CXCR4-EGFR heteromers show ligand-dependent changes in conformation and signaling

  • Cell Chem Biol. 2026 Jul 14:S2451-9456(26)00232-1. doi: 10.1016/j.chembiol.2026.06.008.
Dehan Comez  1 ,  Stephanie M Anbuhl  2 ,  Simon Platt  1 ,  Oliver C Isaac  1 ,  Noemi Karsai  1 ,  Robert Markus  1 ,  Marco Siderius  3 ,  Martine J Smit  3 ,  Raimond Heukers  2 ,  Laura E Kilpatrick  4 ,  Stephen J Hill  5
Affiliations
  • 1. Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands Nottingham, Nottingham, UK.
  • 2. Amsterdam Institute of Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, VU University, Amsterdam, the Netherlands; QVQ, Universiteitsweg 101, 3584 CG Utrecht, the Netherlands.
  • 3. Amsterdam Institute of Molecular and Life Sciences (AIMMS), Division of Medicinal Chemistry, Faculty of Sciences, VU University, Amsterdam, the Netherlands.
  • 4. Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands Nottingham, Nottingham, UK; Division of Bimolecular Science and Medicinal Chemistry, Biodiscovery Institute, School of Pharmacy, University of Nottingham, Nottingham, UK.
  • 5. Division of Physiology, Pharmacology and Neuroscience, School of Life Sciences, University of Nottingham, Nottingham, UK; Centre of Membrane Proteins and Receptors (COMPARE), University of Birmingham and University of Nottingham, The Midlands Nottingham, Nottingham, UK. Electronic address: [email protected].
PMID: 42447861 DOI: 10.1016/j.chembiol.2026.06.008
Abstract

The chemokine CXCR4 receptor and epidermal growth factor receptor (EGFR) are cell surface receptors that are overexpressed in numerous types of Cancer. In this study, we have investigated the formation of CXCR4-EGFR heteromers using bioluminescence resonance energy transfer (BRET) and nanobody-based proximity ligation assays (PLAs). The present study demonstrated that EGFR and CXCR4 can form oligomeric complexes that were capable of coupling to PLCγ, Gi proteins and β-arrestin-2. The presence of these oligomeric complexes was detected by PLA in native HeLa cells at endogenous levels of expression using receptor-selective nanobody-oligonucleotide conjugates. Furthermore, the individual receptor components of the oligomer underwent conformation changes in response to EGF and CXCL12, which in the case of Gi-signalling led to altered responses to combinations of CXCL12 and EGF. This may have clinical implications in those cancers where both EGFR and CXCR4 are overexpressed.

Keywords
CXCR4; EGFR; NanoBRET; nanobodies; proximity ligation assays; receptor oligomerization.
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