Choi Kyu-Sung, Choi Hyun-Jung, Lee Jin-Kyu, Im Suhjean, Zhang Haiying, Jeong Yoonjeong, Park Jeong Ae, Lee In-Kyu, Kim Young-Myeong, Kwon Young-Guen
Department of Biochemistry, College of Life Science and Biotechnology, Yonsei University, Seoul 03722, Republic of Korea.
Severance Integrative Research Institute for Cerebral & Cardiovascular Diseases (SIRIC), College of Medicine, Yonsei University, Seoul 03722, Republic of Korea.
Cell Signal. 2016 Nov;28(11):1642-51. doi: 10.1016/j.cellsig.2016.07.015. Epub 2016 Aug 4.
Cell-to-cell junctions are critical for the formation of endothelial barriers, and its disorganization is required for sprouting angiogenesis. Members of the angiomotin (AMOT) family have emerged as key regulators in the control of endothelial cell (EC) junction stability and permeability. However, the underlying mechanism by which the AMOT family is regulated in ECs remains unclear. Here we report that HECW2, a novel EC ubiquitin E3 ligase, plays a critical role in stabilizing endothelial cell-to-cell junctions by regulating AMOT-like 1 (AMOTL1) stability. HECW2 physically interacts with AMOTL1 and enhances its stability via lysine 63-linked ubiquitination. HECW2 depletion in human ECs decreases AMOTL1 stability, loosening the cell-to-cell junctions and altering subcellular localization of yes-associated protein (YAP) from cytoplasm into the nucleus. Knockdown of HECW2 also results in increased angiogenic sprouting, and this effect is blocked by depletion of ANG-2, a potential target of YAP. These results demonstrate that HECW2 is a novel regulator of angiogenesis and provide new insights into the mechanisms coordinating junction stability and angiogenic activation in ECs.
细胞间连接对于内皮屏障的形成至关重要，而其紊乱是芽生血管生成所必需的。血管动蛋白（AMOT）家族成员已成为控制内皮细胞（EC）连接稳定性和通透性的关键调节因子。然而，EC中AMOT家族受调控的潜在机制仍不清楚。在此我们报告，一种新型的EC泛素E3连接酶HECW2，通过调节类血管动蛋白1（AMOTL1）的稳定性，在稳定内皮细胞间连接中起关键作用。HECW2与AMOTL1发生物理相互作用，并通过赖氨酸63连接的泛素化增强其稳定性。人EC中HECW2的缺失降低了AMOTL1的稳定性，使细胞间连接松散，并将Yes相关蛋白（YAP）的亚细胞定位从细胞质改变到细胞核。敲低HECW2还导致血管生成芽生增加，并且这种效应被YAP的潜在靶标ANG-2的缺失所阻断。这些结果表明HECW2是血管生成的新型调节因子，并为协调EC中连接稳定性和血管生成激活的机制提供了新见解。
