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PLoS Genet. 2016 May 19;12(5):e1006054. doi: 10.1371/journal.pgen.1006054. eCollection 2016 May.

Ubr3, a Novel Modulator of Hh Signaling Affects the Degradation of Costal-2 and Kif7 through Poly-ubiquitination.

Author information

1
Program in Developmental Biology, Baylor College of Medicine, Houston, Texas, United States of America.
2
Markey Cancer Center and Department of Molecular and Cellular Biochemistry, University of Kentucky, Lexington, Kentucky, United States of America.
3
Institute of Neuroscience, University of Oregon, Eugene, Oregon, United States of America.
4
Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, Texas, United States of America.
5
Jan and Dan Duncan Neurological Research Institute, Texas Children's Hospital, Houston, Texas, United States of America.
6
Howard Hughes Medical Institute, Baylor College of Medicine, Houston, Texas, United States of America.
7
Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, United States of America.
8
Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, Texas, United States of America.
9
Department of Neuroscience, Baylor College of Medicine, Houston, Texas, United States of America.

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.

PMID:
27195754
PMCID:
PMC4873228
DOI:
10.1371/journal.pgen.1006054
[Indexed for MEDLINE]
Free PMC Article

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