An activating mutation in ERK causes hyperplastic tumors in a scribble mutant tissue in drosophila

Tatyana Kushnir, Shaked Bar-Cohen, Navit Mooshayef, Rotem Lange, Allan Bar-Sinai, Helit Rozen, Adi Salzberg, David Engelberg*, Ze Paroush

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

7 Scopus citations

Abstract

Receptor tyrosine kinase signaling plays prominent roles in tumorigenesis, and activating oncogenic point mutations in the core pathway components Ras, Raf, or MEK are prevalent in many types of cancer. Intriguingly, however, analogous oncogenic mutations in the downstream effector kinase ERK have not been described or validated in vivo. To determine if a point mutation could render ERK intrinsically active and oncogenic, we have assayed in Drosophila the effects of a mutation that confers constitutive activity upon a yeast ERK ortholog and has also been identified in a few human tumors. Our analyses indicate that a fly ERK ortholog harboring this mutation alone (RolledR80S), and more so in conjunction with the known sevenmaker mutation (RolledR80S+D334N), suppresses multiple phenotypes caused by loss of Ras-Raf-MEK pathway activity, consistent with an intrinsic activity that is independent of upstream signaling. Moreover, expression of RolledR80S and RolledR80S+D334N induces tissue overgrowth in an established Drosophila cancer model. Our findings thus demonstrate that activating mutations can bestow ERK with pro-proliferative, tumorigenic capabilities and suggest that Drosophila represents an effective experimental system for determining the oncogenicity of ERK mutants and their response to therapy.

Original languageAmerican English
Pages (from-to)109-120
Number of pages12
JournalGenetics
Volume214
Issue number1
DOIs
StatePublished - 2020

Bibliographical note

Publisher Copyright:
Copyright © 2020 by the Genetics Society of America.

Keywords

  • Drosophila
  • ERK
  • Hyperplastic tumors
  • Oncogenic mutations
  • Rolled RTK signaling
  • Sevenmaker

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