Journal
DEVELOPMENT
Volume 144, Issue 10, Pages 1841-1850Publisher
COMPANY OF BIOLOGISTS LTD
DOI: 10.1242/dev.144782
Keywords
Drosophila; Signal transduction; Hedgehog; Smoothened; Phosphorylation; Fused kinase; SNAP-tag labeling
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Funding
- Centre Nationnal de la Recherche Scientifique (University Paris 7)
- Fondation ARC pour la recherche sur le Cancer [155032]
- ARC
- Ligue Contre le Cancer
- Universite Paris Diderot
- Fondation ARC pour la recherche sur le Cancer
- Association Franco-argentine
- Paris Sorbonne Cite
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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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