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The chemokine RANTES (regulated on activation normal T cell expressed and secreted) and its cognate receptor CC chemokine receptor 5 (CCR5) have been implicated in regulating immune cell function. Previously we reported that in T cells, RANTES activation of CCR5 results in Stat1 and Stat3 phosphorylation-activation, leading to Stat1:1 and Stat1:3 dimers that exhibit DNA binding activity and the transcriptional induction of a Stat-inducible gene, c-fos. Given that RANTES and CCR5 have been implicated in T cell activation, we have studied RANTES-induced signaling events in a CCR5-expressing T cell line, PM1. RANTES treatment of PM1 T cells results in the rapid phosphorylation-activation of CCR5, Jak2, and Jak3. RANTES-inducible Jak phosphorylation is insensitive to pertussis toxin inhibition, indicating that RANTES-CCR5-mediated tyrosine phosphorylation events are not coupled directly to Gαi protein-mediated events. In addition to Jaks, several other proteins are rapidly phosphorylated on tyrosine residues in a RANTES-dependent manner, including the Src kinase p56lck, which associates with Jak3. Additionally our data confirm that the amino-terminally modified RANTES proteins, aminooxypentane-RANTES and Met-RANTES, are agonists for CCR5 and induce early tyrosine phosphorylation events that are indistinguishable from those inducible by RANTES with similar kinetics. Our data also demonstrate that RANTES activates the p38 mitogen-activated protein (MAP) kinase pathway. This is evidenced by the rapid RANTES-dependent phosphorylation and activation of p38 MAP kinase as well as the activation of the downstream effector of p38, MAP kinase-activated protein (MAPKAP) kinase-2. Pharmacological inhibition of RANTES-dependent p38 MAP kinase activation blocks MAPKAP kinase-2 activity. Thus, activation of Jak kinases and p38 MAP kinase by RANTES regulates the engagement of multiple signaling pathways. The chemokine RANTES (regulated on activation normal T cell expressed and secreted) and its cognate receptor CC chemokine receptor 5 (CCR5) have been implicated in regulating immune cell function. Previously we reported that in T cells, RANTES activation of CCR5 results in Stat1 and Stat3 phosphorylation-activation, leading to Stat1:1 and Stat1:3 dimers that exhibit DNA binding activity and the transcriptional induction of a Stat-inducible gene, c-fos. Given that RANTES and CCR5 have been implicated in T cell activation, we have studied RANTES-induced signaling events in a CCR5-expressing T cell line, PM1. RANTES treatment of PM1 T cells results in the rapid phosphorylation-activation of CCR5, Jak2, and Jak3. RANTES-inducible Jak phosphorylation is insensitive to pertussis toxin inhibition, indicating that RANTES-CCR5-mediated tyrosine phosphorylation events are not coupled directly to Gαi protein-mediated events. In addition to Jaks, several other proteins are rapidly phosphorylated on tyrosine residues in a RANTES-dependent manner, including the Src kinase p56lck, which associates with Jak3. Additionally our data confirm that the amino-terminally modified RANTES proteins, aminooxypentane-RANTES and Met-RANTES, are agonists for CCR5 and induce early tyrosine phosphorylation events that are indistinguishable from those inducible by RANTES with similar kinetics. Our data also demonstrate that RANTES activates the p38 mitogen-activated protein (MAP) kinase pathway. This is evidenced by the rapid RANTES-dependent phosphorylation and activation of p38 MAP kinase as well as the activation of the downstream effector of p38, MAP kinase-activated protein (MAPKAP) kinase-2. Pharmacological inhibition of RANTES-dependent p38 MAP kinase activation blocks MAPKAP kinase-2 activity. Thus, activation of Jak kinases and p38 MAP kinase by RANTES regulates the engagement of multiple signaling pathways. aminooxypentane-RANTES mitogen-activated protein MAP kinase-activated protein polyacrylamide gel electrophoresis Chemokines are 8- to 10-kDa inducible and secreted proteins that comprise the largest mammalian cytokine superfamily. Over 50 chemokines have been identified to date and have been subdivided into four families on the basis of the relative position of their cysteine residues (1Zlotnik A. Morales J. Hedrick J.A. Crit. Rev. Immunol. 