Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential
Abstract
Chemokine receptor 4 (CXCR4) is a member of the chemokine receptor family, exclusively activated by the chemokine CXCL12. While CXCR4 regulates numerous physiological processes associated with cell migration and embryogenesis, its overexpression has been involved in various cancer types. Studies suggest that intracellular CXCR4 rather than CXCL12-induced signaling at the plasma membrane contributes to its pro-tumorigenic functions. Given the role of GPCR-interacting proteins in their trafficking and subcellular localization, we characterized the CXCR4 interactome using an affinity purification coupled to mass spectrometry (AP-MS) strategy. The most abundant protein identified in the CXCR4 interactome is Ephrin B1, a member of the Ephrin protein family that shares several functions with CXCR4, such as the regulation of cell migration and proliferation. Further studies showed that the interaction between CXCR4 and Ephrin B1 is direct and enhanced upon CXCR4 activation by CXCL12. They also indicated that Ephrin B1 prevents CXCR4 N-glycosylation, decreases CXCR4 cell surface expression, and consistently inhibits CXCL12-induced CXCR4 coupling to Gαi1-3 and recruitment of β-arrestins 1 and 2. Conversely, Ephrin B1 signals to Erk1/2 through CXCR4 activation and mediates the decrease in Death Receptor 5 expression elicited by intracellular CXCR4. Collectively, these findings identify Ephrin B1 as a potential regulator of CXCR4-driven tumorigenic signaling.
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BibTeX
@article{rabbito2026physical,
title = {{Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential}},
author = {Alessandro Rabbito and Omolade Otun and Amos Fumagalli and Ana Alonso Bartolomé and Sonya Galant and Martial Séveno and Manuel Counson and Thierry Durroux and Cherine Bechara and Martine J Smit and Sébastien Granier and Martyna Szpakowska and Andy Chevigné and Séverine Chaumont-Dubel and Philippe Marin},
journal = {Cellular and Molecular Life Sciences},
year = {2026},
month = sep,
doi = {10.1007/s00018-026-06281-3},
url = {https://hal.science/hal-05677004v2},
note = {CC BY-NC-ND 4.0},
}
RIS
TY - JOUR
TI - Physical interaction with Ephrin B1 promotes CXCR4 intracellular localization and oncogenic potential
AU - Alessandro Rabbito
AU - Omolade Otun
AU - Amos Fumagalli
AU - Ana Alonso Bartolomé
AU - Sonya Galant
AU - Martial Séveno
AU - Manuel Counson
AU - Thierry Durroux
AU - Cherine Bechara
AU - Martine J Smit
AU - Sébastien Granier
AU - Martyna Szpakowska
AU - Andy Chevigné
AU - Séverine Chaumont-Dubel
AU - Philippe Marin
PY - 2026
DA - 2026/09/17
JO - Cellular and Molecular Life Sciences
DO - 10.1007/s00018-026-06281-3
UR - https://hal.science/hal-05677004v2
AB - Chemokine receptor 4 (CXCR4) is a member of the chemokine receptor family, exclusively activated by the chemokine CXCL12. While CXCR4 regulates numerous physiological processes associated with cell migration and embryogenesis, its overexpression has been involved in various cancer types. Studies suggest that intracellular CXCR4 rather than CXCL12-induced signaling at the plasma membrane contributes to its pro-tumorigenic functions. Given the role of GPCR-interacting proteins in their trafficking and subcellular localization, we characterized the CXCR4 interactome using an affinity purification coupled to mass spectrometry (AP-MS) strategy. The most abundant protein identified in the CXCR4 interactome is Ephrin B1, a member of the Ephrin protein family that shares several functions with CXCR4, such as the regulation of cell migration and proliferation. Further studies showed that the interaction between CXCR4 and Ephrin B1 is direct and enhanced upon CXCR4 activation by CXCL12. They also indicated that Ephrin B1 prevents CXCR4 N-glycosylation, decreases CXCR4 cell surface expression, and consistently inhibits CXCL12-induced CXCR4 coupling to Gαi1-3 and recruitment of β-arrestins 1 and 2. Conversely, Ephrin B1 signals to Erk1/2 through CXCR4 activation and mediates the decrease in Death Receptor 5 expression elicited by intracellular CXCR4. Collectively, these findings identify Ephrin B1 as a potential regulator of CXCR4-driven tumorigenic signaling.
SN - 1420-682X
SN - 1420-9071
ER -