[HTML][HTML] Migration of growth factor-stimulated epithelial and endothelial cells depends on EGFR transactivation by ADAM17

T Maretzky, A Evers, W Zhou, SL Swendeman… - Nature …, 2011 - nature.com
T Maretzky, A Evers, W Zhou, SL Swendeman, PM Wong, S Rafii, K Reiss, CP Blobel
Nature communications, 2011nature.com
The fibroblast growth factor receptor 2-IIIb (FGFR2b) and the vascular endothelial growth
factor receptor 2 (VEGFR2) are tyrosine kinases that can promote cell migration and
proliferation and have important roles in embryonic development and cancer. Here we show
that FGF7/FGFR2b-dependent activation of epidermal growth factor receptor
(EGFR)/ERK1/2 signalling and cell migration in epithelial cells require stimulation of the
membrane-anchored metalloproteinase ADAM17 and release of heparin-binding epidermal …
Abstract
The fibroblast growth factor receptor 2-IIIb (FGFR2b) and the vascular endothelial growth factor receptor 2 (VEGFR2) are tyrosine kinases that can promote cell migration and proliferation and have important roles in embryonic development and cancer. Here we show that FGF7/FGFR2b-dependent activation of epidermal growth factor receptor (EGFR)/ERK1/2 signalling and cell migration in epithelial cells require stimulation of the membrane-anchored metalloproteinase ADAM17 and release of heparin-binding epidermal growth factor (HB-EGF). Moreover, VEGF-A/VEGFR2-induced migration of human umbilical vein endothelial cells also depends on EGFR/ERK1/2 signalling and shedding of the ADAM17 substrate HB-EGF. The pathway used by the FGF7/FGFR2b signalling axis to stimulate shedding of substrates of ADAM17, including ligands of the EGFR, involves Src, p38 mitogen-activated protein-kinase and PI3K, but does not require the cytoplasmic domain of ADAM17. Based on these findings, ADAM17 emerges as a central component in a triple membrane-spanning pathway between FGFR2b or VEGFR2 and EGFR/ERK1/2 that is required for cell migration in keratinocytes and presumably also in endothelial cells.
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