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Ras-Erk signaling induces phosphorylation of human TLE1 and downregulates its repressor function.

T Zahavi1, A Maimon2, T Kushnir1

  • 1Department of Developmental Biology and Cancer Research, IMRIC, Faculty of Medicine, The Hebrew University, Jerusalem, Israel.

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Summary

Phosphorylation of TLE1, a Groucho ortholog, by the Ras-Erk pathway reduces its repressive function. This conserved mechanism impacts gene expression and blocks oncogenic phenotypes driven by mutated H-Ras.

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Area of Science:

  • Molecular Biology
  • Cell Biology
  • Genetics

Background:

  • The Ras-extracellular signal-regulated kinase (Erk) pathway regulates gene expression via transcriptional regulators.
  • In Drosophila, Groucho phosphorylation by Ras-Erk signaling is crucial for target gene induction.
  • Groucho's phosphorylation downregulates its gene-repressive function.

Purpose of the Study:

  • To investigate if human Groucho orthologs, specifically TLE1, are phosphorylated by the Ras-Erk pathway.
  • To determine the functional consequences of TLE1 phosphorylation on transcriptional repression and oncogenic signaling.
  • To explore the role of TLE1 phosphorylation in Ras-Erk pathway-mediated gene expression changes.

Main Methods:

  • Cell culture experiments with human cells to study TLE1 phosphorylation and function.
  • Transgenic Drosophila models to assess the in vivo effects of TLE1 phosphorylation.
  • In vitro and in vivo assays using human mammary cells to evaluate TLE1's role in oncogenic phenotypes.

Main Results:

  • Human TLE1 is phosphorylated upon Ras-Erk pathway activation, reducing its transcriptional repressor activity.
  • Unphosphorylatable TLE1 suppresses Ras-Erk target gene induction, while a phosphomimetic variant has minimal effect.
  • TLE1 is excluded from the nucleus following epidermal growth factor receptor pathway activation.
  • Unphosphorylated TLE1 inhibits oncogenic phenotypes induced by mutated H-Ras in human mammary cells.

Conclusions:

  • TLE1 phosphorylation is a conserved mechanism that attenuates repressor function in response to Ras-Erk signaling.
  • This phosphorylation event is critical for transcriptional responses to Ras-Erk signaling.
  • Dysregulation of TLE1 phosphorylation may contribute to tumorigenesis associated with excessive Ras-Erk pathway activity.