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Cholesterol Efflux Assay
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Cholesterol Efflux Assay

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Cholesterol inhibits assembly and 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, USA.

Biorxiv : the Preprint Server for Biology
|June 25, 2024
PubMed

Insights

Cholesterol inhibits the self-assembly and oncogenic signaling of the receptor tyrosine kinase EphA2, which drives cancer metastasis. Lowering cholesterol promotes EphA2 assembly and activation, suggesting cholesterol acts as a safeguard.

Area of Science:

  • Molecular biology
  • Cell biology
  • Cancer research

Background:

  • The receptor tyrosine kinase EphA2 promotes cancer metastasis.
  • EphA2 exists in monomer, dimer, and oligomer states, but the pro-metastatic signaling state is unknown.

Purpose of the Study:

  • To investigate the role of EphA2 self-assembly states in driving pro-metastatic signaling.
  • To develop a method for quantifying membrane protein self-assembly.
  • To elucidate the mechanism by which cholesterol affects EphA2 assembly and activity.

Main Methods:

  • Developed SiMPull-POP, a single-molecule method for quantifying membrane protein self-assembly.
  • Performed experiments involving plasma membrane cholesterol reduction.
  • Conducted phosphorylation studies in various cell lines.
  • Investigated the mechanism of cholesterol's effect on EphA2 assembly and activity.

Main Results:

  • Reduced plasma membrane cholesterol strongly promoted EphA2 self-assembly, mimicking the effect of the EphA2 ligand.
  • Cholesterol was found to inhibit EphA2 assembly.
  • Low cholesterol increased phospho-serine levels, a marker of oncogenic signaling.
  • Cholesterol inhibits EphA2 assembly and activity via an in-trans effect involving protein kinase A and beta-adrenergic receptor signaling.

Conclusions:

  • Cholesterol inhibits EphA2 self-assembly and activation, thereby preventing uncontrolled oncogenic signaling.
  • Cholesterol acts as a molecular safeguard against EphA2-driven pro-metastatic signaling.
  • These findings provide new mechanistic insights into EphA2's oncogenic function.

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