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https://hdl.handle.net/10356/101257
Title: | ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters | 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 |
Keywords: | DRNTU::Science::Biological sciences::Molecular biology | Issue Date: | 2011 | Source: | 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. | Series/Report no.: | Blood | 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. | URI: | https://hdl.handle.net/10356/101257 http://hdl.handle.net/10220/7264 |
DOI: | 10.1182/blood-2011-01-328716 | Schools: | School of Biological Sciences | Rights: | © 2011 by The American Society of Hematology. | Fulltext Permission: | none | Fulltext Availability: | No Fulltext |
Appears in Collections: | SBS Journal Articles |
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