Passi Mehak, Stöckl Jan B, Fröhlich Thomas, Moser Simone, Vollmar Angelika M, Zahler Stefan
Center for Drug Research, Ludwig-Maximilians-University Munich, Germany.
Laboratory for Functional Genome Analysis, Gene Center Munich, Ludwig-Maximilians-University Munich, Germany.
FEBS Open Bio. 2025 Apr;15(4):647-660. doi: 10.1002/2211-5463.13962. Epub 2024 Dec 30.
MST2 (STK3) is a major upstream kinase in the Hippo signalling pathway, an evolutionary conserved pathway in regulation of organ size, self-renewal and tissue homeostasis. Its downstream effectors are the transcriptional regulators YAP and TAZ. This pathway is regulated by a variety of factors, such as substrate stiffness or cell-cell contacts. Using a yeast two-hybrid screen, we detected a novel interaction between the kinases MST2 and CDK5, which we further confirmed by co-immunoprecipitation experiments. Cyclin-dependent kinase 5 (CDK5) is an unusual member of the family of cyclin-dependent kinases, involved in tumour growth and angiogenesis. Although a link between CDK5 and Hippo has been previously postulated, the mode of action is still elusive. Here, we show that knockdown of CDK5 causes reduced transcriptional activity of YAP and that CDK5 influences the phosphorylation levels of the Hippo upstream kinase LATS1. Moreover, a phosphoproteomics approach revealed that CDK5 interferes with the phosphorylation of DLG5, another upstream kinase, which regulates the Hippo pathway. Hence, CDK5 seems to act as a signalling hub for integrating the Hippo pathway and other signalling cascades. These interactions might have important implications for the use of CDK5 inhibitors, which are already in clinical use for tumour diseases.
MST2（STK3）是Hippo信号通路中的一种主要上游激酶，该通路在调节器官大小、自我更新和组织稳态方面具有进化保守性。其下游效应分子是转录调节因子YAP和TAZ。该通路受多种因素调节，如底物硬度或细胞间接触。通过酵母双杂交筛选，我们检测到激酶MST2和CDK5之间存在一种新的相互作用，并通过免疫共沉淀实验进一步证实。细胞周期蛋白依赖性激酶5（CDK5）是细胞周期蛋白依赖性激酶家族中的一个特殊成员，参与肿瘤生长和血管生成。尽管之前有人推测CDK5与Hippo之间存在联系，但其作用方式仍不清楚。在此，我们表明敲低CDK5会导致YAP的转录活性降低，并且CDK5会影响Hippo上游激酶LATS1的磷酸化水平。此外，磷酸化蛋白质组学方法显示CDK5会干扰另一种调节Hippo通路的上游激酶DLG5的磷酸化。因此，CDK5似乎作为一个信号枢纽，整合Hippo通路和其他信号级联反应。这些相互作用可能对已经在肿瘤疾病临床应用中的CDK5抑制剂的使用具有重要意义。
