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
AUTHORS (17)
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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