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The CXC chemokine receptor 4 ligands ubiquitin and stromal cell-derived factor-1? function through distinct receptor interactions.

ABSTRACT: Recently, we identified extracellular ubiquitin as an endogenous CXC chemokine receptor (CXCR) 4 agonist. However, the receptor selectivity and molecular basis of the CXCR4 agonist activity of ubiquitin are unknown, and functional consequences of CXCR4 activation with ubiquitin are poorly defined. Here, we provide evidence that ubiquitin and the cognate CXCR4 ligand stromal cell-derived factor (SDF)-1? do not share CXCR7 as a receptor. We further demonstrate that ubiquitin does not utilize the typical two-site binding mechanism of chemokine-receptor interactions, in which the receptor N terminus is important for ligand binding. CXCR4 activation with ubiquitin and SDF-1? lead to similar G?(i)-responses and to a comparable magnitude of phosphorylation of ERK-1/2, p90 ribosomal S6 kinase-l and Akt, although phosphorylations occur more transiently after activation with ubiquitin. Despite the similarity of signal transduction events after activation of CXCR4 with both ligands, ubiquitin possesses weaker chemotactic activity than SDF-l? in cell migration assays and does not interfere with productive entry of HIV-1 into P4.R5 multinuclear activation of galactosidase indicator cells. Unlike SDF-1?, ubiquitin lacks interactions with an N-terminal CXCR4 peptide in NMR spectroscopy experiments. Binding and signaling studies in the presence of antibodies against the N terminus and extracellular loops 2/3 of CXCR4 confirm that the ubiquitin CXCR4 interaction is independent of the N-terminal receptor domain, whereas blockade of extracellular loops 2/3 prevents receptor binding and activation. Our findings define ubiquitin as a CXCR4 agonist, which does not interfere with productive cellular entry of HIV-1, and provide new mechanistic insights into interactions between CXCR4 and its natural ligands.

SUBMITTER: Saini V

PROVIDER: S-EPMC3190899 | biostudies-other | 2011 Sep

REPOSITORIES: biostudies-other

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The CXC chemokine receptor 4 ligands ubiquitin and stromal cell-derived factor-1α function through distinct receptor interactions.

Saini Vikas V Staren Daniel M DM Ziarek Joshua J JJ Nashaat Zayd N ZN Campbell Edward M EM Volkman Brian F BF Marchese Adriano A Majetschak Matthias M

The Journal of biological chemistry 20110713 38

Recently, we identified extracellular ubiquitin as an endogenous CXC chemokine receptor (CXCR) 4 agonist. However, the receptor selectivity and molecular basis of the CXCR4 agonist activity of ubiquitin are unknown, and functional consequences of CXCR4 activation with ubiquitin are poorly defined. Here, we provide evidence that ubiquitin and the cognate CXCR4 ligand stromal cell-derived factor (SDF)-1α do not share CXCR7 as a receptor. We further demonstrate that ubiquitin does not utilize the t ...[more]

PMID: 21757744

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Project description:Malignant gliomas manifest frequent tumor recurrence after surgical resection and/or other treatment because of their nature of invasiveness and dissemination. The recognized brain tumor-tracking property of neural progenitor/stem cells opened the possibility of targeting malignant brain tumors using neural progenitor/stem cells. We and others have previously shown that fetal neural progenitor/stem cells can be used to deliver therapeutic molecules to brain tumors. Our recent work has further shown that gene delivery by bone marrow-derived neural progenitor/stem cells achieves therapeutic effects in a glioma model. In this study, we isolate and characterize bone marrow-derived neural progenitor/stem cells, which also express the chemokine receptor chemokine CXC receptor 4 (CXCR4). We show that CXCR4 is required for their chemotaxis and extracellular matrix invasion against a gradient of glioma soluble factors. Furthermore, beta-galactosidase-labeled bone marrow-derived neural progenitor/stem cells implanted in the contralateral side of the brain were shown to track gliomas as early as day 1 and increased through days 3 and 7. Intracranial glioma tracking by bone marrow-derived neural progenitor/stem cells is significantly inhibited by preincubation of bone marrow-derived neural progenitor/stem cells with a blocking anti-CXCR4 antibody, suggesting a CXCR4-dependent tracking mechanism. Glioma tracking bone marrow-derived neural progenitor/stem cells were found to express progenitor/stem cell markers, as well as CXCR4. Although bromodeoxyuridine incorporation assays and proliferating antigen staining indicated that tumor tracking bone marrow-derived neural progenitor/stem cells were mostly nonproliferating, these cells survive in the local tumor environment with little apoptosis. Elucidating the molecular mechanism of brain tumor tracking by adult source stem cells may provide basis for the development of future targeted therapy for malignant brain tumors.

