Mechanism of Activation of Ets-1 and Ets-2 by Ras/MAPK Signaling

Growth factor stimulation of cells leads to activation of the Ras/MAPK signaling pathway that results in phosphorylation of a single threonine in Ets-1 and highly-related Ets-2. The effect of signaling is enhancement of transcriptional activity. We discovered that Ets-1 and Ets-2 recruit the MAPK ERK2 by providing a physical docking site in addition to the phosphoacceptor site (Seidel and Graves 2002). Next, we discovered that the co-activator CBP/p300 binding is enhanced by phosphorylation, thus Ras/MAPK signaling to Ets-1 and Ets-2 functions at the level of co-activator recruitment (Foulds et al. 2004). We plan to pursue this interaction at a structural level to understand how the commonly used co-activators, such as CBP/p300, are specifically recruited to Ets-1 and Ets-2 target genes. In addition, we are investigating the assembly of ETS-1/ETS-2 and these co-activators on endogenous targets that are induced by Ras. Unbiased searches for Ras-inducible, Ets-1 or Ets-2 dependent target genes are in progress. Interesting putative targets include proteases involved in extracellular matrix remodeling that play a role in normal cell migration as well as metastasis.