Department of Pathology, Boston University Medical Campus, 670 Albany St., Boston, MA 02118, USA.
Mol Cell Biol. 2011 May;31(10):2010-25. doi: 10.1128/MCB.01006-10. Epub 2011 Mar 14.
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.
血管内皮生长因子受体 2（VEGFR-2）是一种有效的血管生成受体酪氨酸激酶，其内化和降解是调节 VEGF 协调血管生成作用的核心机制。在这里，我们表明 VEGFR-2 可响应 VEGF 而发生泛素化，并且赖氨酸 48 连接的多泛素化通过 26S 蛋白酶体控制其降解。VEGFR-2 的降解和泛素化受其 PEST 结构域控制，丝氨酸 1188/丝氨酸 1191 的磷酸化是 VEGFR-2 泛素化所必需的。含有 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 结构域还通过磷酸化 Y1173 控制 p38 丝裂原活化蛋白激酶（MAPK）的激活。p38 的激活稳定 VEGFR-2，其失活加速 VEGFR-2 的下调。VEGFR-2 介导的 p38 激活是通过蛋白激酶 A（PKA）/MKK6 途径建立的。PKA 通过 AKAP1/AKAP149 被募集到 VEGFR-2，其磷酸化需要 VEGFR-2 的 Y1173。该研究确定了一种独特的机制，其中 VEGFR-2 的稳定性和降解受到调节。PEST 结构域作为 VEGFR-2 的双重调节剂；S1188/S1191 的磷酸化通过β-Trcp1 控制泛素化和降解，其中通过 PKA/p38 MAPK 的 Y1173 磷酸化控制 VEGFR-2 的稳定性。
