ZFIN ID: ZDB-PUB-081001-3
Smoothened Signaling in Vertebrates Is Facilitated by a G-Protein Coupled Receptor Kinase
Philipp, M., Fralish, G.B., Meloni, A.R., Chen, W., Macinnes, A., Barak, L.S., and Caron, M.G.
Date: 2008
Source: Molecular biology of the cell   19(12): 5478-5489 (Journal)
Registered Authors:
Keywords: none
MeSH Terms:
  • Animals
  • Body Patterning
  • Cells, Cultured
  • G-Protein-Coupled Receptor Kinase 2/genetics
  • G-Protein-Coupled Receptor Kinase 2/metabolism*
  • G-Protein-Coupled Receptor Kinase 3/genetics
  • G-Protein-Coupled Receptor Kinase 3/metabolism*
  • Hedgehog Proteins/genetics
  • Hedgehog Proteins/metabolism
  • Humans
  • Mice
  • Mice, Knockout
  • Phenotype
  • Receptors, G-Protein-Coupled/genetics
  • Receptors, G-Protein-Coupled/metabolism*
  • Signal Transduction/physiology*
  • Transcription, Genetic
  • Zebrafish*/anatomy & histology
  • Zebrafish*/embryology
  • Zebrafish Proteins/genetics
  • Zebrafish Proteins/metabolism*
PubMed: 18815277 Full text @ Mol. Biol. Cell
Smoothened, a heptahelical membrane protein, functions as the transducer of Hedgehog signaling. The kinases that modulate Smoothened have been thoroughly analyzed in flies. However, little is known about how phosphorylation affects Smoothened in vertebrates, mainly, because the residues, where Smoothened is phosphorylated are not conserved from Drosophila to vertebrates. Given its molecular architecture, Smoothened signaling is likely to be regulated in a manner analogous to G protein-coupled receptors (GPCRs). Previously, it has been shown, that arrestins and GPCR kinases, (GRKs) not only desensitize G protein-dependent receptor signaling but also function as triggers for GPCR trafficking and formation of signaling complexes. Here we describe that a GRK contributes to Smoothened-mediated signaling in vertebrates. Knockdown of the zebrafish homolog of mammalian GRK2/3 results in lowered Hedgehog transcriptional responses, impaired muscle development and neural patterning. Results obtained in zebrafish are corroborated both in cell culture, where zGRK2/3 phosphorylates Smoothened and promotes Smoothened signal transduction and in mice where deletion of GRK2 interferes with neural tube patterning. Together, these data suggest that a GRK functions as a vertebrate kinase for Smoothened, promoting Hedgehog signal transduction during early development.