Sec14l3 potentiates VEGFR2 signaling to regulate zebrafish vasculogenesis
Sec14l3 potentiates VEGFR2 signaling to regulate zebrafish vasculogenesis
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Sec14l3 增强 VEGFR2 信号传导以调节斑马鱼血管生成
DOI：
10.1038/s41467-019-09604-0
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发表时间：
2019-04-08
影响因子：
16.6
通讯作者：
Jia, Shunji
中科院分区：
文献类型：
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作者：
Gong, Bo;Li, Zhihao;Jia, Shunji
血管内皮生长因子（VEGF）通过其酪氨酸激酶受体调节血管发生。然而，很少有人知道Sec14样磷脂酰肌醇转移蛋白（PTP）是否参与这一过程。在这里，我们表明，斑马鱼sec14l3，家庭成员之一，具体参与动脉和静脉的形成，通过调节成血管细胞和随后的静脉祖细胞的迁移过程中血管发生。通过在受体或下游效应物水平恢复VEGFR2信号传导，部分挽救了由sec14l3缺失引起的血管缺陷。生物化学分析表明，SEC14l3/SEC14L2与VEGFR2物理结合，并阻止其通过膜周酪氨酸磷酸酶PTP1B特异性地在Y1175位点去磷酸化，从而增强VEGFR2信号传导激活。同时，SEC14l3和SEC14L2与RAB5A/4A相互作用并促进其GTP结合状态的形成，这可能是VEGFR2内吞运输的关键。因此，我们得出结论，Sec14l3通过调节VEGFR2激活来控制斑马鱼的血管发生。
Vascular endothelial growth factor (VEGF) regulates vasculogenesis by using its tyrosine kinase receptors. However, little is known about whether Sec14-like phosphatidylinositol transfer proteins (PTP) are involved in this process. Here, we show that zebrafishsec14l3, one of the family members, specifically participates in artery and vein formation via regulating angioblasts and subsequent venous progenitors’ migration during vasculogenesis. Vascular defects caused bysec14l3depletion are partially rescued by restoration of VEGFR2 signaling at the receptor or downstream effector level. Biochemical analyses show that Sec14l3/SEC14L2 physically bind to VEGFR2 and prevent it from dephosphorylation specifically at the Y1175site by peri-membrane tyrosine phosphatase PTP1B, therefore potentiating VEGFR2 signaling activation. Meanwhile, Sec14l3 and SEC14L2 interact with RAB5A/4A and facilitate the formation of their GTP-bound states, which might be critical for VEGFR2 endocytic trafficking. Thus, we conclude that Sec14l3 controls vasculogenesis in zebrafish via the regulation of VEGFR2 activation.