Signal Transduction Due to HIV-1 Envelope Interactions with Chemokine Receptors CXCR4 or CCR5

Davis, Craig B.; Đikić, Ivan; Unutmaz, Derya; Hill, Connor; Arthos, James; Siani, Michael A.; Thompson, Darren A.; Schlessinger, Joseph; Littman, Dan R.

doi:10.1084/jem.186.10.1793

Cited by 372 publications

(280 citation statements)

References 34 publications

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“…However, little is known about the molecular mechanisms that mediate these functions. We and others have recently shown that CXCR4 can mediate signaling through various components of the focal adhesion complex such as the related adhesion focal tyrosine kinase (RAFTK), also known as Pyk2 or CAK-␤ (23)(24)(25). Furthermore, we also showed that mitogen-activated protein (MAP) kinase and NF-B are activated upon SDF1␣ stimulation (23).…”

mentioning

confidence: 58%

“…These molecules regulate chemotaxis and cell viability, which are important for various cellular functions such as wound repair, metastasis, inflammation, angiogenesis, and development of lymphoid tissue (55)(56)(57). We and others have recently studied signaling molecules activated by SDF1␣ (23)(24)(25). These studies have shown activation of PI3 kinase and focal adhesion components such as RAFTK/Pyk2, paxillin, and Crk in SDF1␣-induced signaling and in chemotaxis responses of pre-B and T cells (23)(24)(25)27).…”

Section: Discussionmentioning

confidence: 99%

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Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Cherla

Ganju

2001

The Journal of Immunology

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Stromal cell-derived factor 1α (SDF1α) and its cognate chemokine receptor CXCR4 act as potent chemoattractants and regulate trafficking and homing of hematopoietic progenitor cells and lymphocytes. However, the molecular mechanisms regulating SDF1α-driven cell migration are not well defined. In this study, we have explored the roles of the second messenger NO and the transcription factor NF-κB in SDF1α-induced T cell migration. SDF1α treatment of Jurkat T cells increased the activity of NO synthase, which catalyzes the generation of NO. We observed that pretreatment of Jurkat cells or activated PBLs with several NO donors significantly enhanced the SDF1α-induced migration, whereas various inhibitors of NO synthase markedly abrogated the chemotactic response in a concentration-dependent manner. Furthermore, we observed that inhibitors of the transcription factor NF-κB, which is linked to NO signaling pathways, also significantly blocked the SDF1α-induced chemotactic response. However, these compounds did not have a significant effect on SDF1α-induced mitogen-activated protein kinase activity. In addition, the MAP/Erk kinase kinase inhibitor PD98059 did not abrogate SDF1α-induced chemotaxis. AKT, which has been shown to mediate NO production, was also phosphorylated upon SDF1α stimulation. These studies suggest that NO-related signaling pathways may mediate SDF1α-induced chemotaxis, but not mitogen-activated protein kinase activation.

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mentioning

confidence: 58%

Section: Discussionmentioning

confidence: 99%

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Cherla

Ganju

2001

The Journal of Immunology

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“…In contrast, T-tropic infection of monocytes or macrophages requires high threshold levels of CXCR4 on the target cells (Tokunaga et al, 2001). M-and T-tropic HIV gp120s function as agonists for CCR5 and CXCR4, respectively (Davis et al, 1997;Weissman et al, 1997). It is possible that M-tropic HIV gp41-mediated membrane fusion occurs efficiently during the long residence time of occupied CCR5 at the plasma membrane.…”

