Understanding how signaling cascades dictate cell fate decisions
The signaling pathway connecting RAS and mitogen-activated protein kinases ERK1 and ERK2 is essential for the regulation of cell fate decisions. Therefore, it comes to no surprise that gain of function mutations in constituents of the RAS-ERK pathway are common, appearing in nearly 30-50% of human cancer. Sustained activation of the ERK1/2 pathway contributes to oncogenic transformation, controlling cell survival and proliferation. My work over the years has been focused on understanding how this pathway signals as well as its deregulation in cancer (for more information on this topic click here ).
In past years, our lab and others have shown that in addition to regulating proliferation and survival, ERK2 but not ERK1, promotes EMT (epithelial-to-mesenchymal transition) and tumor cell motility, invasion and metastasis. These studies also highlight the critical importance of different docking sites on ERK2 and its substrates that mediate the interaction with the kinases in order to provide specificity to signaling pathways. Two types of docking sites have been reported for ERK substrates, the DEF motif, which is present in many nuclear substrates of ERK, and the D-domain, which is important for the interaction between ERK regulators and other kinases, such as RSK (for more information on this topic click here ).
More recently, our lab has been focused on mapping the numerous mechanisms downstream of ERK2 signaling associated with acquisition of metastatic phenotypes. These include changes to chromatin regulation by altered histone deposition (Gomes, Ilter et al. 2019) and regulation of propionate metabolism (Gomes, Ilter, Low et al. 2022). Interestingly, ERK2 was found to control the transcription of critical regulators in both processes. We also found ERK2 to promote FoxO1 expression required for EMT (Shin et al. 2019). Current efforts are aimed at identifying cellular systems (e.g metabolism, membrane traffic, and chromatin) regulated by ERK2 which drive and support the metastatic process.