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.
Bibliographical noteFunding Information:
This research was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST; grants NRF-2015R1A2A1A05001859 and NRF-2013M3A9B6046563 ), and by the Bio and Medical Technology Development Program of the National Research Foundation of Korea (NRF) funded by the Ministry of Education, Science and Technology (MEST; NRF-2015M3A9B6066967 ). This work was also supported by a grant of the Korea Health Technology R&D Project through the Korea Health Industry Development Institute (KHIDI), funded by the Ministry of Health & Welfare, Republic of Korea (Grant Number: HI16C1501 ).
All Science Journal Classification (ASJC) codes
- Cell Biology