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Fig. 8. Model of EGFR-HER2-receptor-mediated reorganisation of N-cadherin, and of changes in glial cell migration. (Left) EGFR-HER2VEKA complexes do not directly interact with N-cadherin–β-catenin, leaving N-cadherin expressed at the plasma membrane. Owing to dominant-negative HER2VEKA the PI3K/Akt pathway is not activated. Therefore, GSK3β is not inhibited and phosphorylates β-catenin, leading to β-catenin degradation, which, consequently, might lead to inhibition of migration. N-cadherin is stabilised at the cell surface and β-catenin stays in the adherens-junction complex. (Right) Constitutively activated EGFR-HER2VE receptor complexes directly interact with N-cadherin–β-catenin. Tyrosine phosphorylation of β-catenin leads to a decrease of N-cadherin–β-catenin complexes in the plasma membrane (Lilien and Balsamo, 2005). Activation of the PI3K/Akt signalling pathway inhibits GSK3β. Thus, β-catenin is not tagged for ubiquitylation. Moreover, it has been shown recently, that Akt can phosphorylate β-catenin at Ser552, leading to its transcriptional activation (Fang et al., 2007). The strong EGFR-HER2VE signal, therefore, leads to disruption of adherens junctions, by disassociation of its components from the cell surface.
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