title: TAK1 kinase signaling regulates embryonic angiogenesis by modulating endothelial cell survival and migration.
abstract: TGF-β activated kinase 1 (TAK1) is a mediator of various cytokine signaling pathways. Germline deficiency of Tak1 causes multiple abnormalities, including dilated blood vessels at midgestation. However, the mechanisms by which TAK1 regulates vessel formation have not been elucidated. TAK1 binding proteins 1 and 2 (TAB1 and TAB2) are activators of TAK1, but their roles in embryonic TAK1 signaling have not been determined. In the present study, we characterized mouse embryos harboring endothelial-specific deletions of Tak1, Tab1, or Tab2 and found that endothelial TAK1 and TAB2, but not TAB1, were critically involved in vascular formation. TAK1 deficiency in endothelial cells caused increased cell death and vessel regression at embryonic day 10.5 (E10.5). Deletion of TNF signaling largely rescued endothelial cell death in TAK1-deficient embryos at E10.5. However, embryos deficient in both TAK1 and TNF signaling still exhibited dilated capillary networks at E12.5. TAB2 deficiency caused reduced TAK1 activity, resulting in abnormal capillary blood vessels, similar to the compound deficiency of TAK1 and TNF signaling. Ablation of either TAK1 or TAB2 impaired cell migration and tube formation. Our results show that endothelial TAK1 signaling is important for 2 biologic processes in angiogenesis: inhibiting TNF-dependent endothelial cell death and promoting TNF-independent angiogenic cell migration.
authors.affiliation: Department of Molecular Biology, Graduate School of Science, Nagoya University, Nagoya, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Morioka
authors.forename: Maiko
authors.initials: M
authors.lastname: Inagaki
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Komatsu
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D002465:Cell Movement / Q000502:physiology*; D002470:Cell Survival; D004622:Embryo, Mammalian; D042783:Endothelial Cells / Q000378:metabolism*; D005434:Flow Cytometry; D006801:Humans; D015151:Immunoblotting; D007150:Immunohistochemistry; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018613:Microscopy, Confocal; D018919:Neovascularization, Physiologic / Q000502:physiology*; D034741:RNA, Small Interfering; D015398:Signal Transduction / Q000502:physiology*; D014471:Umbilical Veins; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D020930:MAP Kinase Kinase Kinases; D034741:RNA, Small Interfering; D000099151:MAP Kinase Kinase Kinase 7; C531463:Tab1 protein, mouse; C498761:Tab2 protein, mouse