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

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

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dc.contributor.author Huang, Royston-Luke
dc.contributor.author Teo, Ziqiang
dc.contributor.author Chong, Han Chung
dc.contributor.author Zhu, Pengcheng
dc.contributor.author Tan, Ming Jie
dc.contributor.author Tan, Chek Kun
dc.contributor.author Lam, Ivan Chee Ren
dc.contributor.author Sng, Ming Keat
dc.contributor.author Leong, David Tai Wei
dc.contributor.author Tan, Suet Mien
dc.contributor.author Kersten, Sander
dc.contributor.author Ding, Jeak Ling
dc.contributor.author Li, Hoi-Yeung
dc.contributor.author Tan, Nguan Soon
dc.date.accessioned 2011-10-13T07:01:19Z
dc.date.available 2011-10-13T07:01:19Z
dc.date.copyright 2011
dc.date.issued 2011-10-13
dc.identifier.citation 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.
dc.identifier.uri http://hdl.handle.net/10220/7264
dc.description.abstract 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.
dc.format.extent 42 p.
dc.language.iso en
dc.relation.ispartofseries Blood
dc.rights © 2011 by The American Society of Hematology.
dc.subject DRNTU::Science::Biological sciences::Molecular biology.
dc.title ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters
dc.type Journal Article
dc.contributor.school School of Biological Sciences
dc.identifier.doi http://dx.doi.org/10.1182/blood-2011-01-328716
dc.identifier.rims 161430

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