Komatsu Yoshihiro, Shibuya Hiroshi, Takeda Naoki, Ninomiya-Tsuji Jun, Yasui Teruhito, Miyado Kenji, Sekimoto Tomohisa, Ueno Naoto, Matsumoto Kunihiro, Yamada Gen
Center for Animal Resources and Development, Graduate School of Molecular and Genomic Pharmacy, Kumamoto University, Honjo 2-2-1, Kumamoto 860-0811, Japan.
Mech Dev. 2002 Dec;119(2):239-49. doi: 10.1016/s0925-4773(02)00391-x.
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.
转化生长因子-β（TGF-β）超家族由一组分泌型信号分子组成，这些分子在细胞生长和分化的调节中发挥着重要作用。TGF-β激活激酶-1结合蛋白-1（TAB1）被鉴定为一种激活TGF-β激活激酶-1（TAK1）的分子。最近的研究表明，TAB1-TAK1相互作用在体外信号转导中起重要作用，但关于这些分子在体内的作用知之甚少。为了研究TAB1在发育过程中的作用，我们克隆了小鼠Tab1基因并通过同源重组对其进行破坏。纯合Tab1突变小鼠死亡，在妊娠后期表现出肿胀外观，伴有广泛的水肿和出血。通过组织学检查发现，突变胚胎表现出心血管和肺部发育异常。Tab1突变胚胎成纤维细胞显示TAK1激酶活性大幅降低，对TGF-β刺激的敏感性降低。这些结果表明，TAB1在哺乳动物胚胎发生中起重要作用，并且是TGF-β信号通路中TAK1激活所必需的。
