Cargando…

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

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 transduce...

Descripción completa

Detalles Bibliográficos
Autores principales: Huang, Shoujun, Zhang, Zhao, Zhang, Chunxia, Lv, Xiangdong, Zheng, Xiudeng, Chen, Zhenping, Sun, Liwei, Wang, Hailong, Zhu, Yuanxiang, Zhang, Jing, Yang, Shuyan, Lu, Yi, Sun, Qinmiao, Tao, Yi, Liu, Feng, Zhao, Yun, Chen, Dahua
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2013
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841102/
https://www.ncbi.nlm.nih.gov/pubmed/24302888
http://dx.doi.org/10.1371/journal.pbio.1001721
_version_ 1782478598563692544
author Huang, Shoujun
Zhang, Zhao
Zhang, Chunxia
Lv, Xiangdong
Zheng, Xiudeng
Chen, Zhenping
Sun, Liwei
Wang, Hailong
Zhu, Yuanxiang
Zhang, Jing
Yang, Shuyan
Lu, Yi
Sun, Qinmiao
Tao, Yi
Liu, Feng
Zhao, Yun
Chen, Dahua
author_facet Huang, Shoujun
Zhang, Zhao
Zhang, Chunxia
Lv, Xiangdong
Zheng, Xiudeng
Chen, Zhenping
Sun, Liwei
Wang, Hailong
Zhu, Yuanxiang
Zhang, Jing
Yang, Shuyan
Lu, Yi
Sun, Qinmiao
Tao, Yi
Liu, Feng
Zhao, Yun
Chen, Dahua
author_sort Huang, Shoujun
collection PubMed
description 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.
format Online
Article
Text
id pubmed-3841102
institution National Center for Biotechnology Information
language English
publishDate 2013
publisher Public Library of Science
record_format MEDLINE/PubMed
spelling pubmed-38411022013-12-03 Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover Huang, Shoujun Zhang, Zhao Zhang, Chunxia Lv, Xiangdong Zheng, Xiudeng Chen, Zhenping Sun, Liwei Wang, Hailong Zhu, Yuanxiang Zhang, Jing Yang, Shuyan Lu, Yi Sun, Qinmiao Tao, Yi Liu, Feng Zhao, Yun Chen, Dahua PLoS Biol Research Article 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. Public Library of Science 2013-11-26 /pmc/articles/PMC3841102/ /pubmed/24302888 http://dx.doi.org/10.1371/journal.pbio.1001721 Text en © 2013 Huang et al http://creativecommons.org/licenses/by/4.0/ This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are properly credited.
spellingShingle Research Article
Huang, Shoujun
Zhang, Zhao
Zhang, Chunxia
Lv, Xiangdong
Zheng, Xiudeng
Chen, Zhenping
Sun, Liwei
Wang, Hailong
Zhu, Yuanxiang
Zhang, Jing
Yang, Shuyan
Lu, Yi
Sun, Qinmiao
Tao, Yi
Liu, Feng
Zhao, Yun
Chen, Dahua
Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover
title Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover
title_full Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover
title_fullStr Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover
title_full_unstemmed Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover
title_short Activation of Smurf E3 Ligase Promoted by Smoothened Regulates Hedgehog Signaling through Targeting Patched Turnover
title_sort activation of smurf e3 ligase promoted by smoothened regulates hedgehog signaling through targeting patched turnover
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3841102/
https://www.ncbi.nlm.nih.gov/pubmed/24302888
http://dx.doi.org/10.1371/journal.pbio.1001721
work_keys_str_mv AT huangshoujun activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT zhangzhao activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT zhangchunxia activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT lvxiangdong activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT zhengxiudeng activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT chenzhenping activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT sunliwei activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT wanghailong activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT zhuyuanxiang activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT zhangjing activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT yangshuyan activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT luyi activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT sunqinmiao activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT taoyi activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT liufeng activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT zhaoyun activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover
AT chendahua activationofsmurfe3ligasepromotedbysmoothenedregulateshedgehogsignalingthroughtargetingpatchedturnover