ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters

Vascular disruption induced by interactions between tumor-secreted permeability factors and adhesive proteins on endothelial cells facilitates metastasis. The role of tumor-secreted angiopoietin-like 4 (cANGPTL4) in vascular leakiness and metastasis is controversial due to the lack of understanding...

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Main Authors: Huang, Royston-Luke, Teo, Ziqiang, Chong, Han Chung, Zhu, Pengcheng, Tan, Ming Jie, Tan, Chek Kun, Lam, Ivan Chee Ren, Tan, Nguan Soon, Sng, Ming Keat, Leong, David Tai Wei, Tan, Suet Mien, Kersten, Sander, Ding, Jeak Ling, Li, Hoi-Yeung
Other Authors: School of Biological Sciences
Format: Article
Language:English
Published: 2011
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Online Access:https://hdl.handle.net/10356/101257
http://hdl.handle.net/10220/7264
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Institution: Nanyang Technological University
Language: English
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spelling sg-ntu-dr.10356-1012572020-03-07T12:18:14Z ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters Huang, Royston-Luke Teo, Ziqiang Chong, Han Chung Zhu, Pengcheng Tan, Ming Jie Tan, Chek Kun Lam, Ivan Chee Ren Tan, Nguan Soon Sng, Ming Keat Leong, David Tai Wei Tan, Suet Mien Kersten, Sander Ding, Jeak Ling Li, Hoi-Yeung School of Biological Sciences DRNTU::Science::Biological sciences::Molecular biology Vascular disruption induced by interactions between tumor-secreted permeability factors and adhesive proteins on endothelial cells facilitates metastasis. The role of tumor-secreted angiopoietin-like 4 (cANGPTL4) in vascular leakiness and metastasis is controversial due to the lack of understanding of how cANGPTL4 modulates vascular integrity. Here, we show that cANGPTL4 instigated the disruption of endothelial continuity by directly interacting with three novel binding partners, integrin α5β1, VE-cadherin and claudin-5, in a temporally sequential manner, thus facilitating metastasis. We showed that cANGPTL4 binds and activates integrin α5β1-mediated Rac1/PAK signaling to weaken cell-cell contacts. cANGPTL4 subsequently associated with and declustered VE-cadherin and claudin-5, leading to endothelial disruption. Interfering with the formation of these cANGPTL4 complexes delayed vascular disruption. In vivo vascular permeability and metastatic assays performed using ANGPTL4-knockout and wild-type mice injected with either control or ANGPTL4-knockdown tumors confirmed that cANGPTL4 induced vascular leakiness and facilitated lung metastasis in mice. Thus, our findings elucidate how cANGPTL4 induces endothelial disruption. Our findings have direct implications for targeting cANGPTL4 to treat cancer and other vascular pathologies. 2011-10-13T07:01:19Z 2019-12-06T20:35:45Z 2011-10-13T07:01:19Z 2019-12-06T20:35:45Z 2011 2011 Journal Article Huang, R. L., Teo, Z., Chong, H. C., Zhu, P., Tan, M. J., Tan, C. K., et al. (2011). ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters. Blood, 118, 3990-4002. https://hdl.handle.net/10356/101257 http://hdl.handle.net/10220/7264 10.1182/blood-2011-01-328716 161430 en Blood © 2011 by The American Society of Hematology. 42 p.
institution Nanyang Technological University
building NTU Library
country Singapore
collection DR-NTU
language English
topic DRNTU::Science::Biological sciences::Molecular biology
spellingShingle DRNTU::Science::Biological sciences::Molecular biology
Huang, Royston-Luke
Teo, Ziqiang
Chong, Han Chung
Zhu, Pengcheng
Tan, Ming Jie
Tan, Chek Kun
Lam, Ivan Chee Ren
Tan, Nguan Soon
Sng, Ming Keat
Leong, David Tai Wei
Tan, Suet Mien
Kersten, Sander
Ding, Jeak Ling
Li, Hoi-Yeung
ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters
description Vascular disruption induced by interactions between tumor-secreted permeability factors and adhesive proteins on endothelial cells facilitates metastasis. The role of tumor-secreted angiopoietin-like 4 (cANGPTL4) in vascular leakiness and metastasis is controversial due to the lack of understanding of how cANGPTL4 modulates vascular integrity. Here, we show that cANGPTL4 instigated the disruption of endothelial continuity by directly interacting with three novel binding partners, integrin α5β1, VE-cadherin and claudin-5, in a temporally sequential manner, thus facilitating metastasis. We showed that cANGPTL4 binds and activates integrin α5β1-mediated Rac1/PAK signaling to weaken cell-cell contacts. cANGPTL4 subsequently associated with and declustered VE-cadherin and claudin-5, leading to endothelial disruption. Interfering with the formation of these cANGPTL4 complexes delayed vascular disruption. In vivo vascular permeability and metastatic assays performed using ANGPTL4-knockout and wild-type mice injected with either control or ANGPTL4-knockdown tumors confirmed that cANGPTL4 induced vascular leakiness and facilitated lung metastasis in mice. Thus, our findings elucidate how cANGPTL4 induces endothelial disruption. Our findings have direct implications for targeting cANGPTL4 to treat cancer and other vascular pathologies.
author2 School of Biological Sciences
author_facet School of Biological Sciences
Huang, Royston-Luke
Teo, Ziqiang
Chong, Han Chung
Zhu, Pengcheng
Tan, Ming Jie
Tan, Chek Kun
Lam, Ivan Chee Ren
Tan, Nguan Soon
Sng, Ming Keat
Leong, David Tai Wei
Tan, Suet Mien
Kersten, Sander
Ding, Jeak Ling
Li, Hoi-Yeung
format Article
author Huang, Royston-Luke
Teo, Ziqiang
Chong, Han Chung
Zhu, Pengcheng
Tan, Ming Jie
Tan, Chek Kun
Lam, Ivan Chee Ren
Tan, Nguan Soon
Sng, Ming Keat
Leong, David Tai Wei
Tan, Suet Mien
Kersten, Sander
Ding, Jeak Ling
Li, Hoi-Yeung
author_sort Huang, Royston-Luke
title ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters
title_short ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters
title_full ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters
title_fullStr ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters
title_full_unstemmed ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters
title_sort angptl4 modulates vascular junction integrity by integrin signaling and disruption of intercellular ve-cadherin and claudin-5 clusters
publishDate 2011
url https://hdl.handle.net/10356/101257
http://hdl.handle.net/10220/7264
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