mTORC1型
生物
细胞生物学
TFEB
磷酸化
GTP酶
转录因子
癌症研究
信号转导
生物化学
PI3K/AKT/mTOR通路
基因
作者
Xia Li,Tiejian Nie,Fangfang Lu,Lu Huang,Xiaolong Shi,Dongni Ren,Jianjun Lu,Xiaobin Li,Tuo Xu,Bozhou Cui,Qing Wang,Guodong Gao,Qian Yang
出处
期刊:Autophagy
[Informa]
日期:2023-09-29
卷期号:20 (3): 505-524
标识
DOI:10.1080/15548627.2023.2259735
摘要
MTOR (mechanistic target of rapamycin kinase) complex 1 (MTORC1) orchestrates diverse environmental signals to facilitate cell growth and is frequently activated in cancer. Translocation of MTORC1 from the cytosol to the lysosomal surface by the RRAG GTPases is the key step in MTORC1 activation. Here, we demonstrated that transcription factors MEF2A and MEF2D synergistically regulated MTORC1 activation via modulating its cyto-lysosome shutting. Mechanically, MEF2A and MEF2D controlled the transcription of FNIP1 and FNIP2, the components of the FLCN-FNIP1 or FNIP2 complex that acts as a RRAGC-RRAGD GTPase-activating element to promote the recruitment of MTORC1 to lysosome and its activation. Furthermore, we determined that the pro-oncogenic protein kinase SRC/c-Src directly phosphorylated MEF2D at three conserved tyrosine residues. The tyrosine phosphorylation enhanced MEF2D transcriptional activity and was indispensable for MTORC1 activation. Finally, both the protein and tyrosine phosphorylation levels of MEF2D are elevated in human pancreatic cancers, positively correlating with MTORC1 activity. Depletion of both MEF2A and MEF2D or expressing the unphosphorylatable MEF2D mutant suppressed tumor cell growth. Thus, our study revealed a transcriptional regulatory mechanism of MTORC1 that promoted cell anabolism and proliferation and uncovered its critical role in pancreatic cancer progression.
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