From the Toronto General Research Institute,
University Health Network, Toronto and Department of Immunology,
University of Toronto, Ontario M5G 2M1, Canada, ¶ Section of
Hematology-Oncology, Department of Medicine, University of Illinois,
Chicago, Illinois and West Side Veterans Affairs Hospital, Chicago,
Illinois 60607, and
Serono Pharmaceutical Research Institute,
1228 Planles Ouates Geneva, Switzerland
Received for publication, November 29, 2000
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ABSTRACT |
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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 G 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 (1-3). Chemokines were named originally for their ability to
act as chemotactic cytokines for functionally mature blood cell types, thereby regulating inflammatory events (4-9),
and have been implicated more recently in the regulation of
hematopoiesis (10) and in the clearance of infectious organisms (7).
Chemokines can also modulate angiogenesis and tumor growth and inhibit
stem cell proliferation (11-16). Chemokines induce their effects by
binding to specific seven-transmembrane-spanning, pertussis
toxin-sensitive, G protein-coupled receptors on target cells (10, 17,
18) that are expressed on a wide range of leukocytes, as well as
epithelial cells, endothelial cells, neurons, astrocytes, and smooth
muscle cells.
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 (19). 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 (20), 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 (21). RANTES has been show to induce
the activation of the tyrosine kinases 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 (25). 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
G 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. 26-30). 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 (31-33). As indicated above RANTES will
stimulate the phosphorylation of focal adhesion kinase, the tyrosine
kinase Cells and Reagents--
Human PM1 T cells expressing CCR5 (36)
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.
Cell Lysis and Immunoblotting--
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 (37). Immunoprecipitations and immunoblotting using an
enhanced chemiluminescence method were performed as described
previously (37).
In Vitro Kinase Assays--
In vitro kinase assays
for Jaks, p38 MAP kinase, and MAPKAP kinase-2 were carried out as
previously described (30, 38, 39). In some experiments the immunoblot
membranes were incubated for 1 h in 1 M KOH at
70° C to select for tyrosine-phosphorylated proteins
(37).
Flow Cytometric Analysis of Antibody Binding to Native CCR5 on
PM1 Cells--
FACScan analyses of CCR1 and CCR5 expression on PM1
cells was performed using monoclonal antibodies against CCR1 (provided by R. Horuk, Berlex Laboratories, Inc.) and CCR5 (National Institutes of Health AIDS Research and Reference Reagent Program) as previously described (40).
The CD4+ clonal PM1 cells used in these studies were derived from
the human T cell line Hut78 (36). At the onset we determined that PM1
cells express cell surface CCR5 (Fig. 1).
To determine whether RANTES induced the phosphorylation of CCR5 in PM1
cells, CCR5 was immunoprecipitated from lysates from RANTES-treated
cells, and the solubilized immunoprecipitate was resolved by SDS-PAGE and then immunoblotted for tyrosine phosphorylation and CCR5. The data
in Fig. 2A reveal that CCR5 is
phosphorylated on tyrosine residues after RANTES treatment of PM1
cells. It is known that the chemokine monocyte chemotactic protein-1
triggers Jak2 activation and tyrosine phosphorylation of CCR2 in the
human monocytic cell line Mono Mac 1 (41) and that RANTES induces
tyrosine phosphorylation of CCR5 in CCR5-transfected human embryonic
kidney HEK-293 cells and association with Jak1 (42). We therefore
examined PM1 cells for RANTES-dependent CCR5 and Jak
phosphorylation. In time-course studies when cell lysates from
RANTES-treated cells were immunoprecipitated with anti-CCR5 antibodies,
resolved by SDS-PAGE, and immunoblotted with anti-Tyr(P)
antibodies, phosphorylated bands that were identified subsequently as
CCR5 and Jak2 appeared within 1 min of RANTES stimulation (Fig.
2B). Apparently phosphorylated Jak2 rapidly associates with
CCR5 in a RANTES-dependent manner.
i 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.
INTRODUCTION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
-associated protein 70 and
p125FAK and their association with paxillin as well as the
tyrosine phosphorylation of the related Pyk2 kinase (22, 23).
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 (24).
i 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.
-associated protein 70, and the focal adhesion protein
paxillin in human T cells (22). Moreover, there is evidence that the
focal adhesion kinase-related tyrosine kinase, Pyk2, will activate p38
MAP kinase (34). Indeed, the activation of p38 MAP kinase has been
implicated in chemokine-induced responses (35). 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.
EXPERIMENTAL PROCEDURES
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
RESULTS AND DISCUSSION
TOP
ABSTRACT
INTRODUCTION
EXPERIMENTAL PROCEDURES
RESULTS AND DISCUSSION
REFERENCES
View larger version (49K):
[in a new window]
Fig. 1.
PM1 cells express cell surface CCR5.
