RANTES (CCL5) uses the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement
| Autor: | Christine Leemann, Alexandra Trkola, Amapola Manrique, Cynthia J. Gordon, Branka Roscic-Mrkic, Marek Fischer, Amanda E. I. Proudfoot, John P. Moore |
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| Rok vydání: | 2003 |
| Předmět: |
MAPK/ERK pathway
Chemokine Syndecans Immunology Down-Regulation Transfection Biochemistry CCL5 Chemokine receptor Humans Phosphorylation Chemokine CCL5 G protein-coupled receptor Mitogen-Activated Protein Kinase 1 Membrane Glycoproteins Mitogen-Activated Protein Kinase 3 biology Kinase Cell Biology Hematology Molecular biology Enzyme Activation Hyaluronan Receptors src-Family Kinases HIV-1 biology.protein Proteoglycans RNA Interference Receptors Chemokine Mitogen-Activated Protein Kinases biological phenomena cell phenomena and immunity Signal transduction HeLa Cells Signal Transduction Proto-oncogene tyrosine-protein kinase Src |
| Zdroj: | Blood. 102:1169-1177 |
| ISSN: | 1528-0020 0006-4971 |
| DOI: | 10.1182/blood-2003-02-0488 |
| Popis: | The CC-chemokine RANTES (regulated on activation normal T-cell expressed and secreted; CCL5) transduces multiple intracellular signals. Like all chemokines, it stimulates G protein–coupled receptor (GPCR) activity through interaction with its cognate chemokine receptor(s), but in addition also activates a GPCR-independent signaling pathway. Here, we show that the latter pathway is mediated by an interaction between RANTES and glycosaminoglycan chains of CD44. We provide evidence that this association, at both low, physiologically relevant, and higher, probably supraphysiologic concentrations of RANTES, induces the formation of a signaling complex composed of CD44, src kinases, and adapter molecules. This triggers the activation of the p44/42 mitogen-activated protein kinase (MAPK) pathway. By specifically reducing CD44 expression using RNA interference we were able to demonstrate that the p44/p42 MAPK activation by RANTES requires a high level of CD44 expression. As well as potently inhibiting the entry of CCR5 using HIV-1 strains, RANTES can enhance HIV-1 infectivity under certain experimental conditions. This enhancement process depends in part on the activation of p44/p42 MAPK. Here we show that silencing of CD44 in HeLa-CD4 cells prevents the activation of p44/p42 MAPK and leads to a substantial reduction in HIV-1 infectivity enhancement by RANTES. |
| Databáze: | OpenAIRE |
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