Language
English
Publication Date
4-10-2026
Journal
eLife
DOI
10.7554/eLife.95639
PMID
41960900
PMCID
PMC13068435
PubMedCentral® Posted Date
4-10-2026
PubMedCentral® Full Text Version
Post-print
Abstract
ZNRF3 and RNF43 are closely related transmembrane E3 ubiquitin ligases with significant roles in development and cancer. 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 ZNRF3/RNF43 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 ZNRF3 reduces EGFR levels and suppresses cancer cell growth in vitro and in vivo, whereas knockout of ZNRF3/RNF43 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.
Keywords
Ubiquitin-Protein Ligases, Humans, ErbB Receptors, Animals, DNA-Binding Proteins, Ubiquitination, Neoplasms, Mice, Signal Transduction, Cell Line, Tumor, Oncogene Proteins
Published Open-Access
yes
Recommended Citation
Yue, Fei; Ku, Amy T; Stevens, Payton D; et al., "Loss of ZNRF3/RNF43 Unleashes EGRFR in Cancer" (2026). Faculty, Staff and Students Publications. 7009.
https://digitalcommons.library.tmc.edu/baylor_docs/7009