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

作者：Huang Royston Luke; Teo Ziqiang; Chong Han Chung; Zhu Pengcheng; Tan Ming Jie; Tan Chek Kun; Lam Chee Ren Ivan; Sng Ming Keat; Leong David Tai Wei; Tan Suet Mien; Kersten Sander; Ding Jeak Ling; Li Hoi Yeung; Tan Nguan Soon^*

来源：Blood, 2011, 118(14): 3990-4002.

DOI：10.1182/blood-2011-01-328716

Vascular disruption induced by interactions between tumor-secreted permeability factors and adhesive proteins on endothelial cells facilitates metastasis. The role of tumor-secreted C-terminal fibrinogen-like domain of angiopoietin-like 4 (cANGPTL4) in vascular leakiness and metastasis is controversial because of the lack of understanding of how cANGPTL4 modulates vascular integrity. Here, we show that cANGPTL4 instigated the disruption of endothelial continuity by directly inter-acting with 3 novel binding partners, integrin alpha 5 beta 1, VE-cadherin, and claudin-5, in a temporally sequential manner, thus facilitating metastasis. We showed that cANGPTL4 binds and activates integrin alpha 5 beta 1-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. (Blood. 2011;118(14):3990-4002)

• 出版日期2011-10-6
• 单位南阳理工学院