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 journalArticle

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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 languageEnglish
Pages (from-to)1642-1651
Number of pages10
JournalCellular Signalling
Volume28
Issue number11
DOIs
Publication statusPublished - 2016 Nov 1

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Ubiquitin-Protein Ligases
Intercellular Junctions
Protein Stability
Ubiquitination
Endothelial Cells
Lysine
Permeability
Cytoplasm
Proteins

All Science Journal Classification (ASJC) codes

  • Cell Biology

Cite this

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. / The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination. In: Cellular Signalling. 2016 ; Vol. 28, No. 11. pp. 1642-1651.
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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.",
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The endothelial E3 ligase HECW2 promotes endothelial cell junctions by increasing AMOTL1 protein stability via K63-linked ubiquitination. / 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.

In: Cellular Signalling, Vol. 28, No. 11, 01.11.2016, p. 1642-1651.

Research output: Contribution to journalArticle

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AU - Choi, Kyu Sung

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AU - Zhang, Haiying

AU - Jeong, Yoonjeong

AU - Park, Jeong Ae

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AU - Kim, Young Myeong

AU - Kwon, Young-Guen

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