PathwayStep5413 PathwayStep5414 PathwayStep5415 PathwayStep5416 ERBB4 binds WWP1/ITCH ubiquitin ligases NEDD4 ubiquitinates ERBB4jmAcyt1s80 dimer NEDD4 binds ERBB4jmAcyt1s80 dimer ERBB4 ubiquitination by WWP1/ITCH Downregulation of ERBB4 signaling Authored: Orlic-Milacic, M, 2011-11-04 Edited: Matthews, L, 2011-11-07 Reactome Database ID Release 431253288 Reactome, http://www.reactome.org ReactomeREACT_115828 Reviewed: Earp HS, 3rd, 2012-02-20 Reviewed: Harris, RC, 2011-11-11 Reviewed: Misior, AM, 2012-02-20 Reviewed: Zeng, F, 2011-11-11 WW-domain binding motifs in the C-tail of ERBB4 play an important role in the downregulation of ERBB4 receptor signaling, enabling the interaction of intact ERBB4, ERBB4 m80 and ERBB4 s80 with NEDD4 family of E3 ubiquitin ligases WWP1 and ITCH. The interaction of WWP1 and ITCH with intact ERBB4 is independent of receptor activation and autophosphorylation. Binding of WWP1 and ITCH ubiquitin ligases leads to ubiquitination of ERBB4 and its cleavage products, and subsequent degradation through both proteasomal and lysosomal routes (Omerovic et al. 2007, Feng et al. 2009). In addition, the s80 cleavage product of ERBB4 JM-A CYT-1 isoform is the target of NEDD4 ubiquitin ligase. NEDD4 binds ERBB4 JM-A CYT-1 s80 (ERBB4jmAcyt1s80) through its PIK3R1 interaction site and mediates ERBB4jmAcyt1s80 ubiquitination, thereby decreasing the amount of ERBB4jmAcyt1s80 that reaches the nucleus (Zeng et al. 2009).