title: TAK1 (MAP3K7) signaling regulates hematopoietic stem cells through TNF-dependent and -independent mechanisms.
abstract: A cytokine/stress signaling kinase Tak1 (Map3k7) deficiency is known to impair hematopoietic progenitor cells. However, the role of TAK1 signaling in the stem cell function of the hematopoietic system is not yet well defined. Here we characterized hematopoietic stem cells (HSCs) harboring deletion of Tak1 and its activators, Tak1 binding proteins 1 and 2 (Tab1 and Tab2) using a competitive transplantation assay in a mouse model. Tak1 single or Tab1/Tab2 double deletions completely eliminated the reconstitution activity of HSCs, whereas Tab1 or Tab2 single deletion did not cause any abnormality. Tak1 single or Tab1/Tab2 double deficient lineage-negative, Sca-1(+), c-Kit(+) (LSK) cells did not proliferate and underwent cell death. We found that Tnfr1 deficiency restored the reconstitution activity of Tak1 deficient bone marrow cells for 6-18 weeks. However, the reconstitution activity of Tak1- and Tnfr1-double deficient bone marrow cells declined over the long term, and the number of phenotypically identified long-term hematopoietic stem cells were diminished. Our results indicate that TAB1- or TAB2-dependent activation of TAK1 is required for maintenance of the hematopoietic system through two mechanisms: one is prevention of TNF-dependent cell death and the other is TNF-independent maintenance of long-term HSC.
authors.affiliation: Center for Integrated Medical Research, Keio University School of Medicine, Tokyo, Japan. takaesug1@z7.keio.jp
authors.forename: Giichi
authors.initials: G
authors.lastname: Takaesu
authors.forename: Maiko
authors.initials: M
authors.lastname: Inagaki
authors.forename: Keiyo
authors.initials: K
authors.lastname: Takubo
authors.forename: Yuji
authors.initials: Y
authors.lastname: Mishina
authors.forename: Paul R
authors.initials: PR
authors.lastname: Hess
authors.forename: Gregg A
authors.initials: GA
authors.lastname: Dean
authors.forename: Akihiko
authors.initials: A
authors.lastname: Yoshimura
authors.forename: Kunihiro
authors.initials: K
authors.lastname: Matsumoto
authors.forename: Toshio
authors.initials: T
authors.lastname: Suda
authors.forename: Jun
authors.initials: J
authors.lastname: Ninomiya-Tsuji
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000378:metabolism; D000818:Animals; D000954:Antigens, Surface / Q000378:metabolism; D001854:Bone Marrow Cells / Q000201:enzymology; D016923:Cell Death; D049109:Cell Proliferation; D046528:Chimerism; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000201:enzymology*; D006801:Humans; D020930:MAP Kinase Kinase Kinases / Q000172:deficiency / Q000378:metabolism*; D020935:MAP Kinase Signaling System; D051379:Mice; D008810:Mice, Inbred C57BL; D047888:Receptors, Tumor Necrosis Factor, Type I / Q000172:deficiency / Q000378:metabolism; D013997:Time Factors; D014409:Tumor Necrosis Factor-alpha / Q000378:metabolism*; D000099151:MAP Kinase Kinase Kinase 7
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D000954:Antigens, Surface; D020930:MAP Kinase Kinase Kinases; D047888:Receptors, Tumor Necrosis Factor, Type I; D014409:Tumor Necrosis Factor-alpha; D000099151:MAP Kinase Kinase Kinase 7; C531463:Tab1 protein, mouse; C498761:Tab2 protein, mouse