The β2-adrenergic receptor associates with CXCR4 multimers in human cancer cells

Author:

Liang Junyi1,Seghiri Mohamed12ORCID,Singh Pradeep Kumar12ORCID,Seo Hyeon Gyu3ORCID,Lee Ji Yeong3ORCID,Jo Yoonjung3ORCID,Song Yong Bhum4ORCID,Park Chulo4ORCID,Zalicki Piotr3,Jeong Jae-Yeon3,Huh Won-Ki345ORCID,Caculitan Niña G.3,Smith Adam W.12ORCID

Affiliation:

1. Department of Chemistry, University of Akron, Akron, OH 44325

2. Department of Chemistry and Biochemistry, Texas Tech University, Lubbock, TX 79409

3. GPCR Therapeutics Inc., Gwanak-gu, Seoul 08790, Republic of Korea

4. School of Biological Sciences, Seoul National University, Seoul 08826, Republic of Korea

5. Institute of Microbiology, Seoul National University, Seoul 08826, Republic of Korea

Abstract

While the existence and functional role of class C G-protein-coupled receptors (GPCR) dimers is well established, there is still a lack of consensus regarding class A and B GPCR multimerization. This lack of consensus is largely due to the inherent challenges of demonstrating the presence of multimeric receptor complexes in a physiologically relevant cellular context. The C-X-C motif chemokine receptor 4 (CXCR4) is a class A GPCR that is a promising target of anticancer therapy. Here, we investigated the potential of CXCR4 to form multimeric complexes with other GPCRs and characterized the relative size of the complexes in a live-cell environment. Using a bimolecular fluorescence complementation (BiFC) assay, we identified the β2 adrenergic receptor (β2AR) as an interaction partner. To investigate the molecular scale details of CXCR4-β2AR interactions, we used a time-resolved fluorescence spectroscopy method called pulsed-interleaved excitation fluorescence cross-correlation spectroscopy (PIE-FCCS). PIE-FCCS can resolve membrane protein density, diffusion, and multimerization state in live cells at physiological expression levels. We probed CXCR4 and β2AR homo- and heteromultimerization in model cell lines and found that CXCR4 assembles into multimeric complexes larger than dimers in MDA-MB-231 human breast cancer cells and in HCC4006 human lung cancer cells. We also found that β2AR associates with CXCR4 multimers in MDA-MB-231 and HCC4006 cells to a higher degree than in COS-7 and CHO cells and in a ligand-dependent manner. These results suggest that CXCR4-β2AR heteromers are present in human cancer cells and that GPCR multimerization is significantly affected by the plasma membrane environment.

Funder

Human Frontier Science Program

Publisher

Proceedings of the National Academy of Sciences

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