Project description:BackgroundSpinal cord injury (SCI) is a worldwide medical concern. This study aimed to elucidate the mechanism underlying the protective effect of hyperbaric oxygen (HBO) against SCI-induced neurologic defects in rats via exploring the stromal cell-derived factor-1 (SDF-1)/CXC chemokine receptor 4 (CXCR4) axis and expression of brain-derived neurotrophic factor (BDNF).MethodsAn acute SCI rat model was established in Sprague-Dawley rats using the Allen method. Sixty rats were divided into four groups (n = 15 in each group): sham-operated, SCI, SCI treated with HBO (SCI + HBO), and SCI treated with both HBO and AMD3100 (an antagonist of CXCR4; SCI + HBO + AMD) groups. The rats were treated with HBO twice a day for 3 days and thereafter once a day after the surgery for up to 28 days. Following the surgery, neurologic assessments were performed with the Basso-Bettie-Bresnahan (BBB) scoring system on postoperative day (POD) 7, 14, 21, and 28. Spinal cord tissues were harvested to assess the expression of SDF-1, CXCR4, and BDNF at mRNA and protein levels, using quantitative real-time polymerase chain reaction, Western blot analysis, and histopathologic analysis.ResultsHBO treatment recovered SCI-induced descent of BBB scores on POD 14, (1.25 ± 0.75 vs. 1.03 ± 0.66, P < 0.05), 21 (5.27 ± 0.89 vs. 2.56 ± 1.24, P < 0.05), and 28 (11.35 ± 0.56 vs. 4.23 ± 1.20, P < 0.05) compared with the SCI group. Significant differences were found in the mRNA levels of SDF-1 (mRNA: day 21, SCI + HBO vs. SCI + HBO + AMD, 2.89 ± 1.60 vs. 1.56 ± 0.98, P < 0.05), CXCR4 (mRNA: day 7, SCI + HBO vs. SCI, 2.99 ± 1.60 vs.1.31 ± 0.98, P < 0.05; day 14, SCI + HBO vs. SCI + HBO + AMD, 4.18 ± 1.60 vs. 0.80 ± 0.34, P < 0.05; day 21, SCI + HBO vs. SCI, 2.10 ± 1.01 vs.1.15 ± 0.03, P < 0.05), and BDNF (mRNA: day 7, SCI + HBO vs. SCI, 3.04 ± 0.41 vs. 2.75 ± 0.31, P < 0.05; day 14, SCI + HBO vs. SCI, 3.88 ± 1.59 vs. 1.11 ± 0.40, P < 0.05), indicating the involvement of SDF-1/CXCR4 axis in the protective effect of HBO.ConclusionsHBO might promote the recovery of neurologic function after SCI in rats via activating the SDF-1/CXCR4 axis and promoting BDNF expression.

Dataset Information

The CXC chemokine receptor 4 ligands ubiquitin and stromal cell-derived factor-1? function through distinct receptor interactions.

Publications

The CXC chemokine receptor 4 ligands ubiquitin and stromal cell-derived factor-1α function through distinct receptor interactions.

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