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

Monnier V, Ho KS, Sanial M, Scott MP, Plessis A - BMC Dev. Biol. (2002)

Bottom Line: In flies, key Hedgehog signal transduction components have been identified including the kinesin-related protein Costal2, the serinethreonine kinase Fused, and the PEST-containing protein Suppressor of Fused.In fly embryos, Costal2, Fused, Suppressor of Fused and Cubitus interruptus are associated in at least one cytoplasmic complex, which interacts with the microtubules in a Hedgehog-dependent manner.Our results provide new insights into the possible mechanism of the cytosolic steps of Hedgehog transduction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratoire de génétique et évolution, Institut Jacques Monod, 2 Place Jussieu, 75005, Paris, France. monnier@ijm.jussieu.fr

ABSTRACT

Background: Hedgehog 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 including the kinesin-related protein Costal2, the serinethreonine kinase Fused, and the PEST-containing protein Suppressor of Fused. These proteins control Cubitus interruptus cleavage, nucleo-cytoplasmic localization and activation. In fly embryos, Costal2, Fused, Suppressor of Fused and Cubitus interruptus are associated in at least one cytoplasmic complex, which interacts with the microtubules in a Hedgehog-dependent manner.

Results: Here we identified and mapped direct interactions between Cos2, Fu, and Ci using an in vitro affinity assay and the yeast two-hybrid system.

Conclusions: Our results provide new insights into the possible mechanism of the cytosolic steps of Hedgehog transduction.

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Related in: MedlinePlus

Model of Hedgehog signaling In the absence of Hh signal, Cos2 and Su(fu) binding to Ci prevents Ci activation and retain it in the cytoplasm. Most of Ci is available for cleavage in a process which is dependent upon its phosphorylation by the PKA and which involves Cos2 and Slimb. Uncleaved, full-length Ci, is actively exported from the nucleus. Upon Hh reception, Fused is activated and acts on Cos2 and Sufu, alleviating thus their negative effect on Ci. As a result, Ci cleavage is reduced, Ci155 nuclear import overcomes its export and Ci is activated. Ci activation requires Cos2 and Fu to antagonize Su(fu) negative effect. Activated nuclear Ci interact with the CBP to fully activate the transcription of Hh target genes.
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Figure 4: Model of Hedgehog signaling In the absence of Hh signal, Cos2 and Su(fu) binding to Ci prevents Ci activation and retain it in the cytoplasm. Most of Ci is available for cleavage in a process which is dependent upon its phosphorylation by the PKA and which involves Cos2 and Slimb. Uncleaved, full-length Ci, is actively exported from the nucleus. Upon Hh reception, Fused is activated and acts on Cos2 and Sufu, alleviating thus their negative effect on Ci. As a result, Ci cleavage is reduced, Ci155 nuclear import overcomes its export and Ci is activated. Ci activation requires Cos2 and Fu to antagonize Su(fu) negative effect. Activated nuclear Ci interact with the CBP to fully activate the transcription of Hh target genes.

Mentions: The present data, together with published results, suggest that the existence of direct multiple interactions between Cos2, Su(fu), Fu, and Ci, each protein interacting with at least two other partners. We propose a model based upon a complex that includes Fu, Cos2, Su(fu), and Ci (Figure 4). Changes in the composition, activity and/or subcellular localization of this complex will control Ci fate in the absence and in the presence of Hh. In the absence of Hh signal, Su(fu) and Cos2 prevent Ci activation, Ci processing into the repressor form is favored and full-length Ci is exported from the nucleus. Upon Hh reception, Fu is activated, opposing Su(fu) to allow Ci to become an activator. Simultaneously the negative effect of Cos2 is alleviated, perhaps by release from the microtubules and/or a change in subcellular location. This lowers the rate of proteolysis of Ci into its repressor form and triggers nuclear import of full-length Ci. Furthermore, Cos2 and Fu promote the conversion of Ci 155 into an activator form, ultimately resulting in the transcription of Hh target genes.


