Regulation of Angiopoietin‐1/Tie‐2 Receptor Signaling in Endothelial Cells by Dual‐Specificity Phosphatases 1, 4, and 5

BACKGROUND: 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. METHODS AND RESULTS: 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. CONCLUSIONS: 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.