期刊
GENES & DEVELOPMENT
卷 24, 期 23, 页码 2654-2665出版社
COLD SPRING HARBOR LAB PRESS, PUBLICATIONS DEPT
DOI: 10.1101/gad.1989110
关键词
EMT; MCF10A; RNAi; RSK; cell migration; high throughput
资金
- March of Dimes Foundation [5-FY09-73]
- Charles H. Hood Foundation
- NIH [CA09361-27, CA129933]
- Howard Hughes Medical Institute
- DF/HCC SPORE in Breast Cancer [2P50 CA89393-09]
- DOD Center of Excellence in Breast Cancer [BC05-COE W81XH-06-2-0033]
- Harvard Medical School
- AID for Cancer Research
- [R21CA135601]
To define the functional pathways regulating epithelial cell migration, we performed a genome-wide RNAi screen using 55,000 pooled lentiviral shRNAs targeting similar to 11,000 genes, selecting for transduced cells with increased motility. A stringent validation protocol generated a set of 31 genes representing diverse pathways whose knockdown dramatically enhances cellular migration. Some of these pathways share features of epithelial-to-mesenchymal transition (EMT), and together they implicate key regulators of transcription, cellular signaling, and metabolism, as well as novel modulators of cellular trafficking, such as DLG5. In delineating downstream pathways mediating these migration phenotypes, we observed universal activation of ERKs and a profound dependence on their RSK effectors. Pharmacological inhibition of RSK dramatically suppresses epithelial cell migration induced by knockdown of all 31 genes, suggesting that convergence of diverse migratory pathways on this kinase may provide a therapeutic opportunity in disorders of cell migration, including cancer metastasis.
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