title: ANGPTL4 modulates vascular junction integrity by integrin signaling and disruption of intercellular VE-cadherin and claudin-5 clusters.
abstract: 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 interacting with 3 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.
authors.affiliation: School of Biological Sciences, Nanyang Technological University, Singapore.
authors.forename: Royston-Luke
authors.initials: RL
authors.lastname: Huang
authors.forename: Ziqiang
authors.initials: Z
authors.lastname: Teo
authors.forename: Han Chung
authors.initials: HC
authors.lastname: Chong
authors.forename: Pengcheng
authors.initials: P
authors.lastname: Zhu
authors.forename: Ming Jie
authors.initials: MJ
authors.lastname: Tan
authors.forename: Chek Kun
authors.initials: CK
authors.lastname: Tan
authors.forename: Chee Ren Ivan
authors.initials: CR
authors.lastname: Lam
authors.forename: Ming Keat
authors.initials: MK
authors.lastname: Sng
authors.forename: David Tai Wei
authors.initials: DT
authors.lastname: Leong
authors.forename: Suet Mien
authors.initials: SM
authors.lastname: Tan
authors.forename: Sander
authors.initials: S
authors.lastname: Kersten
authors.forename: Jeak Ling
authors.initials: JL
authors.lastname: Ding
authors.forename: Hoi Yeung
authors.initials: HY
authors.lastname: Li
authors.forename: Nguan Soon
authors.initials: NS
authors.lastname: Tan
mesh_terms: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D015703:Antigens, CD / Q000378:metabolism*; D015820:Cadherins / Q000378:metabolism*; D002199:Capillary Permeability; D002478:Cells, Cultured; D062507:Claudin-5; D057167:Claudins / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology / Q000378:metabolism; D004730:Endothelium, Vascular / Q000166:cytology; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D039081:Integrin alpha5beta1 / Q000378:metabolism*; D008168:Lung / Q000473:pathology; D051379:Mice; D008819:Mice, Nude; D009362:Neoplasm Metastasis / Q000473:pathology; D009369:Neoplasms / Q000098:blood supply / Q000235:genetics / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism; D000099152:Cadherin 5
chemical_list: D000075803:Angiopoietin-Like Protein 4; D042682:Angiopoietins; D015703:Antigens, CD; D015820:Cadherins; D062507:Claudin-5; D057167:Claudins; D039081:Integrin alpha5beta1; D051176:beta Catenin; D000099152:Cadherin 5; C474772:ANGPTL4 protein, human; C407088:Angptl4 protein, mouse; C107466:CLDN5 protein, human