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

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.

SUBMITTER: Maretzky T

PROVIDER: S-EPMC3074487 | biostudies-literature | 2011

REPOSITORIES: biostudies-literature

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

Maretzky Thorsten T Evers Astrid A Zhou Wenhui W Swendeman Steven L SL Wong Pui-Mun PM Rafii Shahin S Reiss Karina K Blobel Carl P CP

Nature communications 20110101

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-bindin ...[more]

PMID: 21407195

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Project description:The pleiotrophic cytokine interleukin (IL)-13 features prominently in allergic and inflammatory diseases. In allergic asthma, IL-13 is well established as an inducer of airway inflammation and tissue remodeling. We demonstrated previously that IL-13 induces release of transforming growth factor-alpha (TGFalpha) from human bronchial epithelial cells, with proliferation of these cells mediated by the autocrine/paracrine action of this growth factor. TGFalpha exists as an integral membrane protein and requires proteolytic processing to its mature form, with a disintegrin and metalloproteinase (ADAM)17 responsible for this processing in a variety of tissues.In this study, normal human bronchial epithelial (NHBE) cells grown in air/liquid interface (ALI) culture were used to examine the mechanisms whereby IL-13 induces release of TGFalpha and cellular proliferation. Inhibitors and antisense RNA were used to examine the role of ADAM17 in these processes, while IL-13-induced changes in the intracellular expression of TGFalpha and ADAM17 were visualized by confocal microscopy.IL-13 was found to induce proliferation of NHBE cells, and release of TGFalpha, in an ADAM17-dependent manner; however, this IL-13-induced proliferation did not appear to result solely from ADAM17 activation. Rather, IL-13 induced a change in the location of TGFalpha expression from intracellular to apical regions of the NHBE cells. The apical region was also found to be a site of significant ADAM17 expression, even prior to IL-13 stimulation.Results from this study indicate that ADAM17 mediates IL-13-induced proliferation and TGFalpha shedding in NHBE cells. Furthermore, they provide the first example wherein a cytokine (IL-13) induces a change in the intracellular expression pattern of a growth factor, apparently inducing redistribution of intracellular stores of TGFalpha to the apical region of NHBE cells where expression of ADAM17 is prominent. Thus, IL-13-induced, ADAM17-mediated release of TGFalpha, and subsequent epithelial cell proliferation, could contribute to the epithelial hypertrophy, as well as other features, associated with airway remodeling in allergic asthma.

Dataset Information

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

Publications

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

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