Cell surface expression of CCR1 (A) and CCR5 (B)
was determined by flow cytometric analysis of unstained, (gray
fill) or antibody-stained, (black fill) PM1 cells. A
log shift in CCRS fluorescence intensity was observed
(B).
View larger version (23K):
[in a new window]
Fig. 2.
RANTES-dependent CCR5
phosphorylation and association with phosphorylated Jak2. PM1
cells were either left untreated ( ) or treated (+) with RANTES for
the times indicated. Cell lysates were immunoprecipitated
(IP) with anti-CCR5 antibody. A and B,
immunoprecipitated proteins were resolved by SDS-PAGE, then
immunoblotted (WB) with an antibody against Tyr(P) (4G10).
The blot shown in A was stripped and reprobed with anti-CCR5
antibody. In B, the arrows indicate the positions of CCR5
and Jak2. The blot shown in B was stripped and reprobed with
anti-Jak2 antibody. Molecular mass markers (in kDa) are
identified.
To determine whether RANTES-CCR5 interactions result in the activation
of other Jaks, we immunoprecipitated RANTES-induced cell extracts with
different anti-Jak antibodies, resolved the immunoprecipitates by
SDS-PAGE and then immunoblotted with anti-Tyr(P) antibodies. Although
we were unable to detect Jak1 activation, the results in Fig.
3 show RANTES-inducible Jak 2 and Jak3
phosphorylation. Interestingly, the inclusion of pertussis toxin did
not affect RANTES-inducible Jak phosphorylation, suggesting that
Gi protein signaling events are not coupled to Jak
activation. In subsequent experiments we examined whether the kinase
activity of Jak2 and Jak3 is induced by RANTES. PM1 cells were treated
with RANTES, cell lysates were immunoprecipitated with anti-Jak2 or
anti-Jak3 antibodies, and in vitro kinase assays were
performed on the immunoprecipitates. The data in Fig.
4 indicate that RANTES-inducible
phosphorylation of Jak2 and Jak 3 results in activation of their
catalytic domains. The rapid phosphorylation-activation of Jak2 and
Jak3 and the rapid association of Jak2 with CCR5 suggests that these
kinases may effect early receptor tyrosine phosphorylation.
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When cell lysates from RANTES-treated cells were immunoprecipitated
with anti-Jak3 antibodies and Western blots were developed with
anti-Tyr(P) antibodies, we observed a 56-kDa phosphorylated protein
that associated with Jak3 in a RANTES-dependent manner (Fig. 5). Stripping and reprobing the
membrane identified this phosphorylated protein as the Src kinase
p56lck. Moreover, treatment of PM1 cells with the
amino-terminally modified RANTES proteins, AOP-RANTES and Met-RANTES,
resulted in similar Jak3 tyrosine phosphorylation and p56lck
association (Fig. 5). Clearly, despite the fact that both
Met-RANTES and AOP-RANTES inhibit RANTES- induced activities both
in vitro (43) and in vivo (44-47), both exert
agonist activities on CCR5 in the context of early tyrosine
phosphorylation events. Notably, RANTES-, Met-RANTES-, and
AOP-RANTES-dependent association of phosphorylated
p56lck with Jak3 follows ligand-stimulated Jak3 activation.
Because we observe that Jaks are rapidly associated and activated with ligand-stimulated CCR5, followed by the sequential recruitment of
p56lck, the implications are that p56lck is recruited
to the activated receptor complex, perhaps via an interaction with
Jak3. This may occur through CCR5 interaction with CD4 (48). Indeed,
Jak3 may function to phosphorylate p56lck. Interactions between
Src kinases and activated Jak kinases have been reported. Specifically,
both Lyn and p59fyn associate via SH2 domains with interferon
-activated Tyk2 in hemopoietic cells (49, 50). Furthermore, there is
some evidence to suggest that association of p56lck with the
activated interferon-receptor complex influences the antiproliferative
action of interferon in T cells (51). It has been reported that Src
kinases can associate with the
subunits of heterotrimeric G protein
complexes (reviewed in Refs. 52 and 53), and a recent report describes
a functional interaction between the folate receptor and the associated
signaling molecules Lyn and G
i-3 (54). Thus,
RANTES-dependent recruitment of p56lck to CCR5 may
result in complex patterns of interactions among signaling molecules
that may allow for cross-talk between G protein-coupled signaling
cascades and non-G protein-linked cascades.
