Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction

@article{Apionishev2005DrosophilaSP,
  title={Drosophila Smoothened phosphorylation sites essential for Hedgehog signal transduction},
  author={Sergey Apionishev and Natalya Katanayeva and Steven A. Marks and Daniel Kalderon and Andrew Tomlinson},
  journal={Nature Cell Biology},
  year={2005},
  volume={7},
  pages={86-92}
}
The Hedgehog (Hh) signalling pathway is crucial for animal development and is aberrantly activated in several types of cancer. In Drosophila melanogaster, Hh signalling regulates target gene expression through the transcription factor Cubitus interruptus (Ci). Together, Protein Kinase A, Casein Kinase 1 and Glycogen Synthase Kinase 3 silence the pathway in the absence of ligand by phosphorylating Ci at a defined cluster of sites, thereby promoting its proteolytic conversion to a transcriptional… Expand
A G protein functions immediately downstream of Smoothened in Hedgehog signaling
TLDR
In vitro and in vivo evidence is presented that Smo functions as a canonical GPCR, which signals through Gαi to regulate Hh pathway activation, and activates a G protein to modulate intracellular cyclic AMP levels in response to Hh. Expand
The Contributions of Protein Kinase A and Smoothened Phosphorylation to Hedgehog Signal Transduction in Drosophila melanogaster
TLDR
It is shown that Smo containing acidic residues at PKA and CK1 sites can be stimulated further by Hh and acts through Hh pathways that both stabilize Ci-155 and use Fused kinase activity to increase the specific activity of Ci- 155. Expand
Sequential Phosphorylation of Smoothened Transduces Graded Hedgehog Signaling
TLDR
A sequential phosphorylation model is proposed in which precise interpretation of morphogen concentration can be achieved upon versatile phosphatase-mediated regulation of the phosphorylated status of an essential activator in developmental signaling. Expand
Decoding the phosphorylation code in Hedgehog signal transduction
TLDR
This review focuses on the multifaceted roles that phosphorylation plays in Hh signal transduction, and discusses the conservation and difference between Drosophila and mammalian Hh signaling mechanisms. Expand
Switch of PKA substrates from Cubitus interruptus to Smoothened in the Hedgehog signalosome complex.
TLDR
It is shown that Hh signalling activation causes PKA to switch its substrates from Ci to Smo within the H h signalling complex (HSC), and a new model is proposed in which the PKA is constitutively present and activeWithin the HSC. Expand
A Broadly Conserved G-Protein-Coupled Receptor Kinase Phosphorylation Mechanism Controls Drosophila Smoothened Activity
TLDR
Results indicate that GRK phosphorylation in the membrane proximal C-terminus of Drosophila Smo is an evolutionarily ancient mechanism of Smo regulation, and point to a higher degree of similarity in the regulation and signaling mechanisms of bilaterian Smo proteins than has previously been recognized. Expand
Analysis of Smoothened Phosphorylation and Activation in Cultured Cells and Wing Discs of Drosophila.
TLDR
Assays used to examine the activity of Smo in Hh signaling are described, including in vitro kinase, ptc-luciferase reporter assay, cell surface accumulation assay, fluorescence resonance energy transfer assay, and wing disc immunostaining. Expand
Regulation of smoothened by Drosophila G-protein-coupled receptor kinases.
TLDR
The results suggest that Smo is regulated by distinct Ptc-dependent and Gprk2-dependent trafficking mechanisms in vivo, analogous to constitutive and activity-dependent regulation of GPCRs. Expand
Smoothened Regulates Activator and Repressor Functions of Hedgehog Signaling via Two Distinct Mechanisms*
TLDR
Evidence is provided that Smo signals to the Hh signaling complex, which consists of the kinesin-related protein Costal2 (Cos2), the protein kinase Fused (Fu), and the Drosophila Gli homolog cubitus interruptus (Ci), in two distinct manners. Expand
Regulation of Smoothened Phosphorylation and High-Level Hedgehog Signaling Activity by a Plasma Membrane Associated Kinase
TLDR
This 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. Expand
...
1
2
3
4
5
...

References

SHOWING 1-10 OF 30 REFERENCES
Proteolysis of cubitus interruptus in Drosophila requires phosphorylation by protein kinase A.
TLDR
It is proposed that PKA phosphorylation of Ci is required for the proteolysis of Ci-155 to Ci-75 in vivo, and that the activity of Ci5m remains Hedgehog responsive if expressed at low levels, providing further evidence that the full-length form of Ci undergoes a Hedgehog-dependent activation step. Expand
Proteolysis of the Hedgehog Signaling Effector Cubitus interruptus Requires Phosphorylation by Glycogen Synthase Kinase 3 and Casein Kinase 1
TLDR
It is shown that phosphoserines prime further phosphorylation at adjacent Glycogen Synthase Kinase 3 (GSK3) and Casein Kinase I (CK1) sites, which prevent Ci-155 proteolysis and activates Ci in the absence of Hedgehog. Expand
Functional domains and sub-cellular distribution of the Hedgehog transducing protein Smoothened in Drosophila
TLDR
It is shown that Smo accumulates in the plasma membrane of cells in which Ptc activity is abrogated by Hh but is targeted to the degradative pathway in cells where Ptc is active and is likely to be a cause, rather than a consequence, of Hh signal transduction. Expand
Protein kinase A antagonizes Hedgehog signaling by regulating both the activator and repressor forms of Cubitus interruptus.
TLDR
It is shown that PKA inhibits the activity of the full-length Ci in addition to its role in regulating Ci proteolysis, and proposed that phosphorylation of Ci by PKA has two separable roles: it blocks the transcription activity ofthe full- length activator form of Ci, and it targets Ci for Slimb-mediated proteolytic processing to generate the truncated form that functions as a repressor. Expand
Dual pathways for induction of wingless expression by protein kinase A and Hedgehog in Drosophila embryos.
TLDR
It is shown that PKA inhibition, like Hh, leads to increased "carboxy-terminal" Ci staining and Hh target gene expression in embryos, and that Hh signaling in embryos does not depend on cAMP-dependent regulation of PKA activity. Expand
Patched represses the Hedgehog signalling pathway by promoting modification of the Smoothened protein
TLDR
These findings suggest that Smo is modified to yield a non-functional form and this modification is promoted by Ptc in a non -stoichiometric manner. Expand
Identification of a Functional Interaction between the Transmembrane Protein Smoothened and the Kinesin-Related Protein Costal2
TLDR
This work fills in the last major gap in the understanding of the Hh signal transduction pathway by suggesting that no intermediate signal is required to connect Smo to the HSC. Expand
Hedgehog stimulates maturation of Cubitus interruptus into a labile transcriptional activator
TLDR
It is proposed that Fu kinase activity is required for Hh to stimulate the maturation of Ci-155 into a short-lived nuclear transcriptional activator and that Su(fu) opposes this maturation step through a stoichiometric interaction with Ci- 155. Expand
Phosphorylation of the fused protein kinase in response to signaling from hedgehog.
TLDR
It is reported that the fused protein is phosphorylated during the course of Drosophila embryogenesis, as a result of hedgehog activity, and this results suggest that fused and protein kinase A function downstream of Hedgehog but in parallel pathways that eventually converge distal to fused. Expand
Shaggy/GSK3 antagonizes Hedgehog signalling by regulating Cubitus interruptus
TLDR
It is proposed that Sgg/GSK3 acts in conjunction with PKA to cause hyperphosphorylation of Ci, which targets it for proteolytic processing, and that Hh opposes Ci proteolysis by promoting its dephosphorouslation. Expand
...
1
2
3
...