Activation of NF-κB Is Essential for Hepatocyte Growth Factor-Mediated Proliferation and Tubulogenesis

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Abstract
Hepatocyte growth factor (HGF) and its receptor, Met, regulate a number of biological functions in epithelial and nonepithelial cells, such as survival, motility, proliferation, and tubular morphogenesis. The transcription factor NF-κB is activated in response to a wide variety of stimuli, including growth factors, and is involved in biological responses in part overlapping with those triggered by HGF. In this work we used the liver-derived MLP29 cell line to study the possible involvement of NF-κB in HGF/Met signaling. HGF stimulates NF-κB DNA binding and transcriptional activation via the canonical IκB phosphorylation-degradation cycle and via the extracellular signal-regulated kinase 1/2 and p38 mitogen-activated protein kinase cascades. Phosphatidylinositol 3-kinase is not involved in Met-mediated NF-κB activation. Blockage of NF-κB activation in MLP29 cells by forced expression of the NF-κB super-repressor IκBα2A does not interfere with HGF-induced scatter but inhibits proliferation and tubulogenesis. Surprisingly, in the same cells NF-κB appears to be dispensable for the antiapoptotic function of HGF.