PathwayStep5360 PathwayStep5362 PathwayStep5361 PathwayStep5358 PathwayStep5359 PathwayStep5356 PathwayStep5357 PathwayStep5355 Ubiquitinated RNF41 binds P-USP8 Phosphorylation of USP8 by P-AKT RNF41 binds neuregulin-activated ERBB3 Deubiquitination of RNF41 by P-USP8 RNF41 ubiquitinates activated ERBB3 Self-ubiquitination of RNF41 ERBB3 binds RNF41 ubiquitin ligase RNF41 ubiquitinates ERBB3 Downregulation of ERBB2:ERBB3 signaling Authored: Orlic-Milacic, M, 2011-11-04 Edited: D'Eustachio, P, 2011-11-07 Edited: Matthews, L, 2011-11-07 Level of plasma membrane ERBB3 is regulated by E3 ubiquitin ligase RNF41 (also known as NRDP1), which binds and ubiquitinates both inactive and activated ERBB3, targeting it for degradation (Cao et al. 2007). RNF41 is subject to self-ubiquitination which keeps its levels low when ERBB3 is not stimulated, and preserves ERBB3 expression on the cell surface (Qiu et al. 2002). Self-ubiquitination of RNF41 is reversible, through the action of ubiquitin protease USP8, an enzyme stabilized by AKT-mediated phosphorylation. Therefore, activation of AKT by ERBB2:ERBB3 signaling leads to phosphorylation of USP8 (Cao et al. 2007), which increases level of RNF41 through deubiquitination, and results in degradation of activated ERBB3 (Cao et al. 2007) - a negative feedback loop of ERBB3 signaling. Downregulation of EGFR and ERBB4 signaling is explained in pathways Signaling by EGFR and Signaling by ERBB4. Reactome Database ID Release 431358803 Reactome, http://www.reactome.org ReactomeREACT_115662 Reviewed: Neckers, LM, 2011-11-11 Reviewed: Xu, W, 2011-11-11