Hedgehog signal transduction proteins: contacts of the Fused kinase and Ci transcription factor with the Kinesin-related protein Costal2

@article{Monnier2001HedgehogST,
  title={Hedgehog signal transduction proteins: contacts of the Fused kinase and Ci transcription factor with the Kinesin-related protein Costal2},
  author={V. Monnier and Karen S Ho and Matthieu Sanial and M. Scott and A. Plessis},
  journal={BMC Developmental Biology},
  year={2001},
  volume={2},
  pages={4 - 4}
}
BackgroundHedgehog signaling proteins play important roles in development by controlling growth and patterning in various animals including Drosophila and mammals. Hedgehog signaling triggers changes in responsive cells through a novel transduction mechanism that ultimately controls the transcription of specific target genes via the activity of zinc finger transcription factors of the Cubitus interruptus /GLI family. In flies, key Hedgehog signal transduction components have been identified… Expand
Differential regulation of Hedgehog target gene transcription by Costal2 and Suppressor of Fused
The mechanism by which the secreted signaling molecule Hedgehog (Hh) elicits concentration-dependent transcriptional responses from cells is not well understood. In the Drosophila wing imaginal disc,Expand
Evidence for a novel feedback loop in the Hedgehog pathway involving the seven transmembrane-domain protein Smoothened and the kinase Fused.
TLDR
These findings reveal a novel positive-feedback loop in HH transduction and are consistent with a model in which FU and SMO, by mutually enhancing each other's activities, sustain high levels of signaling and render the pathway robust to PTClevel fluctuations. Expand
Hedgehog-regulated Costal2-kinase complexes control phosphorylation and proteolytic processing of Cubitus interruptus.
TLDR
Hedgehog proteins control animal development by regulating the Gli/Ci family of transcription factors and it is proposed that Cos2 recruits multiple kinases to efficiently phosphorylate Ci and that Hh inhibits Ci phosphorylation by specifically interfering with kinase recruitment. Expand
Regulation of mammalian Gli proteins by Costal 2 and PKA in Drosophila reveals Hedgehog pathway conservation
TLDR
It is shown that cos2 binds to three regions of Gli1, just as for Ci, and that Cos2 functions to silence mammalian Gli 1 in Drosophila in a Hh-regulated manner, underscoring a fundamental conserved role for Cos2 family proteins in Hh signaling. Expand
The Kinesin-related Protein Costal2 Associates with Membranes in a Hedgehog-sensitive, Smoothened-independent Manner*
TLDR
It is suggested that an Hh-regulated membrane binding activity of Cos2 is part of the mechanism by which Cos2 contributes to Hh signaling. Expand
Contributions of Costal 2-Fused interactions to Hedgehog signaling in Drosophila
TLDR
It is shown that normal Ci-155 activation by Hh requires Cos2 binding to Fu, supporting the hypothesis that Cos2 mediates the apposition of Fu molecules suitable for cross-phosphorylation and consequent full activation of Fu kinase. Expand
Hedgehog activates fused through phosphorylation to elicit a full spectrum of pathway responses.
TLDR
It is shown that the Fused (Fu) protein kinase is activated by Smo and Cos2 via Fu- and CK1-dependent phosphorylation, which further enhances kinase activity. Expand
The last 59 amino acids of Smoothened cytoplasmic tail directly bind the protein kinase Fused and negatively regulate the Hedgehog pathway.
TLDR
It is proposed that FU could act as a switch, activator in presence of HH signal or inhibitor in absence of HH, and it is shown that the regulatory domain of FU physically interacts with the last 52 amino acids of SMO and that the two proteins colocalize in vivo to vesicles. Expand
Regulation of Hedgehog signaling: a complex story.
TLDR
The mechanism(s) by which Ptc and Smo communicate with the HSC in response to differential ligand concentrations to regulate Ci function are not yet fully elucidated, concentrating on the mechanisms by which the Hh signal is propagated through Smo to the H SC. Expand
Mammalian homologues of Drosophila fused kinase.
TLDR
In vivo data clarify that Stk36 is not required for embryonic development in mice and participates in Shh-independent genesis of motile cilia, and Ulk3 is able to recapitulate both positive and negative roles of fu in vitro, however, UlK3 functioning in vivo remains to be investigated. Expand
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References

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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
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
Costal2, a Novel Kinesin-Related Protein in the Hedgehog Signaling Pathway
TLDR
It is shown that costal2 encodes a kinesin-related protein that accumulates preferentially in cells capable of responding to HH, and that CI associates with COS2 in a large protein complex, suggesting that C OS2 directly controls the activity of CI. Expand
Hedgehog Elicits Signal Transduction by Means of a Large Complex Containing the Kinesin-Related Protein Costal2
The hedgehog gene of Drosophila melanogaster encodes a secreted protein (HH) that plays a vital role in cell fate and patterning. Here we describe a protein complex that mediates signal transductionExpand
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
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TLDR
By sequentially mutating components from the Ci signaling complex, their roles in each aspect of Ci regulation can be analyzed and the Cos2-Ci core complex is able to mediate Hh-regulated activation of Ci but is insufficient to regulate nuclear import and cleavage. Expand
Genetic evidence for a protein kinase A/cubitus interruptus complex that facilitates processing of cubitus interruptus in Drosophila.
TLDR
The mutant PKAr*, defective in binding cAMP, is shown to activate Hh target genes solely through its ability to bind and inhibit endogenous PKAc, and Surprisingly, PKAcA75, a catalytically impaired mutant, also activates Hhtarget genes. Expand
The subcellular localization and activity of Drosophila cubitus interruptus are regulated at multiple levels.
TLDR
The data show that loss of PKA or Costal-2 activity does not fully mimic Hh signaling, demonstrating that Ci proteolysis and Ci activation are two distinct events which are regulated through different paths. Expand
Genetic analysis of hedgehog signalling in the Drosophila embryo.
TLDR
Evidence is presented that transduction of the hh-encoded signal is mediated by the activity of four other segment polarity genes, patched, fused, costal-2 and cubitus interruptus, and that transcription of patched is regulated by the same pathway. Expand
Suppressor of fused links Fused and Cubitus interruptus on the Hedgehog signalling pathway
TLDR
It is proposed that, in the absence of Hh signalling, Su(fu) inhibits Ci by binding to it and that, upon reception of the Hh signal, Fu is activated and counteracts Su(Fu), leading to the activation of Ci. Expand
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