Intact ERBB4 isoforms and their membrane bound and cytosolic cleavage products, m80 and s80, bind NEDD4 family E3 ubiquitin ligases WWP1 and ITCH through WW-binding motifs in the C-tail. This interaction is independent of ligand binding and ERBB4 phosphorylation. CYT1 isoforms of ERBB4 have three WW-binding motifs: PY1, PY2 and PY3. PY2 motif is unique to CYT1 isoforms and overlaps with the PIK3R1 binding site. CYT2 isoform of ERBB4 has two WW-binding motifs: PY1 and PY3. While both CYT1 and CYT2 isoforms of ERBB4 all bind WWP1, CYT1 intracellular domain exhibits higher affinity for WWP1. Based on co-immunoprecipitation experiments in which individual WW-binding motifs of ERBB4 were mutated, Feng et al. established that PY2 had the highest affinity for WWP1, followed by PY3, while PY1 showed the lowest affinity (Omerovic et al. 2007, Feng et al. 2009).
Omerovic, J, Santangelo, L, Puggioni, EM, Marrocco, J, Dall'Armi, C, Palumbo, C, Belleudi, F, Di Marcotullio, L, Frati, L, Torrisi, MR, Cesareni, G, Gulino, A, Alimandi, M
Feng, SM, Muraoka-Cook, RS, Hunter, D, Sandahl, MA, Caskey, LS, Miyazawa, K, Atfi, A, Earp HS, 3rd
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