Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover

PLoS Biol. 2013 Nov;11(11):e1001721. doi: 10.1371/journal.pbio.1001721. Epub 2013 Nov 26.

Abstract

Hedgehog signaling plays conserved roles in controlling embryonic development; its dysregulation has been implicated in many human diseases including cancers. Hedgehog signaling has an unusual reception system consisting of two transmembrane proteins, Patched receptor and Smoothened signal transducer. Although activation of Smoothened and its downstream signal transduction have been intensively studied, less is known about how Patched receptor is regulated, and particularly how this regulation contributes to appropriate Hedgehog signal transduction. Here we identified a novel role of Smurf E3 ligase in regulating Hedgehog signaling by controlling Patched ubiquitination and turnover. Moreover, we showed that Smurf-mediated Patched ubiquitination depends on Smo activity in wing discs. Mechanistically, we found that Smo interacts with Smurf and promotes it to mediate Patched ubiquitination by targeting the K1261 site in Ptc. The further mathematic modeling analysis reveals that a bidirectional control of activation of Smo involving Smurf and Patched is important for signal-receiving cells to precisely interpret external signals, thereby maintaining Hedgehog signaling reliability. Finally, our data revealed an evolutionarily conserved role of Smurf proteins in controlling Hh signaling by targeting Ptc during development.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Cell Line
  • Drosophila Proteins / metabolism*
  • Drosophila Proteins / physiology*
  • Drosophila melanogaster / enzymology*
  • Enzyme Activation
  • Hedgehog Proteins / metabolism*
  • Protein Structure, Tertiary
  • Proteolysis
  • Receptors, Cell Surface / metabolism*
  • Receptors, G-Protein-Coupled / physiology*
  • Signal Transduction
  • Smoothened Receptor
  • Two-Hybrid System Techniques
  • Ubiquitin-Protein Ligases / metabolism*
  • Ubiquitination
  • Wings, Animal / enzymology
  • Zebrafish

Substances

  • Drosophila Proteins
  • Hedgehog Proteins
  • Receptors, Cell Surface
  • Receptors, G-Protein-Coupled
  • Smoothened Receptor
  • ptc protein, Drosophila
  • smo protein, Drosophila
  • Smurf protein, Drosophila
  • Ubiquitin-Protein Ligases

Grants and funding

This work is supported by NSFC (91019022, 31329004 and 31130036) and the Strategic Priority Research Program of the CAS (XDA01010306) to DC and by the National Basic Research Program of China (973 Program: 2013CB945000, 2011CB943902), the “Strategic Priority Research Program” of the Chinese Academy of Sciences (XDA01010405), and the National Natural Science Foundation of China (31171414) to YZ. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.