1998; 19: 1-47Google Scholar, 2Baggiolini M. Dewald B. Moser B. Annu. Rev. Immunol. 1997; 15: 675-705Crossref PubMed Scopus (1998) Google Scholar, 3Devalaraja M.N. Richmond A. Trends Pharmacol. Sci. 1999; 20: 151-156Abstract Full Text Full Text PDF PubMed Scopus (76) Google Scholar). 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RANTES is a CC chemokine that induces both the migration and activation of specific leukocyte subsets by binding to the receptors CCR1, CCR3, CCR5, and CCR9. A number of studies have examined chemokine-induced signal transduction. There is increasing evidence that RANTES may act as an antigen-independent activator of T cells, stimulating protein tyrosine phosphorylation (19Bacon K.B. Premack B.A. Gardner P. Schall T.J. Science. 1995; 269: 1727-1730Crossref PubMed Scopus (422) Google Scholar). RANTES-induced T cell activation is apparently mediated via two distinct signal transduction cascades: one linked to recruitment of pertussis toxin-sensitive G proteins and the other to protein-tyrosine kinase activation. RANTES-induced T cell activation apparently requires CD3 expression (20Dairaghi D.J. Soo K. Oldham E.R. Premack B.A. Kitamura T. Bacon K.B. Schall T.J. J. Immunol. 1998; 160: 426-433PubMed Google Scholar), implying that RANTES may engage the T cell receptor complex as a way of effecting cellular activation. Indeed CCR5 is constitutively associated with membrane raft microdomains (21Manes S. Mira E. Gomez-Mouton C. Lacalle R.A. Keller P. Labrador J.P. Martines-A C. EMBO J. 1999; 18: 6211-6220Crossref PubMed Scopus (279) Google Scholar). RANTES has been show to induce the activation of the tyrosine kinases ζ-associated protein 70 and p125FAK and their association with paxillin as well as the tyrosine phosphorylation of the related Pyk2 kinase (22Bacon K.B. Szabo M.C. Yssel H. Bolen J. Schall T.J. J. Exp. Med. 1996; 184: 873-882Crossref PubMed Scopus (133) Google Scholar, 23Davis C.B. Dikic I. Unutmaz D. Hill M. Arthos J. Siani M.A. Thompson D.A. Schlessinger J. Littman D.R. J. Exp. Med. 1997; 186: 1793-1798Crossref PubMed Scopus (344) Google Scholar). RANTES-induced activation of phospholipase D is dependent on GTP-binding proteins (ADP-ribosylation factor(s) and RhoA) mediated by interactions with the receptor-coupled G proteins and not protein-tyrosine kinases (24Bacon K.B. Schall T.J. Dairaghi D.J. J. Immunol. 1998; 160: 1894-1900PubMed Google Scholar). Many cytokines and growth factors mediate their effects by activation of a common signal transduction pathway, the STAT pathway. Binding of the ligand to its specific transmembrane receptor results in receptor aggregation, which may involve single or multiple receptor chains. Receptor aggregation leads to the catalytic activation of receptor-associated cytoplasmic protein-tyrosine kinases, JAKs, and phosphorylation-activation of latent monomeric STAT proteins. In our earlier investigations of RANTES-mediated signal transduction, we demonstrated the activation of Stat1 and Stat3 by RANTES (25Wong M. Fish E.N. J. Biol. Chem. 1998; 273: 309-314Abstract Full Text Full Text PDF PubMed Scopus (145) Google Scholar). In this study we report that RANTES treatment of human PM1 T cells that express cell surface CCR5 results in the rapid and transient phosphorylation of CCR5 on tyrosine residues and the activation of CCR5-associated Jaks. Furthermore, we provide evidence for the RANTES-dependent association of the Src family kinase, p56lck, with Jak3. Our data reveal that these RANTES-CCR5-mediated tyrosine phosphorylation events are pertussis toxin-insensitive and therefore are not coupled to Gαi protein-mediated events. In comparative experiments we show that the amino-terminally modified RANTES proteins, Met-RANTES and aminooxypentane-RANTES (AOP-RANTES),1 exhibit agonist activity on CCR5 in PM1 cells in the context of tyrosine phosphorylation events with similar kinetics to RANTES. The p38 mitogen-activated protein (MAP) kinases are serine-threonine protein kinases that are activated by diverse stimuli including physical and chemical stresses and by various hemopoietic and pro-inflammatory cytokines (reviewed in Refs. 26Tibbles L.A. Woodgett J.R. Cell. Mol. Life Sci. 1999; 15: 1230-1254Crossref Scopus (557) Google Scholar, 