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Prepublished online as a Blood First Edition Paper on April 24, 2003; DOI 10.1182/blood-2003-02-0488. This Article Full Text (PDF) All Versions of this Article: 2003-02-0488v1 102/4/1169    most recent Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via HighWire Citing Articles via CrossRef Citing Articles via Google Scholar Google Scholar Articles by Roscic-Mrkic, B. Articles by Trkola, A. Search for Related Content PubMed PubMed Citation Articles by Roscic-Mrkic, B. Articles by Trkola, A. Social Bookmarking                   What's this? Submitted February 13, 2003 Accepted April 1, 2003 RANTES (CCL5) utilizes the proteoglycan CD44 as an auxiliary receptor to mediate cellular activation signals and HIV-1 enhancement Branka Roscic-Mrkic, Marek Fischer, Christine Leemann, Amapola Manrique, Cynthia J Gordon, John P Moore, Amanda E I Proudfoot, and Alexandra Trkola* Division of Infectious Diseases, Department of Medicine, University Hospital Zurich, Zurich, Switzerland Department of Pathology, New York School of Medicine, New York, NY, USA Department of Microbiology and Immunology, Weill Medical College of Cornell Univesity, New York, NY, USA Serono Pharmaceutical Research Institute, Geneva, Switzerland * Corresponding author; email: alexandra.trkola{at}usz.ch. The CC-chemokine RANTES (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 supra-physiological 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. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this? This article has been cited by other articles: S. Basu and H. E. Broxmeyer CCR5 Ligands Modulate CXCL12-Induced Chemotaxis, Adhesion, and Akt Phosphorylation of Human Cord Blood CD34+ Cells J. Immunol., December 1, 2009; 183(11): 7478 - 7488. [Abstract] [Full Text] [PDF] H. Gaertner, F. Cerini, J.-M. Escola, G. Kuenzi, A. Melotti, R. Offord, I. Rossitto-Borlat, R. Nedellec, J. Salkowitz, G. Gorochov, et al. Highly potent, fully recombinant anti-HIV chemokines: Reengineering a low-cost microbicide PNAS, November 18, 2008; 105(46): 17706 - 17711. [Abstract] [Full Text] [PDF] M. Huber, V. von Wyl, C. G. Ammann, H. Kuster, G. Stiegler, H. Katinger, R. 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