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

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


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.

MeSH terms

  • Animals
  • Drosophila Proteins / genetics*
  • Drosophila Proteins / metabolism
  • Drosophila melanogaster / genetics
  • Drosophila melanogaster / growth & development
  • Eye / growth & development
  • Eye / metabolism*
  • Hedgehog Proteins / genetics
  • Kinesins / genetics*
  • Kinesins / metabolism
  • Mice
  • Photoreceptor Cells / metabolism
  • Polyubiquitin
  • Proteolysis
  • RNA, Small Interfering
  • Signal Transduction
  • Ubiquitin-Protein Ligases / genetics*
  • Ubiquitin-Protein Ligases / metabolism
  • Ubiquitination
  • Zebrafish / genetics


  • Drosophila Proteins
  • Hedgehog Proteins
  • RNA, Small Interfering
  • cos protein, Drosophila
  • Polyubiquitin
  • UBR3 protein, mouse
  • Ubiquitin-Protein Ligases
  • Kif7 protein, mouse
  • Kinesins