Regulation of angiopoietin-1/Tie-2 receptor signaling in endothelial cells by dual-specificity phosphatases 1,4,and 5.

Angiopoietin-1 (ang-1) promotes survival and migration of endothelial cells,in part through the activation of mitogen-activated protein kinase (mapk) pathways downstream of tie-2 receptors. dual-specificity phosphatases (dusps) dephosphorylate phosphotyrosine and phosphoserine/phosphothreonine residues on target mapks. the mechanisms by which dusps modulate mapk activation in ang-1/tie-2 receptor signaling are unknown in endothelial cells. expression of various dusps in human umbilical vein endothelial cells exposed to ang-1 was measured. the functional roles of dusps in ang-1-induced regulation of mapk activation,endothelial cell survival,migration,differentiation,and permeability were measured using selective sirna oligos. ang-1 differentially induces dusp1,dusp4,and dusp5 in human umbilical vein endothelial cells through activation of the pi-3 kinase,erk1/2,p38,and sapk/jnk pathways. lack-of-function sirna screening revealed that dusp1 preferentially dephosphorylates p38 protein and is involved in ang-1-induced cell migration and differentiation. dusp4 preferentially dephosphorylates erk1/2,p38,and sapk/jnk proteins and,under conditions of serum deprivation,is involved in ang-1-induced cell migration,several antiapoptotic effects,and differentiation. dusp5 preferentially dephosphorylates erk1/2 proteins and is involved in cell survival and inhibition of permeability. dusp1,dusp4,and dusp5 differentially modulate mapk signaling pathways downstream of tie-2 receptors,thus highlighting the importance of these phosphatases to ang-1-induced angiogenesis.