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Ras signaling requires dynamic properties of Ets1 for phosphorylation-enhanced binding to coactivator CBP

Mary L Nelson1, Hyun-Seo Kang, Gregory M Lee

  • 1Department of Oncological Sciences, University of Utah School of Medicine, Huntsman Cancer Institute, University of Utah, Salt Lake City, UT, 84112, USA.

Proceedings of the National Academy of Sciences of the United States of America
|June 11, 2010
PubMed

Insights

Ras/MAPK pathway activation in cancer influences Ets1 protein function through phosphorylation. This structural study reveals a phospho-switch mechanism enhancing Ets1 binding to coactivators, impacting gene expression.

Area of Science:

  • Molecular Biology
  • Biochemistry
  • Cancer Research

Background:

  • Aberrant Ras/MAPK signaling is common in human cancers.
  • ETS gene family transcription factors are downstream effectors of this pathway.

Purpose of the Study:

  • To elucidate the mechanism by which Ras/MAPK signaling regulates Ets1 function via phosphorylation.
  • To determine the structural and biophysical basis of Ets1 regulation.

Main Methods:

  • Cell-based assays
  • Nuclear Magnetic Resonance (NMR) spectroscopy
  • Biophysical measurements

Main Results:

  • Phosphorylation of Ets1 at Thr38 and Ser41 by ERK2 alters its conformation.
  • NMR revealed Ets1's PNT domain is a four-helix bundle with dynamic elements.
  • Phosphorylation enhanced Ets1 affinity for the TAZ1 domain of CBP by 34-fold.
  • Interaction surfaces and electrostatic forces governing binding were mapped.

Conclusions:

  • Ets1 possesses a phospho-switch mechanism involving dynamic helical elements.
  • This switch modulates Ets1's interaction with coactivators like CBP, affecting gene expression.
  • Understanding this mechanism can inform therapeutic strategies targeting ETS proteins in disease.

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