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ErbB-4 s80 intracellular domain abrogates ETO2-dependent transcriptional repression

Bryan Linggi1, Graham Carpenter

  • 1Department of Biochemistry, Vanderbilt University School of Medicine, Nashville, Tennessee 37232-0146, USA.

The Journal of Biological Chemistry
|July 4, 2006
PubMed

Insights

ErbB-4 signaling releases a nuclear protein (s80) that interacts with Eto2, a transcriptional corepressor. This interaction blocks Eto2

Area of Science:

  • Molecular and Cellular Biology
  • Cancer Research
  • Signal Transduction

Background:

  • ErbB-4 signaling pathways are crucial in cell differentiation and implicated in human breast cancer.
  • The intracellular domain of ErbB-4 (s80) translocates to the nucleus and is hypothesized to regulate cell differentiation.
  • Eto2 is a transcriptional corepressor involved in erythrocyte differentiation and linked to breast cancer development.

Purpose of the Study:

  • To investigate the mechanism by which the ErbB-4 intracellular domain (s80) mediates cell differentiation.
  • To determine if s80 regulates the transcriptional corepressor Eto2.
  • To elucidate the functional interaction between s80 and Eto2 in the nucleus.

Main Methods:

  • Studied the nuclear translocation and localization of s80 upon ligand binding to ErbB-4.
  • Investigated the colocalization and interaction between s80 and Eto2 in the nucleus.
  • Assessed the effect of s80 expression on Eto2-mediated transcriptional repression using a heterologous promoter.

Main Results:

  • Ligand binding to ErbB-4 induces nuclear translocation of s80, where it colocalizes and interacts with Eto2.
  • Expression of s80 inhibits Eto2's ability to repress transcription from a heterologous promoter.
  • The inhibitory effect of s80 on Eto2 is mediated by its carboxyl-terminal region and does not require kinase activity.

Conclusions:

  • Presents a novel mechanism of transcriptional corepressor regulation by a receptor intracellular domain.
  • Suggests a direct role for Eto2 in ErbB-4-dependent cell differentiation.
  • Highlights a new pathway linking ErbB-4 signaling to transcriptional regulation in mammary cells.

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