Receptor tyrosine kinases of the EGFR family exert their various effects on cellular function through the formation of different dimeric receptor complexes. To investigate the functional impact of EGFR-HER2 heterodimers on migration of glial tumour cells, we stably transfected different HER2 constructs, including a constitutively active (HER2VE) and a dominant-negative (HER2VEKA) receptor, in the EGFR-overexpressing human glioma cell line LN18. Interference of EGFR activation through HER2VEKA inhibited cellular migration, whereas EGFR activation through HER2VE increased migration. These results were corroborated by inhibition of EGFR-HER2 signalling with tyrosine kinase inhibitors, because only the blocking of both receptors in HER2VE-cells with the bi-specific inhibitor AEE788 downregulated migration to levels comparable with those in HER2VEKA cells. The non-migratory phenotype was mediated through upregulation of N-cadherin and its recruitment to the cell membrane in HER2VEKA cells; downregulation of N-cadherin by RNAi restored migration in HER2VEKA cells and N-cadherin was also downregulated in migrating HER2VE-cells. Downregulation of N-cadherin levels in the plasma membrane was accompanied by a direct interaction of the EGFR-HER2 and N-cadherin-beta-catenin complexes, leading to tyrosine phosphorylation of beta-catenin. These results indicate that HER2 affects glial-cell migration by modulating EGFR-HER2 signal transduction, and that this effect is mediated by N-cadherin.     «

Receptor tyrosine kinases of the EGFR family exert their various effects on cellular function through the formation of different dimeric receptor complexes. To investigate the functional impact of EGFR-HER2 heterodimers on migration of glial tumour cells, we stably transfected different HER2 constructs, including a constitutively active (HER2VE) and a dominant-negative (HER2VEKA) receptor, in the EGFR-overexpressing human glioma cell line LN18. Interference of EGFR activation through HER2VEKA in...     »