Meta-Biol

• Pathways

Protein tyrosine kinase PTPN18 dephosphorylates ERBB2, activated in response to EGF stimulation (Gensler et al. 2004), at tyrosine residues Y1196, Y1112 and Y1248 (Wang et al. 2014). PTPN18 does not dephosphorylate activated EGFR. Dephosphorylation of ERBB2 tyrosines Y1196 and Y1248 attenuates downstream activation of PI3K/AKT and RAS signaling. Dephosphorylation of Y1112 interferes with the recruitment of CBL E3 ubiquitin ligase to activated ERBB2 and CBL-mediated lysosomal route of ERBB2 down-regulation. When phosphorylated by an unknown serine/threonine kinase in an AKT-dependent manner on serine residues S419 and S423, PTPN18 recruits beta-TRCP ubiquitin ligase complex to ERBB2, thus promoting proteasome-dependent ERBB2 degradation (Wang et al. 2014).