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• W385681389 abstract "Ubiquitin has previously beenidentified as another natural agonist of CXC chemokine receptor 4(CXCR4). In addition, recent evidence suggests that ubiquitin mayactivate CXCR4 through a binding site on the receptor, which isdistinct from the binding site for the cognate ligand stromalcell-derived factor (SDF)-1α. The cellular consequencesof ubiquitin induced CXCR4 activation, however, are still poorlydefined and a side-by-side comparison of CXCR4 mediated functionsafter activation with SDF-1α and ubiquitin is lacking.Such information will be instrumental to better understand thephysiological function of CXCR4 and to further define its role as atherapeutic target in various disease processes. Accordingly, theaim of this study was to determine and compare CXCR4 mediatedeffects on important signal transduction pathways and chemotaxis, akey function of CXCR4, upon receptor activation with ubiquitin andSDF-1α. Utilizing a MAPK array in combination withWestern blot experiments, it is shown that activation of CXCR4 withubiquitin and SDF-1α in THP-1 cells leads to increasedphosphorylation of extracellular signal-related kinase (ERK) 1/2,ribosomal S6 kinase (RSK) 1, and protein kinase B (Akt). Analysesof the time progression of the MAPK phosphorylation revealed thatboth ligands induced a comparable degree of MAPK phosphorylation,which occurred transiently after activation of CXCR4 with ubiquitinand was sustained for at least 30 minutes with SDF-1α. Toassess CXCR4 mediated chemotaxis, a filter migration assay wasestablished and optimized. It is shown that THP-1 cells and humanperipheral blood mononuclear cells migrate dose dependently towardsubiquitin and SDF-1α. Under optimized conditions,ubiquitin was 4-5 times less efficacious than SDF-1α inpromoting chemotaxis, but of similar potency. Pharmacologicalinhibition of signal transduction molecules that are known to beinvolved in the regulation of CXCR4 mediated chemotaxis resulted insimilar effects on ubiquitin and SDF-1α inducedchemotaxis in THP1 cells and PBMCs. This suggests that both ligandsrely on a similar pattern of intracellular signaling to inducechemotaxis. In conclusion, activation of CXCR4 with ubiquitin andSDF-1α results in similar intracellular signaling eventsand functional consequences. With activation of CXCR4 by ubiquitin,however, serine/threonine protein kinase phosphorylations occurredmore transiently, which could account for its weaker chemotacticactivity, as compared with SDF-1α. Thus, ubiquitinappears to be a weaker CXCR4 agonist than SDF-1α, whichmay correspond to differential CXCR4 signaling mediated viadistinct ligand binding sites on thereceptor" @default.
• W385681389 created "2016-06-24" @default.
• W385681389 creator A5077366461 @default.
• W385681389 date "2012-01-01" @default.
• W385681389 modified "2023-09-23" @default.
• W385681389 title "Characterization of the Coca Chemokine Receptor Four Agonist Activity of Ubiquitin" @default.
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