Targeted disruption of the Tab1 gene causes embryonic lethality and defects in cardiovascular and lung morphogenesis.
The transforming growth factor-beta (TGF-beta) superfamily consists of a group of secreted signaling molecules that perform important roles in the regulation of cell growth and differentiation. TGF-beta activated kinase-1 binding protein-1 (TAB1) was identified as a molecule that activates TGF-beta activated kinase-1 (TAK1). Recent studies have revealed that the TAB1-TAK1 interaction plays an important role in signal transduction in vitro, but little is known about the role of these molecules in vivo. To investigate the role of TAB1 during development, we cloned the murine Tab1 gene and disrupted it by homologous recombination. Homozygous Tab1 mutant mice died, exhibiting a bloated appearance with extensive edema and hemorrhage at the late stages of gestation. By histological examinations, it was revealed that mutant embryos exhibited cardiovascular and lung dysmorphogenesis. Tab1 mutant embryonic fibroblast cells displayed drastically reduced TAK1 kinase activities and decreased sensitivity to TGF-beta stimulation. These results indicate a possibility that TAB1 plays an important role in mammalian embryogenesis and is required for TAK1 activation in TGF-beta signaling.
Komatsu
Yoshihiro
Y
Center for Animal Resources and Development, Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
Shibuya
Hiroshi
H
Takeda
Naoki
N
Ninomiya-Tsuji
Jun
J
Yasui
Teruhito
T
Miyado
Kenji
K
Sekimoto
Tomohisa
T
Ueno
Naoto
N
Matsumoto
Kunihiro
K
Yamada
Gen
G
D048868:Adaptor Proteins, Signal Transducing; D000483:Alleles; D000595:Amino Acid Sequence; D000818:Animals; D015153:Blotting, Western; D002454:Cell Differentiation; D002455:Cell Division; D003001:Cloning, Molecular; D005838:Genotype; D015699:HIV Envelope Protein gp120 / Q000235:genetics / Q000502:physiology*; D006321:Heart / Q000196:embryology*; D006720:Homozygote; D006801:Humans; D015151:Immunoblotting; D017403:In Situ Hybridization; D008156:Luciferases / Q000378:metabolism; D008168:Lung / Q000196:embryology*; D020930:MAP Kinase Kinase Kinases / Q000378:metabolism; D051379:Mice; D008957:Models, Genetic; D008969:Molecular Sequence Data; D016297:Mutagenesis, Site-Directed; D009154:Mutation; D016376:Oligonucleotides, Antisense / Q000494:pharmacology; D011993:Recombinant Fusion Proteins / Q000235:genetics / Q000502:physiology*; D011995:Recombination, Genetic; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D013997:Time Factors; D014018:Tissue Distribution; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000378:metabolism; D000099151:MAP Kinase Kinase Kinase 7
D048868:Adaptor Proteins, Signal Transducing; D015699:HIV Envelope Protein gp120; D008156:Luciferases; D020930:MAP Kinase Kinase Kinases; D016376:Oligonucleotides, Antisense; D011993:Recombinant Fusion Proteins; D016212:Transforming Growth Factor beta; D000099151:MAP Kinase Kinase Kinase 7; C486300:TAB1 protein, human