PT Journal AU Adamski, V Mentlein, R Lucius, R Synowitz, M Held-Feindt, J Hattermann-Koch, K TI The Chemokine Receptor CXCR6 Evokes Reverse Signaling via the Transmembrane Chemokine CXCL16 SO International journal of molecular sciences PY 2017 VL 18 IS 7 PU MDPI AG DI 10.3390/ijms18071468 WP https://macau.uni-kiel.de/receive/macau_mods_00003034 LA en DE Humans; Glioma; Mitogen-Activated Protein Kinase 1; Mitogen-Activated Protein Kinase 3; Receptors, Chemokine; Cell Communication; Signal Transduction; Cell Movement; Phosphorylation; Chemokine CXCL16; Receptors, CXCR6 SN 1661-6596 AB Reverse signaling is a signaling mechanism where transmembrane or membrane-bound ligands transduce signals and exert biological effects upon binding of their specific receptors, enabling a bidirectional signaling between ligand and receptor-expressing cells. In this study, we address the question of whether the transmembrane chemokine (C-X-C motif) ligand 16, CXCL16 is able to transduce reverse signaling and investigate the biological consequences. For this, we used human glioblastoma cell lines and a melanoma cell line as in vitro models to show that stimulation with recombinant C-X-C chemokine receptor 6 (CXCR6) or CXCR6-containing membrane preparations induces intracellular (reverse) signaling. Specificity was verified by RNAi experiments and by transfection with expression vectors for the intact CXCL16 and an intracellularly-truncated form of CXCL16. We showed that reverse signaling via CXCL16 promotes migration in CXCL16-expressing melanoma and glioblastoma cells, but does not affect proliferation or protection from chemically-induced apoptosis. Additionally, fast migrating cells isolated from freshly surgically-resected gliomas show a differential expression pattern for CXCL16 in comparison to slowly-migrating cells, enabling a possible functional role of the reverse signaling of the CXCL16/CXCR6 pair in human brain tumor progression in vivo. PI Basel ER