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.
We thank Daniel Besser for helpful discussion and reagents.
This work was supported by funds from AIRC and CNR (Progetto Finalizzato Biotecnologie). The continuing support of the Compagnia di San Paolo and Fondazione CRT to C.P.'s laboratory is gratefully acknowledged.