A REFERENCE MAP OF THE ERK PATHWAY INTERACTOME

To survive, cells must be able to change their behavior in response to environmental cues. The proteins transmitting these signals and implementing the appropriate biological outcomes are organized in pathways that maintain signal fidelity through protein-protein interaction, whereas signal strength is regulated by feedback mechanisms including cross-talk among different pathways. A breach in signal fidelity or a change in signal strength can have dire consequences, such as uncontrolled cell proliferation and transformation. A case in point is the hyperactivation of the ERK signaling pathway caused by somatic mutations in RAS, the most potent human oncogene. The RAS/RAF/MEK/ERK signaling pathway consists of four tiers, each containing more than one enzyme (4 RAS, 3 RAF, 2 MEK, 2 ERK). The proteins in the same tier have distinct essential functions, some of which rely on protein-protein interactions and on their ability to cross-talk with other pathways rather than on their enzymatic activity. We are interested in discovering how cancer-causing mutations and chemical inhibitors used in the clinic rewire the interaction network of the ERK pathway.