On March 30, 2022, Professor Zhang Hongquan's team from Peking University School of Basic Medicine published a long research paper titled "Oxidative stress-CBP axis modulates MOB1 acetylation and activates the Hippo signaling pathway" in the journal Nucleic Acids Research, revealing that The role and molecular mechanism of oxidative stress regulating Hippo signaling pathway activation and inhibition of lung adenocarcinoma cell growth
Working model: Oxidative stress regulates Hippo signaling pathway activation through MOB1 acetylation and inhibits lung adenocarcinoma cell growth
The canonical Hippo signaling pathway is a series of kinase cascades, the major members of which in mammals include MST1/2, LATS1/2, SAV1, MOB1 and YAP/TAZ
Among them, MOB1 is a substrate of the kinase MST1/2 and a co-activator of LATS1/2
The researchers found that MOB1 interacts with and is acetylated by the acetyltransferase CBP, while HDAC6 catalyzes its deacetylation
LC-MS/MS analysis showed that the acetylation site of MOB1 was the 11th lysine (K11), and the site-specific acetylated antibody was prepared accordingly
Further research revealed that MOB1 acetylation can positively regulate the Hippo signaling pathway: acetylation weakens the interaction between MOB1 and its E3 ligase praja2, reduces the degradation of MOB1 through the proteasome pathway, and promotes MOB1 to be more stable; at the same time, acetylation promotes MOB1.
Phosphorylation and activation
Compared with the non-acetylated state, acetylated MOB1 has a stronger binding ability to LATS1, promotes the activity of LATS1 kinase, increases the phosphorylation of YAP/TAZ and promotes its degradation in the cytoplasm, preventing its nuclear translocation, thereby inhibiting the Transcription of target genes CYR61, CTGF, ANKRD1, etc.
of Hippo signaling pathway
The researchers also found that MOB1 acetylation loss can lead to rapid proliferation, migration and invasion of lung cancer cells; in vivo experiments confirmed that acetylation loss will accelerate xenograft tumor growth
In the detection and analysis of the acetylation level of MOB1-K11 in 85 lung adenocarcinoma patients with cancer-paracancerous tissues, it was found that the acetylation level of MOB1 in tumor tissues was significantly lower than that in normal adjacent tissues, and high acetylation predicted a good prognosis of patients.
, suggesting that MOB1 acetylation can inhibit the occurrence and development of lung adenocarcinoma
It is particularly striking that upstream oxidative stress as a physiological and pathological factor can promote the acetylation of MOB1 by up-regulating the acetyltransferase CBP, which is independent of the activity of MST1/2 and the phosphorylation of MOB1.
In this way, MOB1 acts as a "signal strength sensor", which senses the intensity of upstream oxidative stress and undergoes different degrees of acetylation.
By controlling the activation of LATS1/2, it regulates the degradation and nuclear translocation of the downstream effector YAP, and then Regulates the activation of Hippo signaling pathway
This study uses MOB1 as a link to link oxidative stress with the precise regulation of the Hippo signaling pathway, revealing the potential application value of MOB1 acetylation in the diagnosis and prognosis judgment of lung adenocarcinoma.
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Jin Jiaqi, a doctoral student at Peking University School of Basic Medicine, is the first author of the paper, and Professor Zhang Hongquan is the responsible author of the paper
The research was assisted by Professor Luo Jianyuan, Department of Medical Genetics, School of Basic Medicine, Peking University, and Dr.
Zhang Wenhao, Key Laboratory of Bioinformatics, Ministry of Education, School of Life Sciences, Tsinghua University
The research was funded by key and general projects of the National Natural Science Foundation of China, major basic research projects of the Ministry of Science and Technology, key projects of Beijing Natural Science Foundation, and key basic research projects of Peking University
Original link: https://academic.