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MAPK activity dynamics regulate non-cell autonomous effects of oncogene expression.

Timothy J Aikin | Amy F Peterson | Michael J Pokrass | Helen R Clark | Sergi Regot
eLife | 2020

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.

Pubmed ID: 32940599

Associated grants

  • Agency: National Science Foundation, International
    Id: DGE-1746891
  • Agency: American Cancer Society, International
    Id: 133537-RSG-19-005-01-CCG
  • Agency: NIGMS NIH HHS, United States
    Id: T32 GM007445
  • Agency: National Science Foundation, International
    Id: MCB-1844994
  • Agency: NIGMS NIH HHS, United States
    Id: 1 R35 GM133499
  • Agency: NIGMS NIH HHS, United States
    Id: R35 GM133499

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