Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover

0301 basic medicine QH301-705.5 Ubiquitin-Protein Ligases Ubiquitination Receptors, Cell Surface Smoothened Receptor Cell Line Protein Structure, Tertiary Receptors, G-Protein-Coupled Enzyme Activation 03 medical and health sciences Drosophila melanogaster Two-Hybrid System Techniques Proteolysis Animals Drosophila Proteins Wings, Animal Hedgehog Proteins Biology (General) Zebrafish Research Article Signal Transduction
DOI: 10.1371/journal.pbio.1001721 Publication Date: 2013-11-26T21:57:28Z
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.
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