Editors' ChoiceMAPK Cascade

From VEGF to Ras Through Sphingosine Kinase

STKE  05 Nov 2002:
Vol. 2002, Issue 157, pp. tw409-TW409
DOI: 10.1126/stke.2002.157.tw409

Many growth factor receptors activate the mitogen-activated protein kinase (MAPK) pathway producing activated, phosphorylated extracellular-regulated kinases 1 and 2 (ERK1 and ERK2), which regulate gene expression. Shu et al. used pharmacological manipulation and expression of dominant-negative constructs in cultured human umbilical vein endothelial cells and T24 bladder cell carcinoma cells. They demonstrated that the pathway activated by vascular endothelial growth factor (VEGF) that produces activated ERK1 and ERK2 involves activation of sphingosine kinase (SPK) by protein kinase C (PKC) and the production of sphingosine-1-phosphate. Inhibition of the SPK blocked the formation of the activated form of Ras [Ras-guanosine triphosphate (GTP)], however the VEGF-stimulated phosphorylation of ERK1 and ERK2 was not blocked by expression of the dominant-negative Ras mutant RasN17, which prevents the activation of Ras by guanine exchange factors. Thus, the authors propose that VEGF stimulates PKC, which activates SPK, which then promotes Ras activation, possibly by inhibiting the function of a Ras GTPase-activating protein (Ras-GAP) to activate the MAPK pathway.

X. Shu, W. Wu, R. D. Mosteller, D. Broek, Sphingosine kinase mediates vascular endothelial growth factor-induced activation of Ras and mitogen-activated protein kinases. Mol. Cell. Biol. 22, 7758-7768 (2002). [Abstract] [Full Text]