The Ras-MAP kinase pathway is a major regulator of a variety of processes that dictate cellular fate decisions. Differences in signal strength, duration and cellular location of ERK-MAPK and the RSK family of protein kinases can lead to the initiation and control of dramatically different biological processes such as cell proliferation, cell migration, cell survival, cell senescence, and cell death. We have recently found that the MAPK, ERK2, utilizes distinct substrate interaction motifs; the CD (common docking) domain and the DBP (DEF binding pocket), to regulate different biological fates including RSK-mediated feedback loops and cell proliferation, or transcription-dependent induction of epithelial-to-mesenchymal transition (EMT), respectively. To extensively examine signaling via these distinct ERK2-regulated pathways, we are completing mass spectrometry-based proteomics and phosphoproteomics, and identifying new effectors of ERK2 and RSK signaling. We anticipate discovering new therapeutic targets and biological markers that will help treat diseases associated with the improper regulation of ERK signaling, such as occurs in cancer.