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Analyzing Cell Surface Adhesion Remodeling in Response to Mechanical Tension Using Magnetic Beads
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Decoding ADGRE5: How Proteolytic Cleavage and Mechanical Forces Unleash Cellular Signals

Ana L Moreno-Salinas1, Arturo Mancini2, Samya Aouad2,3

  • 1Department of Pharmacology-Physiology, Université de Sherbrooke, Sherbrooke, QC J1H 5N4, Canada.

Cells
|August 27, 2025
PubMed

Insights

Adhesion G protein-coupled receptor ADGRE5 (CD97) signaling is complex. This study reveals novel activation pathways, including GPS cleavage-independent mechanisms and mechanical stimulation, crucial for oncology drug development.

Area of Science:

  • Molecular and Cellular Biology
  • G protein-coupled receptor (GPCR) signaling
  • Cancer biology and drug discovery

Background:

  • The adhesion GPCR ADGRE5 (CD97) is frequently overexpressed in various cancers, making it a promising oncology and immuno-oncology target.
  • Understanding the precise activation and signaling pathways of ADGRE5 is critical for developing effective therapeutics.

Purpose of the Study:

  • To elucidate the signaling mechanisms of human ADGRE5 (hADGRE5) using advanced biosensor technologies.
  • To investigate both G protein-dependent and β-arrestin-dependent signaling pathways activated by hADGRE5.
  • To explore novel activation mechanisms, including protease cleavage and mechanical stimulation.

Main Methods:

  • Utilized enhanced bystander bioluminescence resonance energy transfer (ebBRET)-based biosensors to monitor hADGRE5 signaling.
  • Employed a synthetic TEV protease-cleavable receptor chimera for controlled tethered agonist exposure.
  • Investigated signaling induced by Gingipain K (Kgp) and mechanical stimulation (MS) on hADGRE5.

Main Results:

  • Controlled agonist exposure via TEV protease revealed signaling through Gα12/Gα13 and β-arrestin 1/2 recruitment.
  • Gingipain K (Kgp) cleavage activated Gαz/Gα11 and mimicked TEV-induced signaling, demonstrating GPS cleavage-independent activation.
  • Mechanical stimulation (MS) induced β-arrestin 2 recruitment, dependent on the GPCR proteolysis site (GPS) and CD55 interaction.

Conclusions:

  • This study provides significant insights into the multifaceted signaling capabilities of hADGRE5.
  • hADGRE5 exhibits plasticity, activating signaling pathways through both GPS cleavage-dependent and -independent mechanisms.
  • Findings support ADGRE5 as a versatile target in cancer therapy, with potential for targeting mechanical cues.
Keywords:
ADGRE5BRETCD55aGPCRsbiased signalingmechanical stimulation

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