Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, United States; The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of Medicine, Baltimore, United States; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, United States
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, United States; The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of Medicine, Baltimore, United States; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, United States
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, United States; The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of Medicine, Baltimore, United States; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, United States
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, United States; The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of Medicine, Baltimore, United States; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, United States
Department of Molecular Biology and Genetics, The Johns Hopkins University School of Medicine, Baltimore, United States; The Biochemistry, Cellular, and Molecular Biology Graduate Program, The Johns Hopkins Universtiy School of Medicine, Baltimore, United States; Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, United States
A large fraction of human cancers contain genetic alterations within the Mitogen Activated Protein Kinase (MAPK) signaling network that promote unpredictable phenotypes. Previous studies have shown that the temporal patterns of MAPK activity (i.e. signaling dynamics) differentially regulate cell behavior. However, the role of signaling dynamics in mediating the effects of cancer driving mutations has not been systematically explored. Here, we show that oncogene expression leads to either pulsatile or sustained ERK activity that correlate with opposing cellular behaviors (i.e. proliferation vs. cell cycle arrest, respectively). Moreover, sustained–but not pulsatile–ERK activity triggers ERK activity waves in unperturbed neighboring cells that depend on the membrane metalloprotease ADAM17 and EGFR activity. Interestingly, the ADAM17-EGFR signaling axis coordinates neighboring cell migration toward oncogenic cells and is required for oncogenic cell extrusion. Overall, our data suggests that the temporal patterns of MAPK activity differentially regulate cell autonomous and non-cell autonomous effects of oncogene expression.
