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Conventionally, their biological functions have been associated with regulating WNT signaling receptor ubiquitination and degradation. However, our proteogenomic studies have revealed EGFR as the protein most negatively correlated with\n                    <jats:italic>ZNRF3\/RNF43<\/jats:italic>\n                    mRNA levels in multiple human cancers. Through biochemical investigations, we demonstrate that ZNRF3\/RNF43 interact with EGFR via their extracellular domains, leading to EGFR ubiquitination and subsequent degradation facilitated by the E3 ligase RING domain. Overexpression of\n                    <jats:italic>ZNRF3<\/jats:italic>\n                    reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of\n                    <jats:italic>ZNRF3<\/jats:italic>\n                    \/\n                    <jats:italic>RNF43<\/jats:italic>\n                    stimulates cell growth and tumorigenesis through upregulated EGFR signaling. Together, these data suggest ZNRF3 and RNF43 as novel E3 ubiquitin ligases of EGFR and establish the inactivation of ZNRF3\/RNF43 as a driver of increased EGFR signaling, ultimately promoting cancer progression. This discovery establishes a connection between two fundamental signaling pathways, EGFR and WNT, at the level of cytoplasmic membrane receptors, uncovering a novel mechanism underlying the frequent co-activation of EGFR and WNT signaling in development and cancer.\n                  <\/jats:p>","DOI":"10.7554\/elife.95639","type":"journal-article","created":{"date-parts":[[2024,3,19]],"date-time":"2024-03-19T10:29:58Z","timestamp":1710844198000},"update-policy":"https:\/\/doi.org\/10.7554\/elife.95639","source":"Crossref","is-referenced-by-count":2,"title":["Loss of ZNRF3\/RNF43 unleashes EGFR in cancer"],"prefix":"10.7554","volume":"13","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-6057-0393","authenticated-orcid":true,"given":"Fei","family":"Yue","sequence":"first","affiliation":[{"id":[{"id":"https:\/\/ror.org\/02pttbw34","id-type":"ROR","asserted-by":"publisher"}],"name":"Lester and Sue Smith Breast Center, Baylor College of Medicine","place":["Houston, United 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