VEGF mediated activation of ERK1/2 depends on the activity of PKC. Sphingosine kinase 1 (SPHK1) has been identified as the connecting link between PKC and Ras activation. Activated SPHK1 does not activate Ras-GEF directly but rather modulates Ras-GAP activity to favour Ras activation. VEGF-mediated stimulation of SPHK1 results from the direct phosphorylation of SPHK1 by PKC (Shu et al. 2002). S225 in SPHK1 may be the target site of phosphorylation (Piston et al. 2003).