CXC chemokine receptor 4 signaling upon co-activation with stromal cell-derived factor-1alpha and ubiquitin Journal Article

Local Library Link: Find It @ Loyola

Authors: Tripathi, A; Davis, J. D.; Staren, D. M.; Volkman, B. F.; Majetschak, M
Article Title: CXC chemokine receptor 4 signaling upon co-activation with stromal cell-derived factor-1alpha and ubiquitin
Abstract: 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)-1alpha, 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-1alpha 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-1alpha pre-stimulation desensitized ubiquitin induced Ca(2+) fluxes, but not vice versa. Effects of SDF-1alpha and ubiquitin on cAMP levels, Akt and ERK1/2 phosphorylation and chemotactic responses were additive. The chemotactic activities of ubiquitin and SDF-1alpha were sensitive to AMD3100, pertussis toxin, U73122, LY94002 and U0126. These data suggest that CXCR4 activation with SDF-1alpha 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.
Journal Title: Cytokine
Volume: 65
Issue: 2
ISSN: 1096-0023; 1043-4666
Publisher: Unknown  
Journal Place: United States
Date Published: 2014
Start Page: 121
End Page: 125
Language: eng
DOI/URL:

10.1016/j.cyto.2013.12.008
Notes: LR: 20151002; CI: Copyright (c) 2013; GR: R01 AI058072/AI/NIAID NIH HHS/United States; JID: 9005353; 0 (CXCR4 protein, human); 0 (CXCR7 protein, human); 0 (Chemokine CXCL12); 0 (Cmkor1 protein, rat); 0 (Cxcr4 protein, rat); 0 (Receptors, CXCR); 0 (Receptors, CXCR4); 0 (Ubiquitin); SY7Q814VUP (Calcium); OTO: NOTNLM; 2013/08/22 [received]; 2013/10/24 [revised]; 2013/12/09 [accepted]; 2013/12/24 [aheadofprint]; ppublish