Tie2-R849W mutant in venous malformations chronically activates a functional STAT1 to modulate gene expression
Tie2-R849W mutant in venous malformations chronically activates a functional STAT1 to modulate gene expression
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DOI：
10.1038/jid.2008.89
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发表时间：
2008-09-01
影响因子：
6.5
通讯作者：
Wu, Li-Wha
中科院分区：
文献类型：
--
作者：
Hu, Hsiao-Tang;Huang, Yi-Hsien;Wu, Li-Wha
Tie 2是一种内皮受体酪氨酸激酶。在残基849（Tie 2-R849 W）处色氨酸对精氨酸的氨基酸取代导致其激酶活性的配体非依赖性活化。这种突变与家族性静脉畸形（VM）有关，表现为患者病变静脉中平滑肌细胞厚度可变或缺乏。Tie 2-R849 W在内皮细胞中作用的潜在机制仍然难以捉摸。在这项研究中，我们使用腺病毒感染来区分异位Tie 2（野生型，激酶死亡K855 A，或组成型活性R849 W）表达对内皮细胞行为和Tie 2介导的下游靶点的影响。异位Tie 2减少内皮细胞增殖和血清戒断诱导的凋亡，同时刺激迁移。当比较R849 W与K855 A及其野生型对应物时，功能性酪氨酸激酶活性仅为迁移所需，并且组成型活性Tie 2-R849 W赋予对血清诱导的细胞凋亡的最高抗性，但维持在基质胶上形成的管状结构的能力最低。我们进一步证明Tie 2-R849 W长期诱导STAT 1酪氨酸磷酸化和STAT 1应答性IFN-调节因子1（IRFI）的启动子活性。虽然STAT 1磷酸化需要JNK和p38 MAPK激活，但只有JNK激活是Tie 2-R849 W激活IRF 1启动子所必需的。需要更多的研究来研究STAT 1激活在VM中的作用。
Tie2 is an endothelial receptor tyrosine kinase. An amino-acid substitution of tryptophan for arginine at residue 849 (Tie2-R849W) leads to a ligand-independent activation of its kinase activity. This mutation has been associated with familial venous malformations (VMs), manifested by variable thickness or lack of smooth-muscle cells in the veins of patient lesions. The underlying mechanism for Tie2-R849W action in endothelial cells remains elusive. In this study, we used adenoviral infection to differentiate the effects of ectopic Tie2 (wild type, kinase-dead K855A, or constitutively active R849W) expression on endothelial cellular behaviors and Tie2-mediated downstream targets. Ectopic Tie2 reduced endothelial cell proliferation and serum withdrawal-induced apoptosis, while stimulating migration. When comparing R849W with K855A and its wild-type Counterpart, a functional tyrosine kinase activity was required only for migration, and constitutively active Tie2-R849W conferred highest resistance to serum-induced apoptosis, but lowest ability to maintain tube-like structures formed on Matrigel. We further demonstrated that Tie2-R849W chronically induced STAT1 tyrosine phosphorylation and the promoter activity of STAT1-responsive IFN-regulatory factor 1 (IRFI). Although STAT1 phosphorylation required JNK and p38MAPK activation, only JNK activation was essential for IRF1 promoter activation by Tie2-R849W. Additional studies are needed to study the role of STAT1 activation in VMs.