The enzymatic activity of the VEGFR2 receptor for the biosynthesis of dinucleoside polyphosphates
The enzymatic activity of the VEGFR2 receptor for the biosynthesis of dinucleoside polyphosphates
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VEGFR2受体对二核苷多磷酸生物合成的酶活性
DOI：
10.1007/s00109-013-1036-y
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发表时间：
2013
期刊：
影响因子：
--
通讯作者：
J. Jankowski
中科院分区：
文献类型：
--
作者：
V. Jankowski;A. Schulz;A. Kretschmer;H. Mischak;Falko Boehringer;M. Giet;D. Janke;M. Schuchardt;R. Herwig;W. Zidek;J. Jankowski
二核苷多磷酸包括大量由两个核苷组成的分子，这两个核苷通过可变长度的磷酸链连接。虽然对二核苷多磷酸激活的受体及其降解进行了详细研究，但迄今为止其生物合成尚未阐明。由于内皮细胞释放二核苷多磷酸尿苷腺苷四磷酸 (Up4A)，我们测试了从真皮血管获得的人内皮细胞的胞质蛋白的酶活性。当与 ADP 和 UDP 一起孵育时，这些细胞显示出 Up4A 浓度增加。通过色谱法分离出潜在的酶，质谱分析表明酶活性是由血管内皮生长因子受体 2 (VEGFR2) 引起的。由于 VEGFR2 但 VEGFR1 和 VEGFR3 均不能合成二核苷多磷酸，因此 VEGFR2 的 Tyr-1175 很可能对于目标酶活性至关重要。此外，含有 VEGFR2 的细胞如 HepG2、THP-1 和 RAW264.7 能够合成二核苷多磷酸。 VEGFR2 转染的 HEK 293T/17 但非天然 HEK 293T/17 细胞也在体内合成二核苷多磷酸。同时生物合成二核苷多磷酸可以放大对 VEGF 的反应，因为二核苷多磷酸通过 P2Y 嘌呤能受体诱导细胞生长。因此，VEGFR2 生物合成二核苷多磷酸可以增强对 VEGF 的增殖反应。鉴于VEGFR2主要在内皮细胞中表达，二核苷多磷酸的生物合成主要位于血管系统中。由于脉管系统也是二核苷多磷酸激活血管嘌呤受体的主要作用部位，因此血管对于二核苷多磷酸而言表现为自分泌系统。我们得出结论，VEGFR2受体能够合成二核苷多磷酸。这些介质可能由于其增殖作用而调节 VEGFR2 的作用。
The group of dinucleoside polyphosphates encompasses a large number of molecules consisting of two nucleosides which are connected by a phosphate chain of variable length. While the receptors activated by dinucleoside polyphosphates as well as their degradation have been studied in detail, its biosynthesis has not been elucidated so far. Since endothelial cells released the dinucleoside polyphosphate uridine adenosine tetraphosphate (Up4A), we tested cytosolic proteins of human endothelial cells obtained from dermal vessels elicited for enzymatic activity. When incubated with ADP and UDP, these cells showed increasing concentrations of Up4A. The underlying enzyme was isolated by chromatography and the mass spectrometric analysis revealed that the enzymatic activity was caused by the vascular endothelial growth factor receptor 2 (VEGFR2). Since VEGFR2 but neither VEGFR1 nor VEGFR3 were capable to synthesise dinucleoside polyphosphates, Tyr-1175 of VEGFR2 is most likely essential for the enzymatic activity of interest. Further, VEGFR2-containing cells like HepG2, THP-1 and RAW264.7 were capable of synthesising dinucleoside polyphosphates. VEGFR2-transfected HEK 293T/17 but not native HEK 293T/17 cells synthesised dinucleoside polyphosphates in vivo too. The simultaneous biosynthesis of dinucleoside polyphosphates could amplify the response to VEGF, since dinucleoside polyphosphates induce cellular growth via P2Y purinergic receptors. Thus the biosynthesis of dinucleoside polyphosphates by VEGFR2 may enhance the proliferative response to VEGF. Given that VEGFR2 is primarily expressed in endothelial cells, the biosynthesis of dinucleoside polyphosphates is mainly located in the vascular system. Since the vasculature is also the main site of action of dinucleoside polyphosphates, activating vascular purinoceptors, blood vessels appear as an autocrine system with respect to dinucleoside polyphosphates. We conclude that VEGFR2 receptor is capable of synthesising dinucleoside polyphosphates. These mediators may modulate the effects of VEGFR2 due to their proliferative effects.
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DOI：
10.1073/pnas.0405659101
发表时间：
2004-09-14
影响因子：
11.1
作者：
Roux, PP;Ballif, BA;Blenis, J
通讯作者：
Blenis, J
硼烷磷酸等排物控制二核苷多磷酸类似物的 P2Y 受体亚型选择性和代谢稳定性。
影响因子：
7.3
作者：
Yelovitch,Shir;Camden,Jean;Weisman,GaryA;Fischer,Bilha
通讯作者：
Fischer,Bilha
影响因子：
11.2
作者：
Dineen, Sean P.;Lynn, Kristi D.;Brekken, Rolf A.
通讯作者：
Brekken, Rolf A.
α 亚基上蛋白激酶 C 磷酸化位点 S1076 的突变影响 HEK-293 细胞中的 BK(Ca) 通道活性。
DOI：
10.1152/ajplung.90518.2008
发表时间：
2009
期刊：
American journal of physiology. Lung cellular and molecular physiology
影响因子：
--
作者：
Zhu,Shu;Browning,DarrenD;White,RichardE;Fulton,David;Barman,ScottA
通讯作者：
Barman,ScottA