TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation.
Vascular hyperpermeability is critical in ischemic diseases, including stroke and myocardial infarction, as well as in inflammation and cancer. It is well known that the VEGF-VEGFR2 signaling pathways are pivotal in promoting vascular permeability; however, counterbalancing mechanisms that restrict vascular permeability to maintain the integrity of blood vessels are not yet fully understood. We report that TNF superfamily member 15 (TNFSF15), a cytokine largely produced by vascular endothelial cells and a specific inhibitor of the proliferation of these same cells, can inhibit VEGF-induced vascular permeabilityin vitroandin vivo, and that death receptor 3 (DR3), a cell surface receptor of TNFSF15, mediates TNFSF15-induced dephosphorylation of VEGFR2. Src homology region 2 domain-containing phosphatase-1 (SHP-1) becomes associated with DR3 upon TNFSF15 interaction with the latter. In addition, a protein complex consisting of VEGFR2, DR3, and SHP-1 is formed in response to the effects of TNFSF15 and VEGF on endothelial cells. It is plausible that this protein complex provides a structural basis for the molecular mechanism in which TNFSF15 induces the inhibition of VEGF-stimulated vascular hyperpermeability.-Yang, G.-L., Zhao, Z., Qin, T.-T., Wang, D., Chen, L., Xiang, R., Xi, Z., Jiang, R., Zhang, Z.-S., Zhang, J., Li. L.-Y. TNFSF15 inhibits VEGF-stimulated vascular hyperpermeability by inducing VEGFR2 dephosphorylation.
Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center for Biotherapy and Tianjin Key Laboratory of Molecular Drug Research.|Key Laboratory of Post-Neuroinjury Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.
Gui-Li
GL
Yang
Key Laboratory of Post-Neuroinjury Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.
Zilong
Z
Zhao
Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center for Biotherapy and Tianjin Key Laboratory of Molecular Drug Research.
Ting-Ting
TT
Qin
Key Laboratory of Post-Neuroinjury Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.
Dong
D
Wang
State Key Laboratory of Biotherapy, West China Hospital, Sichuan University, Chengdu, China.
Lijuan
L
Chen
Department of Immunology, Medical School of Nankai University, and.
Rong
R
Xiang
Department of Chemical Biology, College of Chemistry, Nankai University, Tianjin, China.
Zhen
Z
Xi
Key Laboratory of Post-Neuroinjury Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.
Rongcai
R
Jiang
Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center for Biotherapy and Tianjin Key Laboratory of Molecular Drug Research, zzs@nankai.edu.cn.
Zhi-Song
ZS
Zhang
Key Laboratory of Post-Neuroinjury Repair and Regeneration in Central Nervous System, Ministry of Education and Tianjin City, Tianjin Neurological Institute, Tianjin Medical University General Hospital, Tianjin, China; and.
Jianning
J
Zhang
Key Laboratory of Medicinal Chemical Biology, College of Pharmacy, Collaborative Innovation Center for Biotherapy and Tianjin Key Laboratory of Molecular Drug Research, liluyuan@nankai.edu.cn.
Lu-Yuan
LY
Li
D042783:Endothelial Cells / Q000378:metabolism*; D006801:Humans; D010539:Permeability; D010766:Phosphorylation; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15 / Q000378:metabolism / Q000494:pharmacology*; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
C439524:TNF protein, human; C117026:TNFSF15 protein, human; D053380:Tumor Necrosis Factor Ligand Superfamily Member 15; D014409:Tumor Necrosis Factor-alpha; D042461:Vascular Endothelial Growth Factor A; C000588866:KDR protein, human; D040301:Vascular Endothelial Growth Factor Receptor-2
DR3; SHP-1; vascular integrity