Department of Critical Care Medicine, McGill University Health Centre, Montréal, Québec, Canada.
J Am Heart Assoc. 2013 Dec 5;2(6):e000571. doi: 10.1161/JAHA.113.000571.
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.
血管生成素-1（Ang-1）通过激活 Tie-2 受体下游的丝裂原活化蛋白激酶（MAPK）途径，促进内皮细胞的存活和迁移。双特异性磷酸酶（DUSPs）去磷酸化靶标 MAPK 上的磷酸酪氨酸和磷酸丝氨酸/苏氨酸残基。在血管内皮细胞中，DUSPs 调节 Ang-1/Tie-2 受体信号传导中 MAPK 激活的机制尚不清楚。
测量了人脐静脉内皮细胞暴露于 Ang-1 时各种 DUSPs 的表达。使用选择性 siRNA 寡核苷酸测量 DUSPs 在 Ang-1 诱导的 MAPK 激活、内皮细胞存活、迁移、分化和通透性调节中的功能作用。Ang-1 通过激活 PI-3 激酶、ERK1/2、p38 和 SAPK/JNK 途径，在人脐静脉内皮细胞中差异诱导 DUSP1、DUSP4 和 DUSP5。功能丧失 siRNA 筛选显示，DUSP1 优先使 p38 蛋白去磷酸化，参与 Ang-1 诱导的细胞迁移和分化。DUSP4 优先使 ERK1/2、p38 和 SAPK/JNK 蛋白去磷酸化，在血清剥夺条件下，参与 Ang-1 诱导的细胞迁移、几种抗细胞凋亡作用和分化。DUSP5 优先使 ERK1/2 蛋白去磷酸化，参与细胞存活和抑制通透性。
DUSP1、DUSP4 和 DUSP5 差异调节 Tie-2 受体下游的 MAPK 信号通路，从而强调了这些磷酸酶在 Ang-1 诱导的血管生成中的重要性。
