VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd.
VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd.
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DOI：
10.1084/jem.20111343
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发表时间：
2012-07-02
期刊：
影响因子：
--
通讯作者：
Claesson-Welsh L
中科院分区：
文献类型：
--
作者：
Sun Z;Li X;Massena S;Kutschera S;Padhan N;Gualandi L;Sundvold-Gjerstad V;Gustafsson K;Choy WW;Zang G;Quach M;Jansson L;Phillipson M;Abid MR;Spurkland A;Claesson-Welsh L
VEGFR 2激活c-Src并通过与衔接蛋白TSAd结合来诱导血管通透性。血管内皮（VE）生长因子（VEGF）诱导的通透性的调节在生理和病理过程中至关重要。我们发现，在Y 951的VEGF受体2（VEGFR 2）的酪氨酸磷酸化促进VEGFR 2的劳斯肉瘤（Src）同源性2-结构域的T细胞特异性接头（TSAd），这反过来又调节VEGF诱导的c-Src酪氨酸激酶和血管通透性的激活的结合。c-Src在体内和体外以VEGF/TSAd依赖性方式被激活，并通过pY 418处磷酸化增加和pY 527处磷酸化减少来调节。Tsad沉默阻断VEGF诱导的c-Src活化，但不影响涉及磷脂酶Cγ、细胞外调节激酶和内皮一氧化氮的途径。VEGF诱导的VE-钙粘蛋白阳性连接的小鼠肺，或小鼠提睾肌血管中分离的内皮细胞的重排，是依赖于TSAd的表达，和TSAd形成了一个复杂的VE-钙粘蛋白，VEGFR 2，和c-Src在内皮连接。tsad−/−小鼠的血管显示出不受干扰的流量和压力，但VEGF诱导的渗透性受损，通过皮肤和气管中的伊文思蓝、葡聚糖和微球外渗来测量。组胺诱导的外渗不受TSAd缺乏的影响。我们的结论是，TSAd是VEGF诱导的，c-Src介导的调节内皮细胞连接和血管通透性。
VEGFR2 activates c-Src and induces vascular permeability by binding to the adaptor protein TSAd Regulation of vascular endothelial (VE) growth factor (VEGF)–induced permeability is critical in physiological and pathological processes. We show that tyrosine phosphorylation of VEGF receptor 2 (VEGFR2) at Y951 facilitates binding of VEGFR2 to the Rous sarcoma (Src) homology 2-domain of T cell–specific adaptor (TSAd), which in turn regulates VEGF-induced activation of the c-Src tyrosine kinase and vascular permeability. c-Src was activated in vivo and in vitro in a VEGF/TSAd-dependent manner, and was regulated via increased phosphorylation at pY418 and reduced phosphorylation at pY527. Tsad silencing blocked VEGF-induced c-Src activation, but did not affect pathways involving phospholipase Cγ, extracellular regulated kinase, and endothelial nitric oxide. VEGF-induced rearrangement of VE–cadherin–positive junctions in endothelial cells isolated from mouse lungs, or in mouse cremaster vessels, was dependent on TSAd expression, and TSAd formed a complex with VE-cadherin, VEGFR2, and c-Src at endothelial junctions. Vessels in tsad−/− mice showed undisturbed flow and pressure, but impaired VEGF-induced permeability, as measured by extravasation of Evans blue, dextran, and microspheres in the skin and the trachea. Histamine-induced extravasation was not affected by TSAd deficiency. We conclude that TSAd is required for VEGF-induced, c-Src-mediated regulation of endothelial cell junctions and for vascular permeability.
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DOI：
10.1161/atvbaha.110.209726
发表时间：
2010-09
期刊：
Arteriosclerosis, thrombosis, and vascular biology
影响因子：
--
作者：
Feng J;Damrauer SM;Lee M;Sellke FW;Ferran C;Abid MR
通讯作者：
Abid MR
DOI：
10.1073/pnas.041359198
发表时间：
2001-02-27
影响因子：
11.1
作者：
Fukumura, D;Gohongi, T;Jain, RK
通讯作者：
Jain, RK
影响因子：
4.8
作者：
Adam, Alejandro P.;Sharenko, Amy L.;Vincent, Peter A.
通讯作者：
Vincent, Peter A.
影响因子：
3
作者：
Granum, Stine;Sundvold-Gjerstad, Vibeke;Spurkland, Anne
通讯作者：
Spurkland, Anne
影响因子：
4.8
作者：
Granum, Stine;Andersen, Thorny Cesilie Bie;Sundvold-Gjerstad, Vibeke
通讯作者：
Sundvold-Gjerstad, Vibeke