The study found that the novel MST-MOB complex regulates the mechanism of Hippo pathway and pancreatic cancer
September 29, 2018 Source: Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences
Window._bd_share_config={ "common":{ "bdSnsKey":{ },"bdText":"","bdMini":"2","bdMiniList":false,"bdPic":"","bdStyle":" 0","bdSize":"16"},"share":{ }};with(document)0[(getElementsByTagName('head')[0]||body).appendChild(createElement('script')) .src='http://bdimg.share.baidu.com/static/api/js/share.js?v=89860593.js?cdnversion='+~(-new Date()/36e5)];On August 2nd, the International Academic Journal Journal of Biological Chemistry published the latest research results of the Zhou Zhaocai Research Group of the Institute of Biochemistry and Cell Biology of the Chinese Academy of Sciences. “The MST4–MOB4 complex disrupts the MST1–MOB1 complex in the Hippo–YAP pathway And plays a pro-oncogenic role in pancreatic cancer". This study resolved the conserved interaction pattern between MST-MOB proteins and revealed the mechanism of action of MST4-MOB4 complex and MST1-MOB1 complex to modulate pancreatic cancer.
The Hippo signaling pathway is highly conserved in evolution and is involved in the regulation of organ size, tissue homeostasis, and regeneration, and is closely related to pathological processes such as tumorigenesis; and the binding of MOB1 to MST1/2 kinase to the Hippo pathway Transduction is crucial. Studies have shown that in addition to MOB1, MOB3A/B/C can also bind to MST1 and participate in the regulation of glioblastoma multiforme. However, the interaction between different MST kinases and MOB proteins has not been systematically studied. It is unclear whether there are other MST-MOB complexes, as well as potential regulatory effects on Hippo signaling pathways and tumorigenesis.
Zhou Zhaocai's research group has long been committed to studying the molecular and cellular signaling mechanisms of tumorigenesis and immune response, and explored the function and mechanism of Hippo pathway in regulating gastrointestinal tumors (Cancer Cell 2014; Cell Research 2014; Oncogene 2017; Journal of Experimental Medicine 2018). A series of research progresses have been made around MST4 protein kinase to analyze the structure and function of MST4 kinase and its complexes with regulatory factors MO25 and CCM3 (Structure, 2013a; Structure, 2013b), revealing the key signals of MST4 through phosphorylation. Molecular TRAF6 dynamically regulates the mechanism of macrophage inflammatory response (Nature Immunology, 2015). On this basis, the study used a combination of biochemical structure and cell biology techniques to systematically study the interaction between MST and MOB proteins, and found a conservative binding mode between the two types of proteins, and focused on MST4-MOB4. Differences in structure and function from MST1/2-MOB1. The study found that MST4 and MOB4 bind in a phosphorylation-dependent manner, and the overall structure of the MST4-MOB4 complex is similar to that of the previously reported MST2-MOB1 complex. However, in contrast to the anti-cancer effect of the MST1-MOB1 complex, the MST4-MOB4 complex promotes proliferation and migration of pancreatic cancer cell PANC-1. Since the key amino acids at the interface of the two complexes are very conserved, MST4 and MOB4 can interfere with the assembly of the MST1-MOB1 complex by competitive binding, thereby affecting its kinase activity, resulting in enhanced downstream YAP activity. This study indicates that the structurally conserved MST-MOB complex eventually evolved into different biological functions during evolution, providing a new perspective for further understanding of the role of the Hippo pathway in tumorigenesis. It is worth noting that whether MST4 can regulate Hippo signaling pathway in other ways, further research is needed in the future.
The research was funded by the Chinese Academy of Sciences' Strategic Science and Technology Pilot Project, the Ministry of Science and Technology Key Research and Development Program, the National Natural Science Foundation of China Outstanding Youth Fund, the Chinese Academy of Sciences Youth Innovation Promotion Association and the China Postdoctoral Science Foundation. The Shanghai Light Source BL19U1 line provides support and assistance in the experimental data collection. The Biochemistry and Cellular Cell Biology Platform and Molecular Biology Platform also provide support.
MST4 regulates Hippo-YAP signal through MST-MOB complex assembly
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The research on hydrogen in the field of biology can be traced back to the beginning of the 21st century. That said, hydrogen inhalation therapy is an emerging treatment method that has received a lot of attention.
In 2007, Japanese scholar Professor Shigeo Ohta reported for the first time in the journal Nature Medicine that hydrogen has a significant therapeutic effect on cerebral ischemia-reperfusion injury. Since then, more and more studies have shown that hydrogen has various biological effects such as antioxidant, anti-inflammatory, and anti-apoptosis, and has potential therapeutic value for a variety of diseases.
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