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首页> 外文期刊>Cell biology international. >Phosphorylation of Dab2 is involved in inhibited VEGF‐VEGFR‐2 signaling induced by downregulation of syndecan‐1 in glomerular endothelial cell
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Phosphorylation of Dab2 is involved in inhibited VEGF‐VEGFR‐2 signaling induced by downregulation of syndecan‐1 in glomerular endothelial cell

机译：DAB2的磷酸化参与抑制VEGF-VEGFR-2信号传导，其在肾小球内皮细胞中的单癸癸癸辛烷-1的下调诱导

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Abstract Disabled‐2 (Dab2) and PAR‐3 (partitioning defective 3) are reported to play critical roles in maintaining retinal microvascular endothelial cells biology by regulating VEGF‐VEGFR‐2 signaling. The role of Dab2 and PAR‐3 in glomerular endothelial cell (GEnC) is unclear. In this study, we found that, no matter whether with vascular endothelial growth factor (VEGF) treatment or not, decreased expression of Dab2 could lead to cell apoptosis by preventing activation of VEGF‐VEGFR‐2 signaling in GEnC, accompanied by reduced membrane VEGFR‐2 expression. And silencing of PAR‐3 gene expression caused increased apoptosis of GEnC by inhibiting activation of VEGF‐VEGFR‐2 signaling and membrane VEGFR‐2 expression. In our previous research, we found that the silencing of syndecan‐1 gene expression inhibited VEGF‐VEGFR‐2 signaling by modulating internalization of VEGFR‐2. And our further research demonstrated that downregulation of syndecan‐1 lead to no significant change in the expression of Dab2 and PAR‐3 both at messenger RNA and protein levels in GEnC, while phosphorylation of Dab2 was significantly increased in GEnC transfected with Dab2 small interfering RNA (siRNA) compared with control siRNA. Atypical protein kinase C (aPKC) could induce phosphorylation of Dab2, thus negatively regulating VEGF‐VEGFR‐2 signaling. And we found that decreased expression of syndecan‐1 lead to activation of aPKC, and aPKC inhibitor treatment could block phosphorylation of Dab2 in GEnC. Besides, aPKC inhibitor treatment could activate VEGF‐VGEFR‐2 signaling in GEnC transfected with syndecan‐1 siRNA in a dose‐dependent manner. In conclusion, we speculated that phosphorylation of Dab2 is involved in preventing activation of VEGF‐VEGFR‐2 signaling in GEnC transfected with syndecan‐1 siRNA. This provides a new target for the therapy of GEnC injury and kidney disease.
机译：标准杆数为2（DAB2）和标准杆数3（分区缺陷3）对VEGF VEGFR 2信号通路的调控起到维持视网膜微血管内皮细胞生物学的作用。标准杆数和PAR 3在肾小球内皮细胞中的作用尚不清楚。在这项研究中，我们发现，无论是否使用血管内皮生长因子（VEGF）治疗，Dab2表达的降低都可能通过阻止GEnC中VEGF-VEGFR-2信号的激活，伴随着膜VEGFR-2表达的降低而导致细胞凋亡。标准杆数3基因表达的沉默通过抑制VEGF VEGFR 2信号转导和VEGFR 2的表达而引起GeNC细胞凋亡增加。在我们之前的研究中，我们发现syndecan-1基因表达的沉默通过调节VEGFR-2的内化抑制了VEGF-VEGFR-2信号传导。标准杆数和标准杆数的变化对GeNC转染DAb2和PAR 1的影响无显著性改变，而DAB2小干扰RNA（siRNA）转染GeNC时，DAB2的磷酸化水平明显高于对照siRNA。非典型蛋白激酶C（aPKC）可诱导Dab2磷酸化，从而负性调节VEGF-VEGFR-2信号。我们发现，syndecan-1表达的降低会导致aPKC的激活，aPKC抑制剂治疗可以阻断GEnC中Dab2的磷酸化。此外，aPKC抑制剂治疗可以剂量依赖性地激活转染syndecan-1 siRNA的GEnC中的VEGF-VGEFR-2信号。总之，我们推测Dab2的磷酸化参与阻止转染syndecan-1 siRNA的GEnC中VEGF-VEGFR-2信号的激活。这为遗传损伤和肾脏疾病的治疗提供了新的靶点。

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