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.