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Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5.

Davis CB, Dikic I, Unutmaz D, Hill CM, Arthos J, Siani MA, Thompson DA, Schlessinger J, Littman DR - J. Exp. Med. (1997)

Bottom Line: In this study, we demonstrate that chemokines and HIV-1 envelope glycoproteins from both T-tropic and macrophage-tropic strains rapidly induce tyrosine phosphorylation of the protein tyrosine kinase Pyk2.The response requires CXCR4 and CCR5 to be accessible on the cell surface.The results presented here provide the first evidence for activation of an intracellular signaling event that can initiate multiple signaling pathways as a consequence of contact between HIV-1 and chemokine receptors.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Pathogenesis, Skirball Institute for Biomolecular Medicine, NYU Medical Center 10016, USA. davis@saturn.med.nyu.edu

ABSTRACT
Infection with HIV-1 requires expression of CD4 and the chemokine receptors CXCR4 or CCR5 at the target cell surface. Engagement of these receptors by the HIV-1 envelope glycoprotein is essential for membrane fusion, but may additionally activate intracellular signaling pathways. In this study, we demonstrate that chemokines and HIV-1 envelope glycoproteins from both T-tropic and macrophage-tropic strains rapidly induce tyrosine phosphorylation of the protein tyrosine kinase Pyk2. The response requires CXCR4 and CCR5 to be accessible on the cell surface. The results presented here provide the first evidence for activation of an intracellular signaling event that can initiate multiple signaling pathways as a consequence of contact between HIV-1 and chemokine receptors.

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Related in: MedlinePlus

Tyrosine phosphorylation of Pyk2 in response to M-tropic  gp120/gp41 requires expression of CCR5 on target cells. DU6 cells (5 ×  106) or the equivalent number of CD4+CCR5− T cells (EU2) were incubated with MIP-1β (500 nM), SDF-1α (500 nM), or JRFL gp120/gp41  (5 μg/ml) for 30 s before lysis.
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Figure 4: Tyrosine phosphorylation of Pyk2 in response to M-tropic gp120/gp41 requires expression of CCR5 on target cells. DU6 cells (5 × 106) or the equivalent number of CD4+CCR5− T cells (EU2) were incubated with MIP-1β (500 nM), SDF-1α (500 nM), or JRFL gp120/gp41 (5 μg/ml) for 30 s before lysis.

Mentions: To determine whether CCR5 is required for signaling after binding of M-tropic envelope glycoprotein, Pyk2 tyrosine phosphorylation was compared in wild-type and CCR5− T cell lines. The mutant cell line was derived from an HIV-1 exposed uninfected patient (EU2) who is homozygous for a 32-bp deletion in the CCR5 coding sequence and lacks cell surface expression of CCR5. The EU2 cell line fails to display calcium mobilization or chemotaxis in response to MIP-1β treatment, and is resistant to M-tropic HIV-1 infection (5; Davis, C.B., unpublished data). DU6 and EU2 cells were treated with MIP-1β, SDF-1α, or soluble oligomerized JRFL gp120/gp41. Pyk2 was strongly phosphorylated in DU6 cells treated with either MIP-1β or JRFL envelope glycoprotein (Fig. 4, left). EU2 cells, in contrast, failed to respond to either stimulus, but responded to SDF-1α, indicating that the signaling pathway between CXCR4 and Pyk2 is intact (Fig. 4, right). Overall, these data indicate that CD4 engagement alone is insufficient for activation of Pyk2 via M-tropic envelope and that CCR5 must be available on the cell surface.


Signal transduction due to HIV-1 envelope interactions with chemokine receptors CXCR4 or CCR5.

Davis CB, Dikic I, Unutmaz D, Hill CM, Arthos J, Siani MA, Thompson DA, Schlessinger J, Littman DR - J. Exp. Med. (1997)

Tyrosine phosphorylation of Pyk2 in response to M-tropic  gp120/gp41 requires expression of CCR5 on target cells. DU6 cells (5 ×  106) or the equivalent number of CD4+CCR5− T cells (EU2) were incubated with MIP-1β (500 nM), SDF-1α (500 nM), or JRFL gp120/gp41  (5 μg/ml) for 30 s before lysis.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2199136&req=5

Figure 4: Tyrosine phosphorylation of Pyk2 in response to M-tropic gp120/gp41 requires expression of CCR5 on target cells. DU6 cells (5 × 106) or the equivalent number of CD4+CCR5− T cells (EU2) were incubated with MIP-1β (500 nM), SDF-1α (500 nM), or JRFL gp120/gp41 (5 μg/ml) for 30 s before lysis.
Mentions: To determine whether CCR5 is required for signaling after binding of M-tropic envelope glycoprotein, Pyk2 tyrosine phosphorylation was compared in wild-type and CCR5− T cell lines. The mutant cell line was derived from an HIV-1 exposed uninfected patient (EU2) who is homozygous for a 32-bp deletion in the CCR5 coding sequence and lacks cell surface expression of CCR5. The EU2 cell line fails to display calcium mobilization or chemotaxis in response to MIP-1β treatment, and is resistant to M-tropic HIV-1 infection (5; Davis, C.B., unpublished data). DU6 and EU2 cells were treated with MIP-1β, SDF-1α, or soluble oligomerized JRFL gp120/gp41. Pyk2 was strongly phosphorylated in DU6 cells treated with either MIP-1β or JRFL envelope glycoprotein (Fig. 4, left). EU2 cells, in contrast, failed to respond to either stimulus, but responded to SDF-1α, indicating that the signaling pathway between CXCR4 and Pyk2 is intact (Fig. 4, right). Overall, these data indicate that CD4 engagement alone is insufficient for activation of Pyk2 via M-tropic envelope and that CCR5 must be available on the cell surface.

Bottom Line: In this study, we demonstrate that chemokines and HIV-1 envelope glycoproteins from both T-tropic and macrophage-tropic strains rapidly induce tyrosine phosphorylation of the protein tyrosine kinase Pyk2.The response requires CXCR4 and CCR5 to be accessible on the cell surface.The results presented here provide the first evidence for activation of an intracellular signaling event that can initiate multiple signaling pathways as a consequence of contact between HIV-1 and chemokine receptors.

View Article: PubMed Central - PubMed

Affiliation: Division of Molecular Pathogenesis, Skirball Institute for Biomolecular Medicine, NYU Medical Center 10016, USA. davis@saturn.med.nyu.edu

ABSTRACT
Infection with HIV-1 requires expression of CD4 and the chemokine receptors CXCR4 or CCR5 at the target cell surface. Engagement of these receptors by the HIV-1 envelope glycoprotein is essential for membrane fusion, but may additionally activate intracellular signaling pathways. In this study, we demonstrate that chemokines and HIV-1 envelope glycoproteins from both T-tropic and macrophage-tropic strains rapidly induce tyrosine phosphorylation of the protein tyrosine kinase Pyk2. The response requires CXCR4 and CCR5 to be accessible on the cell surface. The results presented here provide the first evidence for activation of an intracellular signaling event that can initiate multiple signaling pathways as a consequence of contact between HIV-1 and chemokine receptors.

Show MeSH
Related in: MedlinePlus