proteins
Cilia
cAMP-dependent protein kinase
cilia
Vertebrates
Tail
G-Protein-Coupled Receptors
Gene expression

ASJC Scopus subject areas

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

Cite this

Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase. / Li, Shuangxi; Li, Shuang; Han, Yuhong; Tong, Chao; Wang, Bing; Chen, Yongbin; Jiang, Jin.

In: PLoS Biology, Vol. 14, No. 6, e1002481, 09.06.2016.

Research output: Contribution to journalArticle

Li, Shuangxi ; Li, Shuang ; Han, Yuhong ; Tong, Chao ; Wang, Bing ; Chen, Yongbin ; Jiang, Jin. / Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase. In: PLoS Biology. 2016 ; Vol. 14, No. 6.
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