Sonic hedgehog signaling regulates Gli2 transcriptional activity by suppressing its processing and degradation.
TLDR
These findings provide the first demonstration of a molecular mechanism by which the Gli2 transcriptional activity is regulated by Shh signaling and in addition to being processed, Gli 2 full-length protein is readily degraded.Abstract:
Gli2 and Gli3 are the primary transcription factors that mediate Sonic hedgehog (Shh) signals in the mouse. Gli3 mainly acts as a transcriptional repressor, because the majority of full-length Gli3 protein is proteolytically processed. Gli2 is mostly regarded as a transcriptional activator, even though it is also suggested to have a weak repressing activity. What the molecular basis for its possible dual function is and how its activity is regulated by Shh signaling are largely unknown. Here we demonstrate that unlike the results seen with Gli3 and Cubitus Interruptus, the fly homolog of Gli, only a minor fraction of Gli2 is proteolytically processed to form a transcriptional repressor in vivo and that in addition to being processed, Gli2 full-length protein is readily degraded. The degradation of Gli2 requires the phosphorylation of a cluster of numerous serine residues in its carboxyl terminus by protein kinase A and subsequently by casein kinase 1 and glycogen synthase kinase 3. The phosphorylated Gli2 interacts directly with betaTrCP in the SCF ubiquitin-ligase complex through two binding sites, which results in Gli2 ubiquitination and subsequent degradation by the proteasome. Both processing and degradation of Gli2 are suppressed by Shh signaling in vivo. Our findings provide the first demonstration of a molecular mechanism by which the Gli2 transcriptional activity is regulated by Shh signaling.read more
Citations
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SCF/{beta}-TrCP promotes glycogen synthase kinase 3-dependent degradation of the Nrf2 transcription factor in a Keap1-independent manner.
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References
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Journal ArticleDOI
Cyclopia and defective axial patterning in mice lacking Sonic hedgehog gene function.
Chin Chiang,Ying Litingtung,Eric Lee,Keith E. Young,Jeffrey L Corden,Heiner Westphal,Philip A. Beachy +6 more
TL;DR: Targeted gene disruption in the mouse shows that the Sonic hedgehog(Shh) gene plays a critical role in patterning of vertebrate embryonic tissues, including the brain and spinal cord, the axial skeleton and the limbs.
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Hedgehog signaling in animal development: paradigms and principles.
TL;DR: In their screen for mutations that disrupt the Drosophila larval body plan, these authors identified several that cause the duplication of denticles and an accompanying loss of naked cuticle, characteristic of the posterior half of each segment.
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Regulation of the Hedgehog and Wingless signalling pathways by the F-box/WD40-repeat protein Slimb
Jin Jiang,Gary Struhl +1 more
TL;DR: A new gene is described, slimb (for supernumerary limbs), which negatively regulates both of these signal transduction pathways and encodes a conserved F-box/WD40-repeat protein related to Cdc4p, a protein in budding yeast that targets cell-cycle regulators for degradation by the ubiquitin/proteasome pathway.
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Hedgehog-Regulated Processing of Gli3 Produces an Anterior/Posterior Repressor Gradient in the Developing Vertebrate Limb
TL;DR: It is demonstrated that PKA-dependent processing of vertebrate Gli3 in developing limb similarly generates a potent repressor in a manner antagonized by apparent long-range signaling from posteriorly localized Sonic hedgehog protein.
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The SCFβ-TRCP–ubiquitin ligase complex associates specifically with phosphorylated destruction motifs in IκBα and β-catenin and stimulates IκBα ubiquitination in vitro
TL;DR: The transcription factor NF-κB has a central role in cellular stress and inflammatory responses by controlling cytokine-inducible gene expression and lymphocyte stimulation by antigens and little is known about the molecules responsible for ubiquitination.