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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 \u2018switch\u2019 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.<\/jats:p>","DOI":"10.1242\/jcs.258922","type":"journal-article","created":{"date-parts":[[2021,9,23]],"date-time":"2021-09-23T10:47:53Z","timestamp":1632394073000},"source":"Crossref","is-referenced-by-count":11,"title":["The role of USP7 in the Shoc2-ERK1\/2 signaling axis and Noonan-like syndrome with loose anagen hair"],"prefix":"10.1242","volume":"134","author":[{"given":"Patricia","family":"Wilson","sequence":"first","affiliation":[{"name":"University of Kentucky Department of Molecular and Cellular Biochemistry , , Lexington, KY 40536 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Lina","family":"Abdelmoti","sequence":"additional","affiliation":[{"name":"University of Kentucky Department of Molecular and Cellular Biochemistry , , Lexington, KY 40536 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Rebecca","family":"Norcross","sequence":"additional","affiliation":[{"name":"University of Kentucky Department of Molecular and Cellular Biochemistry , , Lexington, KY 40536 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eun Ryoung","family":"Jang","sequence":"additional","affiliation":[{"name":"University of Kentucky Department of Molecular and Cellular Biochemistry , , Lexington, KY 40536 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malathy","family":"Palayam","sequence":"additional","affiliation":[{"name":"University of Kentucky Department of Molecular and Cellular Biochemistry , , Lexington, KY 40536 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-8743-026X","authenticated-orcid":false,"given":"Emilia","family":"Galperin","sequence":"additional","affiliation":[{"name":"University of Kentucky Department of Molecular and Cellular Biochemistry , , Lexington, KY 40536 , USA"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"237","published-online":{"date-parts":[[2021,11,5]]},"reference":[{"key":"2024061307161873600_JCS258922C1","doi-asserted-by":"publisher","first-page":"3120","DOI":"10.1002\/ajmg.a.36697","article-title":"Phenotypic variability associated with the invariant Shoc2 c.4A&gt;G (p.Ser2Gly) missense mutation","volume":"164","author":"Baldassarre","year":"2014","journal-title":"Am. 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