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Cholesterol inhibits assembly and oncogenic activation of the EphA2 receptor

Ryan J Schuck1, Alyssa E Ward1, Amita R Sahoo2

  • 1Department of Biochemistry & Cellular and Molecular Biology, University of Tennessee, Knoxville, TN, USA.

Communications Biology
|March 12, 2025
PubMed

Insights

Cholesterol inhibits the self-assembly and oncogenic signaling of the receptor tyrosine kinase EphA2, a key driver of cancer metastasis. Lowering cholesterol promotes EphA2 assembly, suggesting cholesterol acts as a safeguard against cancer progression.

Area of Science:

  • Molecular biology
  • Cell biology
  • Cancer research

Background:

  • Receptor tyrosine kinase EphA2 promotes cancer metastasis.
  • EphA2 exists as monomers, dimers, and oligomers, but the pro-metastatic state is unknown.
  • Understanding EphA2 self-assembly is crucial for targeting cancer malignancy.

Purpose of the Study:

  • To investigate the role of EphA2 self-assembly states in pro-metastatic signaling.
  • To develop a method for quantifying membrane protein self-assembly.
  • To elucidate the regulatory role of cholesterol in EphA2 activity.

Main Methods:

  • Development of SiMPull-POP, a single-molecule method for membrane protein self-assembly quantification.
  • Cholesterol manipulation in plasma membranes.
  • Phosphorylation studies in various cell lines.
  • Investigation of signaling pathways involving protein kinase A and beta-adrenergic receptors.

Main Results:

  • Reduced plasma membrane cholesterol significantly promotes EphA2 self-assembly, mimicking the effect of the EphA2 ligand.
  • Cholesterol inhibits EphA2 assembly and phosphorylation at serine residues, a marker of oncogenic signaling.
  • Cholesterol inhibits EphA2 activity via an in-trans mechanism involving protein kinase A and beta-adrenergic receptor signaling.

Conclusions:

  • Cholesterol acts as an inhibitor of EphA2 self-assembly and oncogenic signaling.
  • Low cholesterol levels enhance EphA2 assembly and promote pro-metastatic signaling.
  • Cholesterol functions as a protective mechanism against uncontrolled EphA2 activation and cancer progression.

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