27Widmann C. Gibson S. Jarpe M.B. Johnson G.L. Physiol. Rev. 1999; 79: 143-180Crossref PubMed Scopus (2318) Google Scholar, 28Raingeaud J. Gupta S. Rogers S. Dickens M. Han J. Ulevitch J. Davis R.J. J. Biol. Chem. 1995; 270: 7420-7426Abstract Full Text Full Text PDF PubMed Scopus (2062) Google Scholar, 29Foltz I.N. Lee J.C. Young P.R. Schrader J.W. J. Biol. Chem. 1997; 272: 3296-3301Abstract Full Text Full Text PDF PubMed Scopus (157) Google Scholar, 30Uddin S. Majchrzak B. Woodson J. Arunkumar P. Alsayed Y. Pine R. Young P.R. Fish E.N. Platanias L.C. J. Biol. Chem. 1999; 274: 30127-30131Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). Signal transduction mediated via the p38 MAP kinase pathway seems to play an important role in regulating inflammatory responses including cytokine secretion and apoptosis in a number of different biological systems. p38 MAP kinase activation is regulated by its phosphorylation on threonine and tyrosine residues. Focal adhesion kinase and Pyk2 kinase are nonreceptor protein-tyrosine kinases that are phosphorylated-activated upon T cell activation and after stimulation of G protein-linked receptors (31Schaller M.D. J. Endocrinol. 1996; 150: 1-7Crossref PubMed Scopus (75) Google Scholar, 32Maguire J.E. Danahey M. Burkly L.C. van Seventer G.A. J. Exp. Med. 1995; 182: 2079-2090Crossref PubMed Scopus (90) Google Scholar, 33Berg N.N. Ostergaard H.L. J. Immunol. 1997; 159: 1753-1757PubMed Google Scholar). As indicated above RANTES will stimulate the phosphorylation of focal adhesion kinase, the tyrosine kinase ζ-associated protein 70, and the focal adhesion protein paxillin in human T cells (22Bacon K.B. Szabo M.C. Yssel H. Bolen J. Schall T.J. J. Exp. Med. 1996; 184: 873-882Crossref PubMed Scopus (133) Google Scholar). Moreover, there is evidence that the focal adhesion kinase-related tyrosine kinase, Pyk2, will activate p38 MAP kinase (34Kampen G.T. Stafford S. Adachi T. Jinquan T. Quan S. Grant J.A. Skov P.S. Poulsen L.K. Alam R. Blood. 2000; 95: 1911-1917Crossref PubMed Google Scholar). Indeed, the activation of p38 MAP kinase has been implicated in chemokine-induced responses (35Pandey P. Avraham S. Kumar S. Nakazawa A. Place A. Ghanem L. Rana A. Kumar V. Majumder P.K. Avraham H. Davis R.J. Kharbanda S. J. Biol. Chem. 1999; 274: 10140-10144Abstract Full Text Full Text PDF PubMed Scopus (125) Google Scholar). Viewed together, these observations raise the possibility that RANTES activation of CCR5 in T cells may invoke p38 MAP kinase activation. In this report we provide the first evidence that RANTES-CCR5 interactions result in the rapid phosphorylation of p38 and activation of its catalytic activity. Overall, our data establish that RANTES activation of CCR5 leads to the rapid phosphorylation of distinct signaling intermediates on tyrosine residues that invoke discrete signaling pathways. Human PM1 T cells expressing CCR5 (36Lusso P. Cocchi F. Balotta C. Markham P.D. Louie A. Farci P. Pal R. Gallo R.C. Reitz Jr., M.S. J. Virol. 1995; 69: 3712-3720Crossref PubMed Google Scholar) were obtained from the National Institutes of Health AIDS Research and Reference Reagent Program and maintained in RPMI 1640 medium with 10% fetal calf serum, 100 units/ml penicillin, and 100 mg/ml streptomycin. Recombinant RANTES, Met-RANTES, and AOP-RANTES were provided by Serono Pharmaceutical Research Institute. Polyclonal antibodies against Jak2, Jak3, p38, and CCR5 and a monoclonal antibody against p56lck were obtained from Santa Cruz Biotechnology (Santa Cruz, CA). Polyclonal antibodies recognizing p38, the phosphorylated-activated form of p38, and the phosphorylated-activated form of ATF-2 were obtained from New England Biolabs. Antibodies against MAP kinase-activated protein (MAPKAP)-kinase-2 and phosphorylated tyrosine (4G10) were obtained from Upstate Biotechnology, Inc. The SB203580 inhibitor and pertussis toxin were obtained from Calbiochem. Actively growing cells at a concentration of 1 × 107 cells/ml were stimulated with RANTES as indicated, and the cells were lysed as described previously (37Ahmad S. Alsayed Y. Druker B.J. Platanias L.C. J. Biol. Chem. 1997; 272: 29991-29994Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). Immunoprecipitations and immunoblotting using an enhanced chemiluminescence