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首页> 外文期刊>Molecular and Cellular Biology >PEST Motif Serine and Tyrosine Phosphorylation Controls Vascular Endothelial Growth Factor Receptor 2 Stability and Downregulation
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PEST Motif Serine and Tyrosine Phosphorylation Controls Vascular Endothelial Growth Factor Receptor 2 Stability and Downregulation

机译：PEST主题丝氨酸和酪氨酸磷酸化控制血管内皮生长因子受体2的稳定性和下调。

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The internalization and degradation of vascular endothelial growth factor receptor 2 (VEGFR-2), a potent angiogenic receptor tyrosine kinase, is a central mechanism for the regulation of the coordinated action of VEGF in angiogenesis. Here, we show that VEGFR-2 is ubiquitinated in response to VEGF, and Lys 48-linked polyubiquitination controls its degradation via the 26S proteosome. The degradation and ubiquitination of VEGFR-2 is controlled by its PEST domain, and the phosphorylation of Ser1188/Ser1191 is required for the ubiquitination of VEGFR-2. F-box-containing β-Trcp1 ubiquitin E3 ligase is recruited to S1188/S1191 VEGFR-2 and mediates the ubiquitination and degradation of VEGFR-2. The PEST domain also controls the activation of p38 mitogen-activated protein kinase (MAPK) through phospho-Y1173. The activation of p38 stabilizes VEGFR-2, and its inactivation accelerates VEGFR-2 downregulation. The VEGFR-2-mediated activation of p38 is established through the protein kinase A (PKA)/MKK6 pathway. PKA is recruited to VEGFR-2 through AKAP1/AKAP149, and its phosphorylation requires Y1173 of VEGFR-2. The study has identified a unique mechanism in which VEGFR-2 stability and degradation is modulated. The PEST domain acts as a dual modulator of VEGFR-2; the phosphorylation of S1188/S1191 controls ubiquitination and degradation via β-Trcp1, where the phosphorylation of Y1173 through PKA/p38 MAPK controls the stability of VEGFR-2.
机译：血管内皮生长因子受体2（VEGFR-2）（一种有效的血管生成受体酪氨酸激酶）的内在化和降解是调节VEGF在血管生成中协同作用的主要机制。在这里，我们显示VEGFR-2是响应VEGF的泛素化的，而Lys 48连接的多聚泛素化则通过26S蛋白体控制其降解。 VEGFR-2的降解和泛素化受其PEST域控制，而VEGFR-2的泛素化需要Ser1188 / Ser1191的磷酸化。包含F-box的β-Trcp1泛素E3连接酶被募集到S1188 / S1191 VEGFR-2，并介导VEGFR-2的泛素化和降解。 PEST域还通过磷酸Y1173控制p38丝裂原激活的蛋白激酶（MAPK）的激活。 p38的激活稳定了VEGFR-2，而其失活则加速了VEGFR-2的下调。通过蛋白激酶A（PKA）/ MKK6途径建立了VEGFR-2介导的p38激活。 PKA通过AKAP1 / AKAP149募集到VEGFR-2，其磷酸化需要VEGFR-2的Y1173。这项研究已经确定了调节VEGFR-2稳定性和降解的独特机制。 PEST结构域充当VEGFR-2的双重调节子; S1188 / S1191的磷酸化通过β-Trcp1控制泛素化和降解，其中P117 / p38 MAPK的Y1173磷酸化控制VEGFR-2的稳定性。

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