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

Monnier V, Ho KS, Sanial M, Scott MP, Plessis A - BMC Dev. Biol. (2002)

Model of Hedgehog signaling In the absence of Hh signal, Cos2 and Su(fu) binding to Ci prevents Ci activation and retain it in the cytoplasm. Most of Ci is available for cleavage in a process which is dependent upon its phosphorylation by the PKA and which involves Cos2 and Slimb. Uncleaved, full-length Ci, is actively exported from the nucleus. Upon Hh reception, Fused is activated and acts on Cos2 and Sufu, alleviating thus their negative effect on Ci. As a result, Ci cleavage is reduced, Ci155 nuclear import overcomes its export and Ci is activated. Ci activation requires Cos2 and Fu to antagonize Su(fu) negative effect. Activated nuclear Ci interact with the CBP to fully activate the transcription of Hh target genes.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC101406&req=5

Figure 4: Model of Hedgehog signaling In the absence of Hh signal, Cos2 and Su(fu) binding to Ci prevents Ci activation and retain it in the cytoplasm. Most of Ci is available for cleavage in a process which is dependent upon its phosphorylation by the PKA and which involves Cos2 and Slimb. Uncleaved, full-length Ci, is actively exported from the nucleus. Upon Hh reception, Fused is activated and acts on Cos2 and Sufu, alleviating thus their negative effect on Ci. As a result, Ci cleavage is reduced, Ci155 nuclear import overcomes its export and Ci is activated. Ci activation requires Cos2 and Fu to antagonize Su(fu) negative effect. Activated nuclear Ci interact with the CBP to fully activate the transcription of Hh target genes.
Mentions: The present data, together with published results, suggest that the existence of direct multiple interactions between Cos2, Su(fu), Fu, and Ci, each protein interacting with at least two other partners. We propose a model based upon a complex that includes Fu, Cos2, Su(fu), and Ci (Figure 4). Changes in the composition, activity and/or subcellular localization of this complex will control Ci fate in the absence and in the presence of Hh. In the absence of Hh signal, Su(fu) and Cos2 prevent Ci activation, Ci processing into the repressor form is favored and full-length Ci is exported from the nucleus. Upon Hh reception, Fu is activated, opposing Su(fu) to allow Ci to become an activator. Simultaneously the negative effect of Cos2 is alleviated, perhaps by release from the microtubules and/or a change in subcellular location. This lowers the rate of proteolysis of Ci into its repressor form and triggers nuclear import of full-length Ci. Furthermore, Cos2 and Fu promote the conversion of Ci 155 into an activator form, ultimately resulting in the transcription of Hh target genes.

Bottom Line: In flies, key Hedgehog signal transduction components have been identified including the kinesin-related protein Costal2, the serinethreonine kinase Fused, and the PEST-containing protein Suppressor of Fused.In fly embryos, Costal2, Fused, Suppressor of Fused and Cubitus interruptus are associated in at least one cytoplasmic complex, which interacts with the microtubules in a Hedgehog-dependent manner.Our results provide new insights into the possible mechanism of the cytosolic steps of Hedgehog transduction.

View Article: PubMed Central - HTML - PubMed

Affiliation: Laboratoire de génétique et évolution, Institut Jacques Monod, 2 Place Jussieu, 75005, Paris, France. monnier@ijm.jussieu.fr

ABSTRACT

Background: Hedgehog 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 including the kinesin-related protein Costal2, the serinethreonine kinase Fused, and the PEST-containing protein Suppressor of Fused. These proteins control Cubitus interruptus cleavage, nucleo-cytoplasmic localization and activation. In fly embryos, Costal2, Fused, Suppressor of Fused and Cubitus interruptus are associated in at least one cytoplasmic complex, which interacts with the microtubules in a Hedgehog-dependent manner.

Results: Here we identified and mapped direct interactions between Cos2, Fu, and Ci using an in vitro affinity assay and the yeast two-hybrid system.

Conclusions: Our results provide new insights into the possible mechanism of the cytosolic steps of Hedgehog transduction.

Show MeSH
Related in: MedlinePlus