title: Activation of Smurf E3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover.
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.
authors.affiliation: State Key Laboratory of Reproductive Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing, China.
authors.forename: Shoujun
authors.initials: S
authors.lastname: Huang
authors.forename: Zhao
authors.initials: Z
authors.lastname: Zhang
authors.forename: Chunxia
authors.initials: C
authors.lastname: Zhang
authors.forename: Xiangdong
authors.initials: X
authors.lastname: Lv
authors.forename: Xiudeng
authors.initials: X
authors.lastname: Zheng
authors.forename: Zhenping
authors.initials: Z
authors.lastname: Chen
authors.forename: Liwei
authors.initials: L
authors.lastname: Sun
authors.forename: Hailong
authors.initials: H
authors.lastname: Wang
authors.forename: Yuanxiang
authors.initials: Y
authors.lastname: Zhu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
authors.forename: Shuyan
authors.initials: S
authors.lastname: Yang
authors.forename: Yi
authors.initials: Y
authors.lastname: Lu
authors.forename: Qinmiao
authors.initials: Q
authors.lastname: Sun
authors.forename: Yi
authors.initials: Y
authors.lastname: Tao
authors.forename: Feng
authors.initials: F
authors.lastname: Liu
authors.forename: Yun
authors.initials: Y
authors.lastname: Zhao
authors.forename: Dahua
authors.initials: D
authors.lastname: Chen
mesh_terms: D000818:Animals; D002460:Cell Line; D029721:Drosophila Proteins / Q000378:metabolism* / Q000502:physiology*; D004331:Drosophila melanogaster / Q000201:enzymology*; D004789:Enzyme Activation; D053823:Hedgehog Proteins / Q000378:metabolism*; D017434:Protein Structure, Tertiary; D059748:Proteolysis; D011956:Receptors, Cell Surface / Q000378:metabolism*; D043562:Receptors, G-Protein-Coupled / Q000502:physiology*; D015398:Signal Transduction; D000072086:Smoothened Receptor; D020798:Two-Hybrid System Techniques; D044767:Ubiquitin-Protein Ligases / Q000378:metabolism*; D054875:Ubiquitination; D014921:Wings, Animal / Q000201:enzymology; D015027:Zebrafish
chemical_list: D029721:Drosophila Proteins; D053823:Hedgehog Proteins; D011956:Receptors, Cell Surface; D043562:Receptors, G-Protein-Coupled; D000072086:Smoothened Receptor; C070844:ptc protein, Drosophila; C100664:smo protein, Drosophila; C492378:Smurf protein, Drosophila; D044767:Ubiquitin-Protein Ligases