TY - JOUR
T1 - GPR15LG binds CXCR4 and synergistically modulates CXCL12-induced cell signaling and migration
AU - Albers, Dan Pascal Jean
AU - Novikova, Sofya
AU - Vieyto-Nuñez, Julio
AU - Almeida-Hernández, Yasser
AU - Pastorio, Chiara
AU - Klassen, Florian
AU - Weiss, Dana
AU - von Maltitz, Pascal
AU - Jaikishan, Janeni
AU - Datta, Moumita
AU - Jumaa, Hassan
AU - Jebaraj, Billy Michael Chelliah
AU - Stilgenbauer, Stephan
AU - Kumar, Manish
AU - Maity, Palash Chandra
AU - Buske, Christian
AU - Stifel, Ulrich
AU - Zinngrebe, Julia
AU - Fischer-Posovszky, Pamela
AU - Chevigné, Andy
AU - Kirchhoff, Frank
AU - Sanchez-Garcia, Elsa
AU - Münch, Jan
AU - Harms, Mirja
N1 - Funding:
Open Access funding enabled and organized by Projekt DEAL.
M.H. was funded by the “Bausteinprogramm”, Projektnummer: L.SBN.0209,
of Ulm University. M.H. also receives funding by the Baden-Württemberg
Foundation. This work was supported by the German Research Foundation
(DFG) through the CRC 1279 Projects A04 and A05 to FK, A06 to JM and E.S.G,
B01 to CB, B03 to HJ, and Fritz Thyssen Stiftung (FTS) Project 10.23.1.012MN
to PCM. MK and PCM are paid from FTS Project 10.23.1.012MN and CRC
1279 B01, respectively. E.S.G was supported by the DFG under Germany’s
Excellence Strategy– EXC 2033–390677874– RESOLV and by the DFG Major
Research Instrumentation Program, project number: 436586093. ESG, JVN
and YAH were supported by the DFG,– SFB1430– Project-ID 424228829.
This study was also supported by the Luxembourg Institute of Health (LIH)
through the NanoLux platform, the Cancer Foundation Luxembourg and the
Luxembourg National Research Fund (INTER/FNRS grants 20/15084569 and
CORE C23/BM/18068832) to AC. U.S. was funded by the “Bausteinprogramm”,
Projektnummer: L.SBN.0232, of Ulm University. JZ is a fellow of the Margarete
von Wrangell-Habilitationsprogramm (Ministry of Science, Research and Arts
Baden-Wuerttemberg, European Social Fund) and received funding from the
DFG (project number: 520584003)
Publisher Copyright:
© The Author(s) 2025.
PY - 2025/5/20
Y1 - 2025/5/20
N2 - Background: GPR15LG, a chemokine-like ligand for the G-protein coupled receptor 15 (GPR15), is abundantly expressed in the gastrointestinal mucosa and inflamed skin. Emerging evidence suggests its involvement in inflammatory disorders and cancers. C-X-C chemokine receptor type 4 (CXCR4) plays a critical role in immune cell trafficking and cancer metastasis. Recent evidence suggests a connection between GPR15LG and CXCR4 signaling, which has not been investigated so far. Methods: We investigated the effects of GPR15LG on CXCR4 signaling and downstream functions. Binding assays and computational modeling were performed to assess the interaction between GPR15LG and CXCR4. Functional assays, including wound healing and cell migration assays, were conducted across various cell types, including CD4⁺ T cells and cancer cells, to evaluate the impact of GPR15LG on CXCL12-mediated CXCR4 signaling. Results: The results demonstrate that GPR15LG binds to the orthosteric site of CXCR4, modulating downstream signaling in a context-dependent manner. Specifically, GPR15LG enhances CXCL12-mediated CXCR4 signaling synergistically, promoting wound healing and cell migration across various cell types, including CD4 + T cells and cancer cells. Conclusions: These findings underscore the role of GPR15LG in inflammation and metastasis, offering potential therapeutic avenues for CXCR4-mediated diseases.
AB - Background: GPR15LG, a chemokine-like ligand for the G-protein coupled receptor 15 (GPR15), is abundantly expressed in the gastrointestinal mucosa and inflamed skin. Emerging evidence suggests its involvement in inflammatory disorders and cancers. C-X-C chemokine receptor type 4 (CXCR4) plays a critical role in immune cell trafficking and cancer metastasis. Recent evidence suggests a connection between GPR15LG and CXCR4 signaling, which has not been investigated so far. Methods: We investigated the effects of GPR15LG on CXCR4 signaling and downstream functions. Binding assays and computational modeling were performed to assess the interaction between GPR15LG and CXCR4. Functional assays, including wound healing and cell migration assays, were conducted across various cell types, including CD4⁺ T cells and cancer cells, to evaluate the impact of GPR15LG on CXCL12-mediated CXCR4 signaling. Results: The results demonstrate that GPR15LG binds to the orthosteric site of CXCR4, modulating downstream signaling in a context-dependent manner. Specifically, GPR15LG enhances CXCL12-mediated CXCR4 signaling synergistically, promoting wound healing and cell migration across various cell types, including CD4 + T cells and cancer cells. Conclusions: These findings underscore the role of GPR15LG in inflammation and metastasis, offering potential therapeutic avenues for CXCR4-mediated diseases.
KW - Cancer metastasis
KW - CXCR4 signaling
KW - GPR15LG
KW - Immune cell migration
KW - Wound healing
KW - Chemokine CXCL12/metabolism
KW - Signal Transduction
KW - Cell Movement/drug effects
KW - Humans
KW - Receptors, Peptide/metabolism
KW - Receptors, G-Protein-Coupled/metabolism
KW - Receptors, CXCR4/metabolism
KW - Protein Binding
KW - Cell Line, Tumor
UR - http://www.scopus.com/inward/record.url?scp=105005527943&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/40394646/
U2 - 10.1186/s12964-025-02231-x
DO - 10.1186/s12964-025-02231-x
M3 - Article
C2 - 40394646
AN - SCOPUS:105005527943
SN - 1478-811X
VL - 23
JO - Cell Communication and Signaling
JF - Cell Communication and Signaling
IS - 1
M1 - 234
ER -