Fig. 4.

Proposed model for the cross-talk between HGF/c-Met and SphK1/S1P/Spns2/S1P1 signaling axis in HGF-mediated lamellipodia formation. HGF activates its receptor c-Met, which initiates phosphorylation of Erk and Akt kinase. Activation of Erk by HGF stimulates SPHK1 phosphorylation, which in turn converts sphingosine into S1P. HGF-mediated activation of PI3K/Akt pathway phosphorylates S1P transporter, Spns2, which facilitates efflux of intracellular S1P to extracellular milieu. The secreted S1P binds to its receptor S1P1 to initiate downstream pathways mediating lamellipodia formation of lung endothelial cells.