Rho-mediated activation of PI(4)P5K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D.
Rho-mediated activation of PI(4)P5K and lipid second messengers is necessary for promotion of angiogenesis by Semaphorin 4D.
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DOI：
10.1007/s10456-011-9214-4
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发表时间：
2011-09
期刊：
影响因子：
9.8
通讯作者：
Basile JR
中科院分区：
文献类型：
--
作者：
Binmadi NO;Proia P;Zhou H;Yang YH;Basile JR
磷脂酰肌醇4-磷酸5-激酶（PI（4）P5 K）是一种I型脂质激酶，其产生脂质第二信使磷脂磷脂酰肌醇4，5-二磷酸（PI（4，5）P2）并且在肌动蛋白组织中在RhoA下游起作用。已知它在神经突重塑中起重要作用，产生与用Semaphorin 4D（Sema 4D）处理的细胞中所见相同的表型，Semaphorin 4D是一种在许多不同细胞类型中调节增殖、粘附和迁移的蛋白质。丛蛋白-B1，Sema 4D的受体，激活RhoA，以在内皮细胞中产生促血管生成信号。因此，我们观察了人脐静脉内皮细胞（HUVEC），以确定丛蛋白-B1是否通过调节PI（4）P5 K活性来控制细胞骨架。在这里，我们证明了在用Sema 4D处理HUVEC时PI（4，5）P2的Rho/ Rho激酶（ROK）依赖性产生，以及PI（4）P5 K α与丛蛋白-B1的共定位。PI（4，5）P2的形成是细胞骨架聚合所必需的，因为磷酸酶synaptojanin的表达阻断了这种作用。我们注意到用Sema 4D处理HUVEC后PLCγ的磷酸化和活化以及细胞内钙的增加，这些反应是体外观察到的促血管生成表型所必需的。综上所述，这些结果表明丛蛋白-B1通过PI（4）P5 K α信号传导和产生脂质第二信使促进内皮细胞中的血管生成。
Phosphatidylinositol 4-phosphate 5-kinase (PI(4)P5K) is a type I lipid kinase that generates the lipid second messenger phospholipid phosphatidylinositol 4,5-bisphosphate (PI(4,5)P2) and functions downstream of RhoA in actin organization. It is known to play an essential role in neurite remodeling, yielding a phenotype identical to that seen in cells treated with Semaphorin 4D (Sema4D), a protein that regulates proliferation, adhesion and migration in many different cell types. Plexin-B1, the receptor for Sema4D, activates RhoA in order to generate a pro-angiogenic signal in endothelial cells. Therefore, we looked in human umbilical vein endothelial cells (HUVEC) to determine if Plexin-B1 exerted control over the cytoskeleton by regulation of PI(4)P5K activity. Here we demonstrate the Rho/ Rho Kinase (ROK)-dependent generation of PI(4,5)P2 upon treatment of HUVEC with Sema4D, as well as co-localization of PI(4)P5Kα with Plexin-B1. Formation of PI(4,5)P2 was necessary for cytoskeletal polymerization, as expression of the phosphatase synaptojanin blocked this effect. We noted phosphorylation and activation of PLCγ and an increase in intracellular calcium upon treatment of HUVEC with Sema4D, responses that were necessary for a pro-angiogenic phenotype observed in vitro. Taken together, these results suggest that Plexin-B1 promotes angiogenesis in endothelial cells by signaling through PI(4)P5Kα and generating lipid second messengers.
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影响因子：
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