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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.
DOI: 10.1182/blood-2011-01-328716
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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