Section: Discussionmentioning

confidence: 99%

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

Venkatesan

Rose

Lodge

et al. 2003

MBoC

105

111

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Here we demonstrate that the rate of ligand-induced endocytosis of CCR5 in leukocytes and expression systems is significantly slower than that of CXCR4 and requires prolonged agonist treatment, suggesting that these two receptors use distinct mechanisms. We show that the C-terminal domain of CCR5 is the determinant of its slow endocytosis phenotype. When the C-tail of CXCR4 was exchanged for that of CCR5, the resulting CXCR4-CCR5 (X4-R5) chimera displayed a CCR5-like trafficking phenotype. We found that the palmitoylated cysteine residues in this domain anchor CCR5 to plasma membrane rafts. CXCR4 and a C-terminally truncated CCR5 mutant (CCR5-KRFX) lacking these cysteines are not raft associated and are endocytosed by a clathrin-dependent pathway. Genetic inhibition of clathrin-mediated endocytosis demonstrated that a significant fraction of ligand-occupied CCR5 trafficked by clathrin-independent routes into caveolin-containing vesicular structures. Thus, the palmitoylated C-tail of CCR5 is the major determinant of its raft association and endocytic itineraries, differentiating it from CXCR4 and other chemokine receptors. This novel feature of CCR5 may modulate its signaling potential and could explain its preferential use by HIV for person-to-person transmission of disease. INTRODUCTIONClathrin-mediated endocytosis has been the general paradigm and the most extensively studied mechanism of ligand-induced receptor internalization (Schmid, 1997). However, in recent years, alternative clathrin-independent mechanisms have been described for the uptake of viruses, toxins, and receptors that lack conventional endocytic signals ). Among the latter mechanisms, cholesterol-rich structures called caveolae (Anderson, 1998;Kurzchalia and Parton, 1999) and lipid rafts have been implicated in diverse membrane processes including the assembly of signaling receptor complexes (Simons and Toomre, 2000). Endocytosis of some receptors such as the ␣ subunit of the IL-2 receptor (Tac antigen) and MHC-I, which lack canonical endocytic signals, follow distinct itineraries regulated by the small GTP binding protein, ADP-ribosylation factor 6 (Arf6; Radhakrishna and Donaldson, 1997;Sugita et al., 1999). Clathrin-independent endocytic itineraries are slower than the clathrin-dependent pathway and are functionally relevant in that the long residence time of occupied receptors at the cell surface may enable coupling to multiple signaling pathways.Article published online ahead of print. Mol. Biol. Cell 10.1091/ mbc.E02-11-0714. Article and publication date are available at www.molbiolcell.org/cgi/doi/10.1091/mbc.E02-11-0714. † Corresponding author. E-mail address: aradhana@helix.nih.gov or sv1s@nih.gov. § Present address: INRS-Institut Armand-Frappier, Université du Québec, 531 des Prairies, Laval (Québec), Canada H7V 1B7. Abbreviations used: AOP-RANTES, aminooxypentane-regulated on activation, normal T-cell expressed and secreted; APC, allophycocyanin; Arf6, ADP-ribosylation factor 6; CCV, clathrin-coated vesicles; CHO, Chinese hamster o...

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“…Another report shows an enhancement of tyrosine phosphorylation of CCR5 and the association of Janus kinase 1/STAT5 with CCR5 after activation by RANTES (53). Furthermore, RANTES can lead to focal adhesion kinase association with CCR5 and Zap70; Lck and Pyk2 are activated after ligand binding (53)(54)(55)(56). How these signals participate in the internalization process or other signaling events is not yet established.…”

Section: Figurementioning

confidence: 99%

“…How these signals participate in the internalization process or other signaling events is not yet established. CCR5 down-modulation could affect signaling elicited by the chemokines or, potentially, the HIV envelope protein (55,57), which may profoundly influence lymphocyte responses because the two crucial signal molecules Lck and Zap70 are affected. It is also important to note that under circumstances in which the TCR is strongly reengaged (for a review, see Ref.…”

Section: Figurementioning

confidence: 99%

TNF-α-Induced Secretion of C-C Chemokines Modulates C-C Chemokine Receptor 5 Expression on Peripheral Blood Lymphocytes

Hornung¹,

Scala

Lenardo³

2000

The Journal of Immunology

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Peripheral blood lymphocytes express CCR5, a chemokine receptor for immune cell migration and calcium signaling that serves as an important coreceptor for the HIV. After in vitro stimulation, CCR5 expression is dramatically increased on mature T lymphocytes, especially on the CD45RO+ memory subset. In this study, we report that TNF-α delays the surface expression of CCR5 on PBLs after activation and diminishes CCR5 irrespective of its initial level. Functional loss of CCR5 is reflected in a decreased capability of the treated cells to migrate and signal calcium after MIP-1β stimulation. The effect is mediated via the p80 type II TNF receptor (TNFR2), which induces NF-κB among other factors, leading to an enhanced secretion of the chemokines macrophage-inflammatory protein-1α, macrophage-inflammatory protein-1β, and RANTES. Expression of these chemokines directly down-regulates CCR5. These findings reveal a new regulatory mechanism utilized by activated peripheral T cells to modulate their chemotaxis and potentially other functions mediated by CCR5, including the infection of T lymphocytes by macrophage-tropic HIV strains.

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Signal Transduction Due to HIV-1 Envelope Interactions with Chemokine Receptors CXCR4 or CCR5

Cited by 372 publications

References 34 publications

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Stromal Cell-Derived Factor 1α-Induced Chemotaxis in T Cells Is Mediated by Nitric Oxide Signaling Pathways

Distinct Mechanisms of Agonist-induced Endocytosis for Human Chemokine Receptors CCR5 and CXCR4

TNF-α-Induced Secretion of C-C Chemokines Modulates C-C Chemokine Receptor 5 Expression on Peripheral Blood Lymphocytes

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