Discovering Novel Feedback and Crosstalk Mechanisms in Cellular Signaling Pathways

Abstract

Multiple signaling pathways control cellular response to environmental cues such as nutrients, growth factors and stress. Interpretation of these cues requires coordinated regulation of intracellular signaling pathways. Our attempt to understand how cells coordinate different signaling pathways led to the discovery of two crosstalk mechanisms between different signaling cascades. We found that PI3K-AKT signaling reduces EGFR signaling to the parallel ERK-MAPK pathway by enhancing EGF induced EGFR degradation. At the molecular level AKT activates PIKfyve to facilitate EGFR trafficking from early endosomes to the lysosomes. Using a mass spectrometry based approach we also found growth factor signaling by EGF inhibits stress response. In particular, inhibiting RSK signaling downstream of EGF increased the activity of stress activated kinases p38, MSK2 and ERK5. We propose that when growth factors are present active RSK phosphorylates and inhibits a master regulator of stress response MEKK3, which leads to termination of MEKK3 signaling to downstream kinases. Our unbiased phosphoproteomic approach also lead to identification of many ERK and RSK substrates that will help us explain how growth factor signaling regulates a wide variety of biological processes.