method were performed as described previously (37Ahmad S. Alsayed Y. Druker B.J. Platanias L.C. J. Biol. Chem. 1997; 272: 29991-29994Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). In vitro kinase assays for Jaks, p38 MAP kinase, and MAPKAP kinase-2 were carried out as previously described (30Uddin S. Majchrzak B. Woodson J. Arunkumar P. Alsayed Y. Pine R. Young P.R. Fish E.N. Platanias L.C. J. Biol. Chem. 1999; 274: 30127-30131Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar, 38Colamonici O. Yan H. Domanski P. Handa R. Smalley D. Mullersman J. Witte M. Krishnan K. Krolewski J. Mol. Cell. Biol. 1994; 14: 8133-8142Crossref PubMed Google Scholar, 39Somani A.-K. Bignon J.S. Mills G.B. Siminovitch K. Branch D.R. J. Biol. Chem. 1997; 272: 21113-21119Abstract Full Text Full Text PDF PubMed Scopus (143) Google Scholar). In some experiments the immunoblot membranes were incubated for 1 h in 1 m KOH at 70° C to for proteins (37Ahmad S. Alsayed Y. Druker B.J. Platanias L.C. J. Biol. Chem. 1997; 272: 29991-29994Abstract Full Text Full Text PDF PubMed Scopus (92) Google Scholar). of and CCR5 expression on PM1 cells performed using monoclonal antibodies against by R. and CCR5 Institutes of Health AIDS Research and Reference Reagent as previously described J. Fish E.N. J. Immunol. 1994; Google Scholar). The PM1 cells in these studies were from the human T cell (36Lusso P. Cocchi F. Balotta C. Markham P.D. Louie A. Farci P. Pal R. Gallo R.C. Reitz Jr., M.S. J. Virol. 1995; 69: 3712-3720Crossref PubMed Google Scholar). the we that PM1 cells express cell surface CCR5 RANTES the phosphorylation of CCR5 in PM1 cells, CCR5 from from cells, and the by and for tyrosine phosphorylation and The data in A reveal that CCR5 is phosphorylated on tyrosine residues after RANTES treatment of PM1 cells. is that the chemokine chemotactic activation and tyrosine phosphorylation of in the human cell 1 M. A. A. Jr., F. C. J. Immunol. 1998; PubMed Google Scholar) and that RANTES induces tyrosine phosphorylation of CCR5 in human cells and association with A. M. F. C. M. J. Biol. 1999; PubMed Scopus Google Scholar). therefore examined PM1 cells for RANTES-dependent CCR5 and Jak In studies cell from cells were with by and with phosphorylated that were identified as CCR5 and 1 of RANTES stimulation phosphorylated rapidly associates with CCR5 in a RANTES-dependent CCR5 phosphorylation and association with phosphorylated PM1 cells were or with RANTES for the were with A and proteins were by with an antibody against The in A and with In the the of CCR5 and The in and with are RANTES-CCR5 interactions result in the activation of other Jaks, we RANTES-induced cell with different the by and with we were to activation, the results in show RANTES-inducible Jak and the of pertussis toxin not RANTES-inducible Jak that Gαi protein signaling events are not coupled to Jak activation. In experiments we examined the kinase activity of and is by RANTES. PM1 cells were with RANTES, cell were with or and in vitro kinase assays were performed on the The data in that RANTES-inducible phosphorylation of and Jak results in activation of their catalytic The rapid phosphorylation-activation of and and the rapid association of with CCR5 that these kinases may early receptor tyrosine induction of the kinase of and Jak3. PM1 cells were or with RANTES for the were with an or an were to an in vitro kinase the proteins were by and phosphorylated and were by cell from cells were with antibodies and were with we a phosphorylated protein that associated with in a RANTES-dependent and the membrane identified this phosphorylated protein as the Src kinase Moreover, treatment of PM1 cells with the amino-terminally modified RANTES proteins, AOP-RANTES and Met-RANTES, in similar tyrosine phosphorylation and the that both Met-RANTES and AOP-RANTES inhibit vitro P.R. L. R. A.E. Science. 1997; PubMed Scopus Google Scholar) and in A. D.J. J.C. J. Exp. Med. 1997; PubMed Scopus Google Scholar, C. A.E. Immunol. 