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RANTES-inducible activation of T cells influences their
proliferation and differentiation, adhesion molecule expression, and cytokine release (reviewed in Ref. 49). The precise biochemical pathways that determine specific biological consequences are unknown. The preceding provides compelling evidence for protein-tyrosine kinase
involvement in mediating RANTES-CCR5 signal transduction. Apparently,
non-CCR5-associated protein-tyrosine kinases such as Jaks and
p56lck can be recruited to the activated receptor. The
implications are that membrane-localized protein-tyrosine kinases are
recruited to the ligand-stimulated receptor where they are activated
and act in concert to initiate intracellular signaling cascades. MAP kinases are included among the signaling kinases regulated by chemokines (50, 51) and are known to be activated by phosphorylation on
tyrosine and threonine residues. Recently, we reported that the p38 MAP
kinase pathway regulates interferon-dependent gene transcription without affecting DNA binding of Stat proteins, suggesting a cooperation between the p38 MAP kinase pathway and the
Jak-Stat pathway in transcriptional regulation (30). Therefore, we examined whether RANTES activation of CCR5 in PM1 T cells
leads to p38 MAP kinase activation. In time-course studies, whole-cell lysates from untreated and RANTES-treated PM1 cells were analyzed by SDS-PAGE and immunoblotted with an antibody against the
phosphorylated form of p38 MAP kinase. Maximum phosphorylation of p38
occurred at 15 min post-RANTES treatment (Fig.
6A). In subsequent
experiments, we demonstrated that the kinase activity of p38 is
inducible by RANTES. In vitro kinase assays were performed
on whole-cell lysates, from untreated and RANTES-treated cells that had
been immunoprecipitated with an anti-p38 antibody, using a glutathione
fusion protein encoding for ATF-2 as an exogenous substrate.
Stimulation of PM1 cells resulted in the phosphorylation of ATF-2 with
maximal p38 kinase activity exhibited at 30 min after RANTES treatment
(Fig. 6B).
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In vivo, p38 phosphorylates and activates mitogen-activated protein kinase-activated protein kinase-2, which in turn phosphorylates heat-shock proteins (Hsp) 25 and 27 (55). Accordingly, lysates from untreated and RANTES-treated cells were immunoprecipitated with an antibody against MAPKAP kinase-2, and in vitro kinase assays were performed on the immunoprecipitates using Hsp25 as the exogenous substrate. The results in Fig. 6C indicate that MAPKAP kinase-2 is activated by RANTES treatment. The data reveal a concordance between the kinetics of maximal inducible kinase activity of p38 and MAPKAP kinase-2 at 30 min post-RANTES stimulation. Moreover, using a p38-specific inhibitor, the pyridinyl imidazole compound SB203580, we provide evidence that MAPKAP kinase-2 is indeed a downstream effector of the p38 MAP kinase pathway in RANTES-stimulated T cells (Fig. 6C).
The specific role(s) of p38 MAP kinase in RANTES-inducible biological responses remains unknown. A recent report describes a role for p38 MAP kinase in the serine phosphorylation of paxillin and the concurrent disassembly of focal adhesion complexes (56). The implications are that p38 MAP kinase signaling may function to negatively regulate RANTES-inducible T cell activation in the context of disassembling T cell focal adhesions (22). Certainly, the kinetics of RANTES activation of p38 kinase activity are consistent with a role for this MAP kinase in negative feedback inhibition.
In conclusion, our findings provide direct evidence for the
RANTES-CCR5-dependent recruitment and activation of
distinct protein kinases in T cells: the Jaks, Jak2 and Jak3; the Src
kinase p56lck; and the MAP kinases p38 and MAPKAP kinase 2. Whereas activation of Jak2, Jak3, and p56lck requires their
phosphorylation on tyrosines, activation of p38 requires both threonine
and tyrosine phosphorylations. Furthermore the hierarchical p38
signaling pathway invokes serine phosphorylation of target substrates.
Clearly the RANTES-dependent sequestering of different
signaling molecules to CCR5 provides for signal integration or
reciprocal modulation of interacting signaling pathways. The specific
roles of these interacting pathways during RANTES activation of CCR5
remain to be elucidated and are the subject of our ongoing investigations.
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FOOTNOTES |
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* This work was supported by grants from the Medical Research Council of Canada (MT-13709) and the Arthritis Society of Canada (to E. N. F.), National Institutes of Health Grants CA73381 and CA77816 (to L. C. P.), and a Merit Review Grant from the Department of Veterans Affairs (to L. C. P.).The costs of publication of this article were defrayed in part by the payment of page charges. The article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
§ Recipient of a Canadian Institutes of Health Research Scholarship.
** To whom correspondence should be addressed: Toronto General Research Inst., University Health Network, Canadian Blood Services Bldg., 67 College St., Rm. 424, Toronto, Ontario M5G 2M1, Canada. Tel.: 416-340-5380; Fax: 416-340-3453; E-mail: en.fish@utoronto.ca.
Published, JBC Papers in Press, January 18, 2001, DOI 10.1074/jbc.M010750200
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ABBREVIATIONS |
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The abbreviations used are: AOP-RANTES, aminooxypentane-RANTES; MAP, mitogen-activated protein; MAPKAP, MAP kinase-activated protein; PAGE, polyacrylamide gel electrophoresis.
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REFERENCES |
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