ETS1 is a genome-wide effector of RAS/ERK signaling in epithelial cells.
Bottom Line: Genome-wide expression analysis showed that ETS1 was required for activation of RAS-regulated cell migration genes, but also identified a surprising role for ETS1 in the repression of genes such as DUSP4, DUSP6 and SPRY4 that provide negative feedback to the RAS/ERK pathway.Consistently, ETS1 was required for robust RAS/ERK pathway activation.Therefore, ETS1 has dual roles in mediating epithelial-specific RAS/ERK transcriptional functions.
Affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA.Show MeSH
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Mentions: If RAS/ERK signaling functions through ETS1 to activate a cell migration gene expression program, then ETS1, despite being ubiquitously expressed, should only be necessary for cell migration in cell lines with high levels of RAS/ERK activity. To test this, we first examined PC3 prostate cancer cells, which have low ERK activation, but migrate due to high expression of the oncogenic ETS gene ETV4 (21,25). In PC3 cells, depletion of ETV4 decreased cell migration, but depletion of ETS1 had no effect (Figure 3A and B), indicating no ETS1 role when RAS/ERK activity is low. In addition, the RWPE1/2 cell system was used to directly compare ETS1 roles in cell lines where the only difference is in RAS/ERK activation. RWPE1 cells are derived from normal prostate epithelia and have low levels of ERK activation (21). Expression of Ki-RAS in RWPE1 cells activates ERK signaling, and these cells are called RWPE2. We have previously shown that overexpression of oncogenic ETS proteins such as ERG and ETV1 increases migration of RWPE1, but not RWPE2 cells (21). Here, in contrast, we show that ETS1 overexpression has no effect on RWPE1 migration (Figure 3C), but significantly increases the migration of RWPE2 cells (Figure 3D). Consistent with this observation, depleting endogenous ETS1 from RWPE2 cells results in a significant loss of cell migration (Figure 3E). In conclusion, the ability of ETS1 to transactivate through ETS/AP-1 sequences and drive cell migration requires RAS/ERK activation and the ERK phosphorylation residues T38 and S41.
Affiliation: Department of Biology, Indiana University, Bloomington, Indiana, USA.