title: Axl-EGFR receptor tyrosine kinase hetero-interaction provides EGFR with access to pro-invasive signalling in cancer cells.
abstract: Acquired resistance to conventional and targeted therapies is becoming a major hindrance in cancer management. It is increasingly clear that cancer cells are able to evolve and rewire canonical signalling pathways to their advantage, thus evading cell death and promoting cell invasion. The Axl receptor tyrosine kinase (RTK) has been shown to modulate acquired resistance to EGFR-targeted therapies in both breast and lung cancers. Glioblastoma multiforme (GBM) is a highly infiltrative and invasive form of brain tumour with little response to therapy. Both Axl and EGFR have been identified as major players in gliomagenesis and invasiveness. However, the mechanisms underlying a potential signalling crosstalk between EGFR and Axl RTKs are unknown. The purpose of this study was to investigate this novel and unconventional interaction among RTKs of different families in human GBM cells. With the use of western blotting, in vitro kinase activity, co-immunoprecipitation and bimolecular fluorescence complementation assays, we show that EGF stimulates activation of Axl kinase and that there is a hetero-interaction between the two RTKs. Through small interfering RNA knockdown and quantitative PCR screening, we identified distinct gene expression patterns in GBM cells that were specifically regulated by signalling from EGFR-EGFR, Axl-Axl and EGFR-Axl RTK parings. These included genes that promote invasion, which were activated only via the EGFR-Axl axis (MMP9), while EGFR-EGFR distinctly regulated the cell cycle and Axl-Axl regulated invasion. Our findings provide critical insights into the role of EGFR-Axl hetero-dimerisation in cancer cells and reveal regulation of cell invasion via Axl as a novel function of EGFR signalling.
authors: Institute of Biomedical and Biomolecular Science, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors: M
authors: M
authors: Vouri
authors: Garvan Institute of Medical Research, Sydney, New South Wales, Australia.|St Vincent's Hospital Clinical School, University of New South Wales, Sydney, New South Wales, Australia.|School of Medicine and Medical Science, University College, Dublin, Ireland.
authors: D R
authors: DR
authors: Croucher
authors: Garvan Institute of Medical Research, Sydney, New South Wales, Australia.|Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
authors: S P
authors: SP
authors: Kennedy
authors: Institute of Biomedical and Biomolecular Science, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors: Q
authors: Q
authors: An
authors: Institute of Biomedical and Biomolecular Science, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors: G J
authors: GJ
authors: Pilkington
authors: Institute of Biomedical and Biomolecular Science, School of Pharmacy and Biomedical Sciences, University of Portsmouth, Portsmouth, UK.
authors: S
authors: http://orcid.org/0000-0002-4539-0888
authors: S
authors: Hafizi