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 zebrafish sec14l3, 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 by sec14l3 depletion 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 Y¹¹⁷⁵ site 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.

血管内皮生长因子（VEGF）通过使用其酪氨酸激酶受体来调节血管生成。但是，关于此过程是否涉及Sec14样磷脂酰肌醇转移蛋白（PTP）知之甚少。在这里，我们显示，斑马鱼sec14l3（家族成员之一）通过调节成血管细胞和随后的血管祖细胞在血管生成过程中的迁移而专门参与动脉和静脉的形成。通过在受体或下游效应子水平上恢复VEGFR2信号传导，可以部分挽救由sec14l3耗竭引起的血管缺陷。生化分析表明，Sec14l3 / SEC14L2与VEGFR2物理结合，可防止其在Y ¹¹⁷⁵处特别去磷酸化膜上酪氨酸磷酸酶PTP1B的位点，因此增强了VEGFR2信号的激活。同时，Sec1413和SEC14L2与RAB5A / 4A相互作用并促进其GTP结合状态的形成，这对于VEGFR2内吞运输至关重要。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生成。