The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination

Kyu Sung Choi; Hyun Jung Choi; Jin Kyu Lee; Suhjean Im; Haiying Zhang; Yoonjeong Jeong; Jeong Ae Park; In Kyu Lee; Young Myeong Kim; Young Guen Kwon

doi:10.1016/j.cellsig.2016.07.015

The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination

Kyu Sung Choi, Hyun Jung Choi, Jin Kyu Lee, Suhjean Im, Haiying Zhang, Yoonjeong Jeong, Jeong Ae Park, In Kyu Lee, Young Myeong Kim, Young Guen Kwon

Research output: Contribution to journal › Article › peer-review

32 Citations (Scopus)

Abstract

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.

Original language	English
Pages (from-to)	1642-1651
Number of pages	10
Journal	Cellular Signalling
Volume	28
Issue number	11
DOIs	https://doi.org/10.1016/j.cellsig.2016.07.015
Publication status	Published - 2016 Nov 1

Bibliographical note

Funding 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 ).

Publisher Copyright:
© 2016 The Authors

All Science Journal Classification (ASJC) codes

Cell Biology

Access to Document

10.1016/j.cellsig.2016.07.015

Cite this

@article{148da0a624434e7c83967253efd6637d,

title = "The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination",

abstract = "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.",

author = "Choi, {Kyu Sung} and Choi, {Hyun Jung} and Lee, {Jin Kyu} and Suhjean Im and Haiying Zhang and Yoonjeong Jeong and Park, {Jeong Ae} and Lee, {In Kyu} and Kim, {Young Myeong} and Kwon, {Young Guen}",

note = "Funding 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 ). Publisher Copyright: {\textcopyright} 2016 The Authors",

year = "2016",

month = nov,

day = "1",

doi = "10.1016/j.cellsig.2016.07.015",

language = "English",

volume = "28",

pages = "1642--1651",

journal = "Cellular Signalling",

issn = "0898-6568",

publisher = "Elsevier Inc.",

number = "11",

}

TY - JOUR

T1 - The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination

AU - Choi, Kyu Sung

AU - Choi, Hyun Jung

AU - Lee, Jin Kyu

AU - Im, Suhjean

AU - Zhang, Haiying

AU - Jeong, Yoonjeong

AU - Park, Jeong Ae

AU - Lee, In Kyu

AU - Kim, Young Myeong

AU - Kwon, Young Guen

N1 - Funding 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 ). Publisher Copyright: © 2016 The Authors

PY - 2016/11/1

Y1 - 2016/11/1

N2 - 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.

AB - 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.

UR - http://www.scopus.com/inward/record.url?scp=84982787957&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=84982787957&partnerID=8YFLogxK

U2 - 10.1016/j.cellsig.2016.07.015

DO - 10.1016/j.cellsig.2016.07.015

M3 - Article

C2 - 27498087

AN - SCOPUS:84982787957

SN - 0898-6568

VL - 28

SP - 1642

EP - 1651

JO - Cellular Signalling

JF - Cellular Signalling

IS - 11

ER -

The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination

Abstract

Bibliographical note

All Science Journal Classification (ASJC) codes

Access to Document

Other files and links

Fingerprint

Cite this