Promotion of Cell Spreading and Migration by Vascular Endothelial-Protein Tyrosine Phosphatase (VE-PTP) in Cooperation With Integrins
Promotion of Cell Spreading and Migration by Vascular Endothelial-Protein Tyrosine Phosphatase (VE-PTP) in Cooperation With Integrins
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DOI：
10.1002/jcp.22122
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发表时间：
2010-07-01
影响因子：
5.6
通讯作者：
Matozaki, Takashi
中科院分区：
文献类型：
--
作者：
Mori, Munemasa;Murata, Yoji;Matozaki, Takashi
血管内皮蛋白酪氨酸磷酸酶（VE-PTP）是一种受体型蛋白酪氨酸磷酸酶，其胞质区具有单个催化结构域，胞外区具有多个纤连蛋白III型样结构域。 VE-PTP 在内皮细胞中特异性表达，参与血管生成的调节。然而，VE-PTP 的这种调节的分子基础在很大程度上仍然未知。我们现在表明，VE-PTP 的强制表达促进了细胞铺展以及铺在纤连蛋白上的培养成纤维细胞中板状伪足和丝状伪足的形成。 VE-PTP 对细胞形态的这些影响需要其催化活性以及整合素和 Ras 的激活。此外，抑制 Src 家族激酶或 Rac 或 Cdc42 可以防止 VE-PTP 诱导的细胞扩散和片状伪足形成。事实上，VE-PTP 的强制表达增加了 c-Src 酪氨酸 416 处的磷酸化水平。此外，VE-PTP诱导的细胞形态变化受到FRG或Vav2显性失活形式的表达的抑制，这两种形式都是Rho家族蛋白的鸟嘌呤核苷酸交换因子，并被酪氨酸磷酸化激活。 VE-PTP 的强制表达还增强了培养的成纤维细胞的纤连蛋白依赖性迁移。相反，在人脐静脉内皮细胞或小鼠内皮瘤细胞中通过RNA干扰消除VE-PTP会抑制细胞在纤连蛋白上的扩散。这些结果表明VE-PTP与整合素协同调节血管生成过程中内皮细胞的扩散和迁移。 J.细胞。生理学。 224：195-204，2010。 (C) 2010 Wiley-Liss, Inc.
Vascular endothelial-protein tyrosine phosphatase (VE-PTP) is a receptor-type protein tyrosine phosphatase with a single catalytic domain in its cytoplasmic region and multiple fibronectin type III-like domains in its extracellular region. VE-PTP is expressed specifically in endothelial cells and is implicated in regulation of angiogenesis. The molecular basis for such regulation by VE-PTP has remained largely unknown, however. We now show that forced expression of VE-PTP promoted cell spreading as well as formation of lamellipodia and filopodia in cultured fibroblasts plated on fibronectin. These effects of VE-PTP on cell morphology required its catalytic activity as well as activation of integrins and Ras. In addition, VE-PTP-induced cell spreading and lamellipodium formation were prevented by inhibition of Src family kinases or of Rac or Cdc42. Indeed, forced expression of VE-PTP increased the level of c-Src phosphorylation at tyrosine-416. Moreover, the VE-PTP-induced changes in cell morphology were suppressed by expression of dominant negative forms of FRG or Vav2, both of which are guanine nucleotide exchange factors for Rho family proteins and are activated by tyrosine phosphorylation. Forced expression of VE-PTP also enhanced fibronectin-dependent migration of cultured fibroblasts. Conversely, depletion of VE-PTP by RNA interference in human umbilical vein endothelial cells or mouse endothelioma cells inhibited cell spreading on fibronectin. These results suggest that VE-PTP, in cooperation with integrins, regulates the spreading and migration of endothelial cells during angiogenesis. J. Cell. Physiol. 224: 195-204,2010. (C) 2010 Wiley-Liss, Inc.