ERK is a key coordinator of the epithelial-to-mesenchymal transition (EMT) in that a variety of EMT-inducing factors activate signaling pathways that converge on ERK to regulate EMT transcription programs. However, the mechanisms by which ERK controls the EMT program are not well understood. Through an analysis of the global changes of gene expression mediated by ERK2, we identified the transcription factor FoxO1 as a potential mediator of ERK2-induced EMT, and thus we investigated the mechanism by which ERK2 regulates FoxO1. Additionally, our analysis revealed that ERK2 induced the expression of Dock10, a Rac1/Cdc42 GEF, during EMT. We demonstrate that the activation of the Rac1/JNK signaling axis downstream of Dock10 leads to an increase in FoxO1 expression and EMT. Taken together, our study uncovers mechanisms by which epithelial cells acquire less proliferative but more migratory mesenchymal properties and reveals potential therapeutic targets for cancers evolving into a metastatic disease state.
1.Univ Illinois, Dept Canc Biol & Pharmacol, Coll Med, Peoria, IL 61605 USA 2.Weill Cornell Med, Dept Pharmacol, New York, NY 10021 USA 3.Weill Cornell Med, Meyer Canc Ctr, New York, NY 10021 USA 4.St Jude Childrens Res Hosp, Dept Hematol, 332 N Lauderdale St, Memphis, TN 38105 USA 5.Univ Montreal, Inst Res Immunol & Canc, Montreal, PQ H3C 3J7, Canada
Recommended Citation:
Shin, Sejeong,Buel, Gwen R.,Nagiec, Michal J.,et al. ERK2 regulates epithelial-to-mesenchymal plasticity through DOCK10-dependent Rac1/FoxO1 activation[J]. PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA,2019-01-01,116(8):2967-2976