Regulatory mechanism of the tumor suppressive Hippo pathway

为了阐明调控哺乳动物Hippo通路的分子机制，我们首先寻找了在功能和物理上与已知组分如FAT4、Merlin、rassf、Salvador和MOB1相互作用的分子。然而，这一尝试并不成功。随后，我们建立了几个基于细胞的检测系统来监测Hippo通路的活性，并寻找上调或下调Hippo通路的化合物。我们发现ß -肾上腺素能兴奋剂上调Hippo通路。这是首次报道G蛋白偶联受体在Hippo通路调控中的意义。我们还获得了几种调节Hippo通路的候选化合物。这些化合物包括促进肌肉形成和抑制癌症侵袭和转移的候选化合物。我们目前正在分析这些化合物是如何发挥作用的，并试图找出Hippo通路的新调控机制，以及开发治疗肌肉萎缩和癌症的有用试剂。我们还分析了秀丽隐杆线虫的同源基因RASSF和YAP，这两个基因都是Hippo通路的组成部分，发现Hippo通路在秀丽隐杆线虫中并不保守。然而，关于秀丽隐杆线虫RASSF同源性的发现揭示了RASSF的假设功能，这可能对未来哺乳动物河马通路的研究有用。

To clarify the molecular mechanism that regulates the mammalian Hippo pathway, we first searched for molecules that functionally and physically interact with the known components such as FAT4, Merlin, RASSFs, Salvador, and MOB1. However, this attempt was not successful. We subsequently established several cell-based assay systems to monitor the activity of the Hippo pathway and searched for chemical compounds that up-regulate or down-regulate the Hippo pathway. We found that ss-adrenergic stimulants up-regulate the Hippo pathway. This is the first study to report the implication of G protein-coupled receptors in the regulation of the Hippo pathway. We have additionally obtained several candidate compounds that modulate the Hippo pathway. These compounds include candidates that promote myogenesis and that inhibit cancer invasiveness and metastasis. We are currently analyzing how these compounds exhibit the effects and trying to find out new regulatory mechanisms of the Hippo pathway as well as to develop useful reagents for the treatment of muscle atrophy and cancer. We also analyzed Caenorhabditis elegans homologs of RASSF and YAP, both of which are the components of the Hippo pathway, and found that the Hippo pathway is not conserved in Caenorhabditis elegans. However the findings about Caenorhabditis elegans RASSF homolog has shed light on the putative function of RASSF, which may be useful for the future study in the mammalian Hippo pathway.