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.