Romano David, Matallanas David, Frederick Dennie T, Flaherty Keith T, Kolch Walter
*Systems Biology Ireland, University College Dublin, Belfield, Dublin 4, Ireland.
†Division of Surgical Oncology, Massachusetts General Hospital, 55 Fruit Street, Boston, MA 02114, U.S.A.
Biochem Soc Trans. 2014 Aug;42(4):816-21. doi: 10.1042/BST20140030.
The Hippo/MST2 (mammalian sterile 20-like kinase 2) pathway is a signalling cascade evolutionarily conserved in its structure. Originally described in Drosophila melanogaster as a regulator of organ size, this pathway has greater functions in mammals. Disturbance of mammalian MST2 pathway is associated with tumorigenesis by affecting apoptosis, cell cycle and polarity. In addition, this pathway has been shown to cross-talk with mitogenic pathways at multiple levels. In the present mini-review, we discuss our contribution highlighting the regulation of MST2 signalling by frequently observed oncogenic perturbations affecting mitogenic pathways. In particular, we review the role of RAS isoforms and PI3K (phosphoinositide 3-kinase)/Akt in the regulation of MST2 activity by phosphorylation. We also put the emphasis on RAF-induced control of MST2 signalling by protein-protein interactions. Finally, we recapitulate some of the direct mechanisms, such as ubiquitin-dependent degradation or gene silencing by promoter hypermethylation, involved in MST2 pathway component down-regulation in cancers.
河马/MST2（哺乳动物不育20样激酶2）信号通路是一种在结构上具有进化保守性的信号级联反应。该通路最初在黑腹果蝇中被描述为器官大小的调节因子，在哺乳动物中具有更广泛的功能。哺乳动物MST2信号通路的紊乱通过影响细胞凋亡、细胞周期和极性与肿瘤发生相关。此外，该信号通路已被证明在多个水平上与促有丝分裂信号通路相互作用。在本综述中，我们讨论了我们的贡献，重点介绍了影响促有丝分裂信号通路的常见致癌扰动对MST2信号的调控。特别是，我们回顾了RAS亚型和PI3K（磷脂酰肌醇3激酶）/Akt在通过磷酸化调节MST2活性中的作用。我们还强调了RAF通过蛋白质-蛋白质相互作用对MST2信号的诱导控制。最后，我们总结了一些直接机制，如泛素依赖性降解或启动子高甲基化导致的基因沉默，这些机制参与了癌症中MST2信号通路成分的下调。
