Signal transduction networks regulated by MAP kinase cascades

MAP 激酶级联调节的信号转导网络

基本信息

批准号：
17207012
负责人：
MATSUMOTO Kunihiro
金额：
$ 33.11万
依托单位：
Nagoya University
依托单位国家：
日本
项目类别：
Grant-in-Aid for Scientific Research (A)
财政年份：
2005
资助国家：
日本
起止时间：
2005 至 2006
项目状态：
已结题

来源：
https://kaken.nii.ac.jp/en/grant/KAKENHI-PROJECT-17207012/
关键词：
signal transduction MAP kinase cascades stress response NF-_KB TAO2 JNK mesoderm formation ERK キネシン足場蛋白質シナプス小胞

项目摘要

1. Osmotic stress activates MAPKs, including JNK and p38, which play important roles in cellular stress responses. TAK1 is a member of the MAPKKK family and can activate JNK and p38. TAK1 can also activate IKK that leads to NF-KB activation. We found that TAK1 is essential for osmotic stress-induced activation of JNK but is not an exclusive mediator of p38 activation. Furthermore, we found that although TAK1 was highly activated upon osmotic stress, it could not induce activation of NF-_KB. These results suggest that TAK1 activity is somehow modulated to function specifically in osmotic stress signaling, leading to the activation of JNK but not of IKK. To elucidate the mechanism underlying this modulation, we screened for potential TAK1-binding proteins. We found that TAO2 associates with TAK1 and can inhibit TAK1-mediated activation of NF-_KB but not of JNK. We observed that TAO2 can interfere with the interaction between TAK1 and IKK and thus may regulate TAK1 function.2. Distinct modes of ERK MAPK activation, sustained or transient, are critical for cell fate decision in cultured cells. We found that the duration of ERK activity contributes to the establishment of dorsoventral patterning during mesoderm formation in Xenopus. While transient activation of ERK is sufficient to induce expression of the pan-mesodermal gene Xbra, sustained ERK activation is necessary for expression of the dorsal mesodermal gene Chd. Consistently, at early gastrula, prolonged activation of ERK occurs in dorsal mesoderm where both Xbra and Chd are expressed. Consequently, Xenopus Fos protein accumulates in the dorsal mesoderm. Furthermore, we found that xFos can function as a molecular sensor of the duration of ERK signaling in Xenopus embryos.

1。渗透应力激活包括JNK和P38在内的MAPK，它们在细胞应力反应中起着重要作用。 TAK1是Mapkkk家族的成员，可以激活JNK和P38。 TAK1还可以激活导致NF-KB激活的IKK。我们发现TAK1对于渗透应力诱导的JNK激活至关重要，但不是p38激活的独家介质。此外，我们发现，尽管在渗透应力时TAK1被高度激活，但它不能诱导NF-_KB的激活。这些结果表明，TAK1活性在某种程度上调节以在渗透应力信号传导中专门起作用，从而导致JNK的激活，而不是IKK的激活。为了阐明该调制的基础机制，我们筛选了潜在的tak1结合蛋白。我们发现TAO2与TAK1相关，并且可以抑制NF-_KB的TAK1介导的激活，但不能抑制JNK的激活。我们观察到TAO2可以干扰TAK1与IKK之间的相互作用，因此可以调节TAK1函数2。 ERK MAPK激活的不同模式持续或瞬态，对于培养细胞中的细胞命运决策至关重要。我们发现，ERK活性的持续时间有助于在Xenopus的中胚层形成期间建立背腹形图。虽然ERK的瞬时激活足以诱导泛中胚层基因XBRA的表达，但持续的ERK激活对于表达背性中胚层基因CHD的表达是必要的。一致地，在早期的胃肠道中，ERK的延长激活发生在表达XBRA和CHD的背侧中胚层中。因此，爪蟾FOS蛋白在背侧中胚层积聚。此外，我们发现XFO可以充当异爪蟾胚胎中ERK信号持续时间的分子传感器。