Schematic representation of the putative signaling involved in S1P-induced HIF-1α expression in ML-1 cells.

<p>S1P stimulation up-regulates the HIF-1α protein in normoxia. This effect is dependent on activity of S1P₃ and G_i as well as their downstream effectors PKCβI, PI3K and MEK (S1P receptor signaling reviewed in 3 and 4). We suggest S1P to regulate both stability and translation of HIF-1α. S1P stimulation increases phosphorylation of mTOR via MEK and PI3K and phoshorylation of p70S6K, eIF-4E and 4E-BP1 via MEK and/or PI3K/mTOR and inhibition of p70S6K prevents S1P-induced up-regulation of HIF-1α. HIF-1 is involved in both basal and S1P-induced ML-1 migration.