Back to Search
Start Over
Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 through Poly-ubiquitination
- Source :
- PLoS Genetics, PLoS Genetics, Vol 12, Iss 5, p e1006054 (2016)
- Publication Year :
- 2016
- Publisher :
- Public Library of Science, 2016.
-
Abstract
- Hedgehog (Hh) signaling regulates multiple aspects of metazoan development and tissue homeostasis, and is constitutively active in numerous cancers. We identified Ubr3, an E3 ubiquitin ligase, as a novel, positive regulator of Hh signaling in Drosophila and vertebrates. Hh signaling regulates the Ubr3-mediated poly-ubiquitination and degradation of Cos2, a central component of Hh signaling. In developing Drosophila eye discs, loss of ubr3 leads to a delayed differentiation of photoreceptors and a reduction in Hh signaling. In zebrafish, loss of Ubr3 causes a decrease in Shh signaling in the developing eyes, somites, and sensory neurons. However, not all tissues that require Hh signaling are affected in zebrafish. Mouse UBR3 poly-ubiquitinates Kif7, the mammalian homologue of Cos2. Finally, loss of UBR3 up-regulates Kif7 protein levels and decreases Hh signaling in cultured cells. In summary, our work identifies Ubr3 as a novel, evolutionarily conserved modulator of Hh signaling that boosts Hh in some tissues.<br />Author Summary Hedgehog signaling regulates many important biological processes and has been linked to developmental disorders, wound healing, and cancer. Although the major components in the pathway have been well studied in Drosophila and vertebrates, how the signaling is regulated by different modulators is not well understood. Here, we take advantage of a fly forward genetic screen to isolate Ubr3. We show that it is a novel modulator that regulates Hh signaling. Loss of ubr3 leads to Hh signaling defects in developing eyes of Drosophila, and affects eye, and somite and sensory neuron development in zebrafish. However, Hh signaling is not affected in all cells known to be dependent on Hh signaling as loss of ubr3 in the fly wing and zebrafish inner ear are not affected. This suggests that Ubr3 is a modulator that is only required in some Hh dependent organs/cells. We have shown that Ubr3 down-regulates the levels of Cos2 and its mammalian homolog Kif7, key negative regulators of Hh signaling, through poly-ubiquitination. The poly-ubiquitination of Cos2 by Ubr3 is enhanced by Hh activation, suggesting that it functions in a positive feedback that modulates Hh activation.
- Subjects :
- 0301 basic medicine
Cancer Research
Kinesins
Eye
Biochemistry
Mice
0302 clinical medicine
Ubiquitin
Cell Signaling
Medicine and Health Sciences
Drosophila Proteins
Small interfering RNAs
Post-Translational Modification
RNA, Small Interfering
Polyubiquitin
Zebrafish
Genetics (clinical)
Tissue homeostasis
Genetics
biology
Drosophila Melanogaster
Fishes
Animal Models
Hedgehog signaling pathway
3. Good health
Ubiquitin ligase
Cell biology
Precipitation Techniques
Insects
Nucleic acids
Osteichthyes
Vertebrates
Drosophila
Signal transduction
Anatomy
Drosophila Protein
Research Article
Signal Transduction
animal structures
lcsh:QH426-470
Arthropoda
Ubiquitin-Protein Ligases
Research and Analysis Methods
03 medical and health sciences
Model Organisms
Ocular System
Animals
Immunoprecipitation
Hedgehog Proteins
Photoreceptor Cells
Molecular Biology Techniques
Non-coding RNA
Hedgehog
Molecular Biology
Ecology, Evolution, Behavior and Systematics
Ubiquitination
Organisms
Biology and Life Sciences
Proteins
Cell Biology
biology.organism_classification
Invertebrates
Gene regulation
lcsh:Genetics
030104 developmental biology
Proteolysis
biology.protein
Hedgehog Signaling
Eyes
RNA
Gene expression
Head
030217 neurology & neurosurgery
Cloning
Subjects
Details
- Language :
- English
- ISSN :
- 15537404 and 15537390
- Volume :
- 12
- Issue :
- 5
- Database :
- OpenAIRE
- Journal :
- PLoS Genetics
- Accession number :
- edsair.doi.dedup.....9d4e429f088e7ca634a9194b1547931f