CXC chemokine receptor 4 signaling upon co-activation with stromal cell-derived factor-1α and ubiquitin. Cytokine 2014 Feb;65(2):121-5
Date
01/01/2014Pubmed ID
24373940Pubmed Central ID
PMC4615604DOI
10.1016/j.cyto.2013.12.008Scopus ID
2-s2.0-84892483373 (requires institutional sign-in at Scopus site) 29 CitationsAbstract
Recently, we reported that extracellular ubiquitin functions as another agonist of CXC chemokine receptor (CXCR)4. Whereas the cognate CXCR4 ligand, stromal cell-derived factor (SDF)-1α, is also a CXCR7 agonist, ubiquitin does not bind to CXCR7. Because both ligands are present in the extracellular environment, co-activation of CXCR4 appears to be physiologically relevant. CXCR4 mediated effects of ubiquitin, however, are not well understood and consequences of co-activation of CXCR4 with both ligands are unknown. Utilizing proximity ligation assays and flow cytometry, we detected CXCR4, but not CXCR7, on the cell surface of THP-1 cells, which suggests that confounding effects of CXCR7 are unlikely. Time course and magnitude of reduction of cell surface CXCR4 expression were comparable after stimulation of THP-1 cells with both ligands. SDF-1α was more efficacious than ubiquitin to mobilize Ca(2+). Co-stimulation of THP-1 cells with both ligands resulted in synergistic effects on Ca(2+) fluxes at suboptimal ligand concentrations. Homologous desensitization of Ca(2+) fluxes was detectable with both ligands. SDF-1α pre-stimulation desensitized ubiquitin induced Ca(2+) fluxes, but not vice versa. Effects of SDF-1α and ubiquitin on cAMP levels, Akt and ERK1/2 phosphorylation and chemotactic responses were additive. The chemotactic activities of ubiquitin and SDF-1α were sensitive to AMD3100, pertussis toxin, U73122, LY94002 and U0126. These data suggest that CXCR4 activation with SDF-1α and ubiquitin results in partially synergistic effects on cellular signaling events and in differential effects on receptor desensitization. The ligand ratio that is present in the extracellular environment may contribute to the regulation of CXCR4 mediated functions.
Author List
Tripathi A, Davis JD, Staren DM, Volkman BF, Majetschak MAuthor
Brian F. Volkman PhD Professor in the Biochemistry department at Medical College of WisconsinMESH terms used to index this publication - Major topics in bold
AnimalsCalcium
Chemokine CXCL12
Humans
Intracellular Space
Rats
Receptors, CXCR
Receptors, CXCR4
Signal Transduction
Ubiquitin
