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Similarities and differences in RANTES- and (AOP)-RANTES-triggered signals: implications for chemotaxis.

Rodríguez-Frade JM, Vila-Coro AJ, Martín A, Nieto M, Sánchez-Madrid F, Proudfoot AE, Wells TN, Martínez-A C, Mellado M - J. Cell Biol. (1999)

Bottom Line: Chemokines mediate their effects via interaction with seven transmembrane G protein-coupled receptors (GPCR).Using CCR5-transfected HEK-293 cells, we show that both the CCR5 ligand, RANTES, as well as its derivative, aminooxypentane (AOP)- RANTES, trigger immediate responses such as Ca2+ influx, receptor dimerization, tyrosine phosphorylation, and Galphai as well as JAK/STAT association to the receptor.The results are discussed in the context of the dissociation of the late signals, provoked by the chemokines required for cell migration, from early signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnolog¿ia, CSIC/UAM, Campus de Cantoblanco, E-28049 Madrid, Spain.

ABSTRACT
Chemokines are a family of proinflammatory cytokines that attract and activate specific types of leukocytes. Chemokines mediate their effects via interaction with seven transmembrane G protein-coupled receptors (GPCR). Using CCR5-transfected HEK-293 cells, we show that both the CCR5 ligand, RANTES, as well as its derivative, aminooxypentane (AOP)- RANTES, trigger immediate responses such as Ca2+ influx, receptor dimerization, tyrosine phosphorylation, and Galphai as well as JAK/STAT association to the receptor. In contrast to RANTES, (AOP)-RANTES is unable to trigger late responses, as measured by the association of focal adhesion kinase (FAK) to the chemokine receptor complex, impaired cell polarization required for migration, or chemotaxis. The results are discussed in the context of the dissociation of the late signals, provoked by the chemokines required for cell migration, from early signals.

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Diagrammatic representation of the signals delivered  following binding of chemokines to their receptors. The emphasis  is placed on the division between early (left) and late signals  (right), indicating the biochemical signals (bottom) implicated in  the function (top). The figure shows the differential ability of  RANTES and (AOP)-RANTES to trigger early and late signals.
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Figure 8: Diagrammatic representation of the signals delivered following binding of chemokines to their receptors. The emphasis is placed on the division between early (left) and late signals (right), indicating the biochemical signals (bottom) implicated in the function (top). The figure shows the differential ability of RANTES and (AOP)-RANTES to trigger early and late signals.

Mentions: The data presented here can be incorporated in a model in which signaling through chemokine receptors directly involves early signals that occur in the first few minutes after ligand binding, including receptor dimerization; association and activation of JAK tyrosine kinases, and activation of STAT transcriptional factors, as well as late signals such as cell polarization, activation, and association of p125FAK kinase to the chemokine receptor (Fig. 8). The fact that chemokine receptors activate the JAK/STAT pathway and that dimerization may be a general mechanism for chemokine activity adds a new perspective to understanding how the multiplicity of chemokine functions are achieved. Furthermore, it suggests an interesting new objective for therapeutic intervention in chemokine-associated pathologies, including inflammation and AIDS.


Similarities and differences in RANTES- and (AOP)-RANTES-triggered signals: implications for chemotaxis.

Rodríguez-Frade JM, Vila-Coro AJ, Martín A, Nieto M, Sánchez-Madrid F, Proudfoot AE, Wells TN, Martínez-A C, Mellado M - J. Cell Biol. (1999)

Diagrammatic representation of the signals delivered  following binding of chemokines to their receptors. The emphasis  is placed on the division between early (left) and late signals  (right), indicating the biochemical signals (bottom) implicated in  the function (top). The figure shows the differential ability of  RANTES and (AOP)-RANTES to trigger early and late signals.
© Copyright Policy
Related In: Results  -  Collection

Show All Figures
getmorefigures.php?uid=PMC2132943&req=5

Figure 8: Diagrammatic representation of the signals delivered following binding of chemokines to their receptors. The emphasis is placed on the division between early (left) and late signals (right), indicating the biochemical signals (bottom) implicated in the function (top). The figure shows the differential ability of RANTES and (AOP)-RANTES to trigger early and late signals.
Mentions: The data presented here can be incorporated in a model in which signaling through chemokine receptors directly involves early signals that occur in the first few minutes after ligand binding, including receptor dimerization; association and activation of JAK tyrosine kinases, and activation of STAT transcriptional factors, as well as late signals such as cell polarization, activation, and association of p125FAK kinase to the chemokine receptor (Fig. 8). The fact that chemokine receptors activate the JAK/STAT pathway and that dimerization may be a general mechanism for chemokine activity adds a new perspective to understanding how the multiplicity of chemokine functions are achieved. Furthermore, it suggests an interesting new objective for therapeutic intervention in chemokine-associated pathologies, including inflammation and AIDS.

Bottom Line: Chemokines mediate their effects via interaction with seven transmembrane G protein-coupled receptors (GPCR).Using CCR5-transfected HEK-293 cells, we show that both the CCR5 ligand, RANTES, as well as its derivative, aminooxypentane (AOP)- RANTES, trigger immediate responses such as Ca2+ influx, receptor dimerization, tyrosine phosphorylation, and Galphai as well as JAK/STAT association to the receptor.The results are discussed in the context of the dissociation of the late signals, provoked by the chemokines required for cell migration, from early signals.

View Article: PubMed Central - PubMed

Affiliation: Department of Immunology and Oncology, Centro Nacional de Biotecnolog¿ia, CSIC/UAM, Campus de Cantoblanco, E-28049 Madrid, Spain.

ABSTRACT
Chemokines are a family of proinflammatory cytokines that attract and activate specific types of leukocytes. Chemokines mediate their effects via interaction with seven transmembrane G protein-coupled receptors (GPCR). Using CCR5-transfected HEK-293 cells, we show that both the CCR5 ligand, RANTES, as well as its derivative, aminooxypentane (AOP)- RANTES, trigger immediate responses such as Ca2+ influx, receptor dimerization, tyrosine phosphorylation, and Galphai as well as JAK/STAT association to the receptor. In contrast to RANTES, (AOP)-RANTES is unable to trigger late responses, as measured by the association of focal adhesion kinase (FAK) to the chemokine receptor complex, impaired cell polarization required for migration, or chemotaxis. The results are discussed in the context of the dissociation of the late signals, provoked by the chemokines required for cell migration, from early signals.

Show MeSH
Related in: MedlinePlus