Abstract
Deregulation of the evolutionarily conserved Hippo pathway has been implicated in abnormal development of animals and in several types of cancer. One mechanism of Hippo pathway regulation is achieved by controlling the stability of its regulatory components. However, the executive E3 ligases that are involved in this process, and how the process is regulated, remain poorly defined. In this study, we identify, through a genetic candidate screen, the SCFSlmb E3 ligase as a novel negative regulator of the Hippo pathway in Drosophila imaginal tissues via mediation of the degradation of Expanded (Ex). Mechanistic study shows that Slmb-mediated degradation of Ex is inhibited by the Hippo signaling. Considering the fact that Hippo signaling suppresses the transcription of ex, we propose that the Hippo pathway employs a double security mechanism to ensure fine-tuned homeostasis during development.
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Abbreviations
- Hpo:
-
Hippo
- Wts:
-
Warts
- Yki:
-
Yorkie
- Ft:
-
Fat
- Mer:
-
Merlin
- Ex:
-
Expanded
- D:
-
Dachs
- Fj:
-
Four-jointed
- Ds:
-
Dachsous
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Acknowledgements
We thank Drs E Knust, E Verheyen, Z Wang and Y Zhao for fly stocks; Drs I Edery, H McNeill, X Lin, D Pan and Z Yuan for plasmids; Drs R Fehon and K Irvine for anitibodies; William H Palmer, Jennifer Kennedy and Nick Contreras for critical reading of the manuscript. We thank all the Jiao lab members and members from Dr Li Liu and Yan Zhu's lab for stimulating discussions at the joint fly meetings. We are particularly grateful to Xuehong Liang for her technical assistance. This work was financially supported by the National Natural Science Foundation of China (31228015, 31271573, 81470846), the National Basic Research Program of China (973 Program; 2012CB825504) and the Chinese Academy of Sciences (XDA04020413-02). W-M D is supported by NIH R01GM072562 and NSF IOS-1052333. C L is supported by Beijing Natural Science Foundation (5122027).
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( Supplementary information is linked to the online version of the paper on the Cell Research website.)
Supplementary information
Supplementary information, Figure S1
slmb negatively regulates Hippo pathway activity. (PDF 330 kb)
Supplementary information, Figure S2
Genetic interaction between slmb and Hippo signaling components. (PDF 108 kb)
Supplementary information, Figure S3
Slmb specifically degrades Ex in imaginal discs. (PDF 337 kb)
Supplementary information, Figure S4
Wts antagonizes the Slmb-mediated Ex degradation. (PDF 252 kb)
Supplementary information, Figure S5
In vivo effects of crbIntra and ft on Ex stability are dependent on slmb. (PDF 443 kb)
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Zhang, H., Li, C., Chen, H. et al. SCFSlmb E3 ligase-mediated degradation of Expanded is inhibited by the Hippo pathway in Drosophila. Cell Res 25, 93–109 (2015). https://doi.org/10.1038/cr.2014.166
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DOI: https://doi.org/10.1038/cr.2014.166
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