Interaction of the CC-Chemokine RANTES with Glycosaminoglycans Activates a p44/p42 Mitogen-Activated Protein Kinase-Dependent Signaling Pathway and Enhances Human Immunodeficiency Virus Type 1 Infectivity

Abstract

The interaction of the CC-chemokine RANTES with its cell surface receptors transduces multiple intracellular signals: low concentrations of RANTES (1 to 10 nM) stimulate G-protein-coupled receptor (GPCR) activity, and higher concentrations (1 M) activate a phosphotyrosine kinase (PTK)-dependent pathway. Here, we show that the higher RANTES concentrations induce rapid tyrosine phosphorylation of multiple proteins. Several src-family kinases (Fyn, Hck, Src) are activated, as is the focal adhesion kinase p125 FAK and, eventually, members of the p44/p42 mitogen-activated protein kinase (MAPK) family. This PTK signaling pathway can be activated independently of known seven-transmembrane GPCRs for RANTES because it occurs in cells that lack any such RANTES receptors. Instead, activation of the PTK signaling pathway is dependent on the expression of glycosaminoglycans (GAGs) on the cell surface, in that it could not be activated by RANTES in GAG-deficient cells. We have previously demonstrated that RANTES can both enhance and inhibit infection of cells with human immunodeficiency virus type 1 (HIV-1). Here we show that activation of both PTK and MAPK is involved in the enhancement of HIV-1 infectivity caused by RANTES in cells that lack GPCRs for RANTES but which express GAGs.

Chemokine Signaling Regulates Apoptosis as well as Immune Cell Traffic in Host Defense

“…This finding is consistent with reports of CCL5 multimer formation at higher concentrations that bind cell surface GAGs and activate SRC kinase-dependent signaling. 9 Together, our observations indicate that high levels of CCL5 (capable of multimer formation) signal through HCK independently of the CCR5 G-protein coupled receptor, but at physiologic levels, CCL5 (acting as a monomer) signals through CCR5 and independently of any SRC family kinases. In this case, CCR5 activation initiates dual signals to G ai /MEK/ERK or G ai /PI3K/AKT.…”

HIV-1 p17 Matrix Protein Interacts with Heparan Sulfate Side Chain of CD44v3, Syndecan-2, and Syndecan-4 Proteoglycans Expressed on Human Activated CD4+ T Cells Affecting Tumor Necrosis Factor α and Interleukin 2 Production

“…Sy-2, Sy-4, and CD44v3 PGs are expressed on activated human primary CD4 ϩ T cells and are involved in positive or negative regulation of T cell proliferation and TNF-␣ production (26,29). It has been published that the engagement of the GAG moiety of CD44 by RANTES (regulated on activation normal T cell expressed and secreted) induces cellular activation and enhances HIV-1 infectivity, triggering the activation of the p44/ p42 MAPK pathway (29). Activated MAPKs are known to phosphorylate various cytoplasmic and membrane-bound cellular substrate (30).…”

“…Therefore, at low concentrations monomeric HIV-p17 binds HS side chains of CD44v3, Sy-2, and Sy-4, inducing an overall up-regulation of the activated CD4 ϩ T cells. The interaction between the HS side chains of CD44v3 and p17 could activate Src family kinases as occurs for RANTES (29).…”

HIV-1 Glycoprotein 41 Ectodomain Induces Activation of the CD74 Protein-mediated Extracellular Signal-regulated Kinase/Mitogen-activated Protein Kinase Pathway to Enhance Viral Infection

“…Besides MIF and CD74, stimuli, such as growth factors, cytokines, mitogens, as well as receptors, including receptor tyrosine kinase and G protein-coupled receptors, can also mediate the ERK/MAPK pathway (42,43). Earlier studies on RANTES (CCL5, the CCR5 ligand) have revealed that RANTES at low concentrations displays mainly HIV-1 inhibitory activities as a consequence of its strong binding to CCR5 which inhibits the membrane fusion process.…”

“…Earlier studies on RANTES (CCL5, the CCR5 ligand) have revealed that RANTES at low concentrations displays mainly HIV-1 inhibitory activities as a consequence of its strong binding to CCR5 which inhibits the membrane fusion process. However, at higher concentrations, RANTES efficiently activates the cellular ERK/MAPK pathway, resulting in an enhanced HIV-1 infection (43)(44)(45). Thus, two mechanisms have been proposed to explain the enhancement of HIV-1 infection by activation of the ERK/MAPK pathway.…”