EGFR-dependent migration of glial cells is mediated by reorganisation of 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 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.
Rappl
Anne
A
Division of Neuropathology, Institute of Pathology, Technische Universität München, Ismaninger Str. 22, 81675 München, Germany.
Piontek
Guido
G
Schlegel
Jürgen
J
D015820:Cadherins / Q000378:metabolism*; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D015536:Down-Regulation; D066246:ErbB Receptors / Q000037:antagonists & inhibitors / Q000378:metabolism*; D006801:Humans; D009457:Neuroglia / Q000166:cytology / Q000378:metabolism / Q000502:physiology*; D010766:Phosphorylation / Q000502:physiology; D011687:Purines / Q000494:pharmacology; D034741:RNA, Small Interfering / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism*; D015398:Signal Transduction; D015854:Up-Regulation; D051176:beta Catenin / Q000378:metabolism*
D015820:Cadherins; D066246:ErbB Receptors; D011687:Purines; D034741:RNA, Small Interfering; D018719:Erb-b2 Receptor Tyrosine Kinases; D051176:beta Catenin; C489254:AEE 788