ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning.
ERG activity is regulated by endothelial FAK coupling with TRIM25/USP9x in vascular patterning.
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ERG活性受血管图案化中与TRIM 25/USP 9 x偶联的内皮FAK调节。
DOI：
10.1242/dev.200528
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发表时间：
2022-07-01
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影响因子：
--
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中科院分区：
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精确的血管构型对正常生长和发育至关重要。ERG转录因子驱动Delta样配体4(DLL4)/Notch信号转导，被认为是内皮细胞(EC)动力学和发育血管生成的关键调节因子。然而，ERG活性的分子调控仍然不清楚。使用一系列EC特异的粘着斑激酶(FAK)敲除(KO)和点突变FAK敲入小鼠，我们发现在FAK-Y397处ECFAK及其激酶活性或磷酸化的丢失，而不是FAK-Y861，降低了ERG和DLL4的表达水平，并伴随着血管构型的异常。内源性蛋白质的快速免疫沉淀质谱学证实，内皮核FAK与脱泛素酶USP9X和泛素连接酶TRIM25相互作用。进一步的计算机分析证实ERG与USP9X和TRIM25相互作用。此外，通过涉及USP9X和TRIM25的泛素介导的翻译后修饰计划，FAKKO EC中的ERG水平得到降低。ERG在体内和体外的重新表达挽救了在没有ECFAK的情况下观察到的异常血管萌发缺陷。我们的研究结果表明，ECFAK通过TRIM25/USP9X控制ERG蛋白的降解，从而调节视网膜血管构型。摘要：FAK与TRIM25/USP9X的偶联可控制内皮细胞中ERG的降解，从而决定视网膜的血管构型。
Precise vascular patterning is crucial for normal growth and development. The ERG transcription factor drives Delta-like ligand 4 (DLL4)/Notch signalling and is thought to act as a pivotal regulator of endothelial cell (EC) dynamics and developmental angiogenesis. However, molecular regulation of ERG activity remains obscure. Using a series of EC-specific focal adhesion kinase (FAK)-knockout (KO) and point-mutant FAK-knock-in mice, we show that loss of ECFAK, its kinase activity or phosphorylation at FAK-Y397, but not FAK-Y861, reduces ERG and DLL4 expression levels together with concomitant aberrations in vascular patterning. Rapid immunoprecipitation mass spectrometry of endogenous proteins identified that endothelial nuclear-FAK interacts with the deubiquitinase USP9x and the ubiquitin ligase TRIM25. Further in silico analysis confirms that ERG interacts with USP9x and TRIM25. Moreover, ERG levels are reduced in FAKKO ECs via a ubiquitin-mediated post-translational modification programme involving USP9x and TRIM25. Re-expression of ERG in vivo and in vitro rescues the aberrant vessel-sprouting defects observed in the absence of ECFAK. Our findings identify ECFAK as a regulator of retinal vascular patterning by controlling ERG protein degradation via TRIM25/USP9x. Summary: Coupling of FAK with TRIM25/USP9x controls ERG degradation in endothelial cells, thus determining vascular patterning in the retina.
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影响因子：
11.8
作者：
Dermit M;Dodel M;Lee FCY;Azman MS;Schwenzer H;Jones JL;Blagden SP;Ule J;Mardakheh FK
通讯作者：
Mardakheh FK
影响因子：
9.8
作者：
Franco CA;Jones ML;Bernabeu MO;Geudens I;Mathivet T;Rosa A;Lopes FM;Lima AP;Ragab A;Collins RT;Phng LK;Coveney PV;Gerhardt H
通讯作者：
Gerhardt H
DOI：
10.1002/path.4911
发表时间：
2017-07
期刊：
The Journal of pathology
影响因子：
--
作者：
Alexopoulou AN;Lees DM;Bodrug N;Lechertier T;Fernandez I;D'Amico G;Dukinfield M;Batista S;Tavora B;Serrels B;Hodivala-Dilke K
通讯作者：
Hodivala-Dilke K
影响因子：
64.5
作者：
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通讯作者：
Ye, Weilan
影响因子：
16
作者：
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通讯作者：
Wei W