The ERK1/2 (also known as MAPK3 and MAPK1, respectively) signaling pathway is critical in organismal development and tissue morphogenesis. Deregulation of this pathway leads to congenital abnormalities with severe developmental dysmorphisms. The core ERK1/2 cascade relies on scaffold proteins, such as Shoc2 to guide and fine-tune its signals. Mutations in SHOC2 lead to the development of the pathology termed Noonan-like Syndrome with Loose Anagen Hair (NSLAH). However, the mechanisms underlying the functions of Shoc2 and its contributions to disease progression remain unclear. Here, we show that ERK1/2 pathway activation triggers the interaction of Shoc2 with the ubiquitin-specific protease USP7. We reveal that, in the Shoc2 module, USP7 functions as a molecular 'switch' that controls the E3 ligase HUWE1 and the HUWE1-induced regulatory feedback loop.We also demonstrate that disruption of Shoc2-USP7 binding leads to aberrant activation of the Shoc2-ERK1/2 axis. Importantly, our studies reveal a possible role for USP7 in the pathogenic mechanisms underlying NSLAH, thereby extending our understanding of how ubiquitin-specific proteases regulate intracellular signaling.
|Journal||Journal of Cell Science|
|State||Published - Nov 2021|
Bibliographical noteFunding Information:
This project was supported by grants from the National Institute of General Medical Sciences, National Institutes of Health and the Office of Extramural Research, National Institutes of Health (R35GM136295 and 1S10OD025033-01, respectively, to E.G.). Its contents are solely the responsibility of the authors and do not
We thank Drs Tianyan Gao, Louis Hersh, Ann Morris and Charles Waechter for critical reading of the manuscript, and Ryan Potts for providing critical reagents. This study makes use of data generated by the DECIPHER community who bear no responsibility for the further analysis or interpretation of the data. A full list of centers who contributed to the generation of the data is available from www.decipher. sanger.ac.uk/about/stats and via email from email@example.com. Funding for the DECIPHER project was provided by The Wellcome Trust. Some of the text in this paper formed part of Hyeln Jang’s PhD thesis in the Department of Molecular and Cellular Biochemistry at the University of Kentucky in 2018.
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- Shoc2 scaffold
ASJC Scopus subject areas
- Cell Biology