Role of c-Met/PI3k/Akt Signaling in HGF-mediated Lamellipodia Formation, ROS Generation and Motility of Lung Endothelial Cells [Cell Biology]

March 14th, 2014 by Usatyuk, P. V., Fu, P., Mohan, V., Epshtein, Y., Jacobson, J. R., Gomez-Cambronero, J., Wary, K. K., Bindokas, V., Dudek, S. M., Salgia, R., Garcia, J. G. N., Natarajan, V.

Hepatocyte growth factor (HGF) mediated signaling promotes cell proliferation and migration in a variety of cell types and plays a key role in tumorigenesis. As cell migration is important to angiogenesis, we characterized HGF-mediated effects on the formation of lamellipodia, a pre-requisite for migration using human lung microvascular endothelial cells (HLMVECs). HGF, in a dose-dependent manner, induced c-Met phosphorylation (Y1234/1235, Y1349, S985, Y1003 and Y1313), activation of PI3k (phospho-Yp85) and Akt (phospho-Thr308 and phospho-Ser473) and potentiated lamellipodia formation and HLMVEC migration. Inhibition of c-Met kinase by SU11274 significantly attenuated c-Met, PI3k and Akt phosphorylation, suppressed lamellipodia formation and endothelial cell migration. LY294002, an inhibitor of PI3k, abolished HGF-induced PI3k (Y458), and Akt (T308 and S473) phosphorylation and suppressed lamellipodia formation. Furthermore, HGF stimulated p47phox/Cortactin/Rac1 translocation to lamellipodia and ROS generation. Moreover, inhibition of c-Met/PI3k/Akt signaling axis and NADPH oxidase attenuated HGF- induced lamellipodia formation, ROS generation and cell migration. Ex Vivo experiments with mouse aortic rings revealed a role for c-Met signaling in HGF-induced sprouting and lamellipodia formation. Taken together, these data provide evidence in support of a significant role for HGF-induced c-Met/PI3k/Akt signaling and NADPH oxidase activation in lamellipodia formation and motility of lung endothelial cells.
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