1997; 57: PubMed Scopus Google Scholar, J.A. D. J.P. A. C. M. T. J.C. J. Exp. Med. 1998; PubMed Scopus Google Scholar, C. T. A.E. D. P.J. J. 1999; PubMed Scopus Google Scholar), both agonist on CCR5 in the context of early tyrosine phosphorylation events. and association of phosphorylated p56lck with activation. we that are rapidly associated and activated with CCR5, by the recruitment of p56lck, the are that p56lck is to the activated receptor via an with Jak3. This may CCR5 with L. Y. S. H. Natl. Sci. S. A. 1999; PubMed Scopus Google Scholar). Indeed, may to Src kinases and activated Jak kinases have been both and via with in hemopoietic cells S.G. J. J. 1998; PubMed Scopus Google Scholar, C. Young S. J.A. Johnson G.L. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar). Furthermore, there is some evidence to that association of p56lck with the activated complex the of in T cells P.M. D. J.A. R.A. J. Immunol. 1996; Google Scholar). has been reported that Src kinases can with the of G protein (reviewed in Refs. Annu. Rev. 1998; PubMed Scopus Google and M. Mol. Biol. 1999; Google Scholar), and a report a the receptor and the associated signaling and S. M. A. S. J. Sci. 2000; Google Scholar). Thus, RANTES-dependent recruitment of p56lck to CCR5 may result in complex of interactions signaling that may for G protein-coupled signaling and protein-linked RANTES-inducible activation of T cells their proliferation and adhesion and cytokine (reviewed in S.G. J. J. 1998; PubMed Scopus Google Scholar). The that specific biological are The evidence for protein-tyrosine kinase in RANTES-CCR5 signal transduction. protein-tyrosine kinases as and p56lck can to the activated The are that protein-tyrosine kinases are to the receptor are activated and act in to signaling MAP kinases are the signaling kinases regulated by chemokines C. Young S. J.A. Johnson G.L. J. Biol. Chem. 1996; Full Text Full Text PDF PubMed Scopus Google Scholar, P.M. D. J.A. R.A. J. Immunol. 1996; Google Scholar) and are to activated by phosphorylation on tyrosine and threonine residues. we reported that the p38 MAP kinase pathway regulates DNA binding of proteins, a the p38 MAP kinase pathway and the pathway in transcriptional regulation (30Uddin S. Majchrzak B. Woodson J. Arunkumar P. Alsayed Y. Pine R. Young P.R. Fish E.N. Platanias L.C. J. Biol. Chem. 1999; 274: 30127-30131Abstract Full Text Full Text PDF PubMed Scopus (207) Google Scholar). we examined RANTES activation of CCR5 in PM1 T cells leads to p38 MAP kinase activation. In from and PM1 cells were by and with an antibody against the phosphorylated form of p38 MAP phosphorylation of p38 at treatment In we demonstrated that the kinase activity of p38 is inducible by RANTES. In vitro kinase assays were performed on from and cells that been with an using a protein for ATF-2 as an of PM1 cells in the phosphorylation of ATF-2 with p38 kinase activity at after RANTES treatment In p38 and activates mitogen-activated protein kinase-activated protein which in proteins and from and cells were with an antibody against MAPKAP and in vitro kinase assays were performed on the using as the The results in C that MAPKAP kinase-2 is activated by RANTES The data reveal a the kinetics of inducible kinase activity of p38 and MAPKAP kinase-2 at Moreover, using a the we provide evidence that MAPKAP kinase-2 is a downstream effector of the p38 MAP kinase pathway in T cells The specific of p38 MAP kinase in RANTES-inducible biological responses A report a role for p38 MAP kinase in the phosphorylation of paxillin and the of focal adhesion R. L. A. J. Kumar R. 1999; 18: PubMed Scopus Google Scholar). The are that p38 MAP kinase signaling may to RANTES-inducible T cell activation in the context of T cell focal (22Bacon K.B. Szabo M.C. Yssel H. Bolen J. Schall T.J. J. Exp. Med. 1996; 184: 873-882Crossref PubMed Scopus (133) Google Scholar). the kinetics of RANTES activation of p38 kinase activity are with a role for this MAP kinase in In our provide evidence for the recruitment and activation of distinct protein kinases in T the Jaks, and the Src kinase and the MAP kinases p38 and MAPKAP kinase activation of Jak2, Jak3, and p56lck requires their phosphorylation on activation of p38 requires both threonine and tyrosine the p38 signaling pathway phosphorylation of target the RANTES-dependent of different signaling to CCR5 for signal or of signaling pathways. The specific of these RANTES activation of CCR5 to and are the of our
Wong et al. (Sun,) studied this question.
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