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    Angiopoietin-Like 4 and Its Use in Modulating Cell Leakiness
    6.
    发明申请
    Angiopoietin-Like 4 and Its Use in Modulating Cell Leakiness 审中-公开

    公开(公告)号：US20180319878A1

    公开(公告)日：2018-11-08

    申请号：US16036848

    申请日：2018-07-16

    Applicant: Nanyang Technological University

    Inventor： Nguan Soon Tan

    IPC: C07K16/22 ,  C07K16/28

    CPC classification number: C07K16/22 ,  C07K16/2842 ,  C07K2317/76 ,  G01N2800/52 ,  G01N2800/7028

    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 (cANG-PTL4) 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. Interfacing with the formation of the 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 finding have direct implications for targeting cANGPTL4 to treat cancer and other vascular pathologies.

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