Dose-dependent transduction of hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor smoothened and the kinase fused

Matthieu Sanial, Isabelle Bécam, Line Hofmann, Julien Behague, Camilla Argüelles, Vanessa Gourhand, Lucia Bruzzone, Robert A Holmgren, Anne Plessis*

*Corresponding author for this work

Research output: Contribution to journalArticle

3 Citations (Scopus)

Abstract

Smoothened (SMO) is a G-protein-coupled receptor-related protein required for the transduction of Hedgehog (HH). The HH gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases. How thresholds in HH morphogen regulate SMO to promote switch-like transcriptional responses is a central unsolved issue. Using the wing imaginal disc model in Drosophila, we identified new SMO phosphosites that enhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membrane and its activity. Surprisingly, phosphorylation at these sites is induced by the kinase Fused (FU), a known downstream effector of SMO. In turn, activation of SMO induces FU to act on its downstream targets. Overall, our data provide evidence for a SMO/FU positive regulatory loop nested within a multikinase phosphorylation cascade. We propose that this complex interplay amplifies signaling above a threshold that allows high HH signaling.

Original languageEnglish (US)
Pages (from-to)1841-1850
Number of pages10
JournalDevelopment (Cambridge)
Volume144
Issue number10
DOIs
StatePublished - May 15 2017

Fingerprint

G-Protein-Coupled Receptor Kinases
Hedgehogs
Phosphorylation
Phosphotransferases
Imaginal Discs
G-Protein-Coupled Receptors
Drosophila
Cell Membrane
Proteins

Keywords

  • Drosophila
  • Fused kinase
  • Hedgehog
  • Phosphorylation
  • SNAP-tag labeling
  • Signal transduction
  • Smoothened

ASJC Scopus subject areas

  • Molecular Biology
  • Developmental Biology

Cite this

Sanial, Matthieu ; Bécam, Isabelle ; Hofmann, Line ; Behague, Julien ; Argüelles, Camilla ; Gourhand, Vanessa ; Bruzzone, Lucia ; Holmgren, Robert A ; Plessis, Anne. / Dose-dependent transduction of hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor smoothened and the kinase fused. In: Development (Cambridge). 2017 ; Vol. 144, No. 10. pp. 1841-1850.
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Dose-dependent transduction of hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor smoothened and the kinase fused. / Sanial, Matthieu; Bécam, Isabelle; Hofmann, Line; Behague, Julien; Argüelles, Camilla; Gourhand, Vanessa; Bruzzone, Lucia; Holmgren, Robert A; Plessis, Anne.

In: Development (Cambridge), Vol. 144, No. 10, 15.05.2017, p. 1841-1850.

Research output: Contribution to journalArticle

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T1 - Dose-dependent transduction of hedgehog relies on phosphorylation-based feedback between the G-protein-coupled receptor smoothened and the kinase fused

AU - Sanial, Matthieu

AU - Bécam, Isabelle

AU - Hofmann, Line

AU - Behague, Julien

AU - Argüelles, Camilla

AU - Gourhand, Vanessa

AU - Bruzzone, Lucia

AU - Holmgren, Robert A

AU - Plessis, Anne

PY - 2017/5/15

Y1 - 2017/5/15

N2 - Smoothened (SMO) is a G-protein-coupled receptor-related protein required for the transduction of Hedgehog (HH). The HH gradient leads to graded phosphorylation of SMO, mainly by the PKA and CKI kinases. How thresholds in HH morphogen regulate SMO to promote switch-like transcriptional responses is a central unsolved issue. Using the wing imaginal disc model in Drosophila, we identified new SMO phosphosites that enhance the effects of the PKA/CKI kinases on SMO accumulation, its localization at the plasma membrane and its activity. Surprisingly, phosphorylation at these sites is induced by the kinase Fused (FU), a known downstream effector of SMO. In turn, activation of SMO induces FU to act on its downstream targets. Overall, our data provide evidence for a SMO/FU positive regulatory loop nested within a multikinase phosphorylation cascade. We propose that this complex interplay amplifies signaling above a threshold that allows high HH signaling.

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