| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
, Mitogen-Activated Protein Kinase Kinase, and c-Jun NH2-Terminal Kinase1
*
Servei d’Immunologia, Institut D’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Barcelona, Spain; and
Division of Biology, California Institute of Technology, Pasadena, CA 91125
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
(PKC-) and members of the
mitogen-activated protein kinase (MAPK) cascade (MAPK kinase and c-Jun
NH2-terminal kinase), but not the NF-
B, are downstream
events of the CD5 signaling pathway. A-SMase, PKC-, and MAPK family
members are key mediators of cell responses as diverse as
proliferation, differentiation, and growth arrest and may contribute to
CD5-mediated modulation of TCR or BCR signaling. |
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
It has been shown that CD5 acts as a receptor and/or substrate for the
protein tyrosine kinases p59fyn,
p56lck (12), and ZAP-70 (13) and for the protein
serine/threonine kinases casein kinase II
(CKII)3 (14, 15) and
Ca2+/calmodulin-dependent kinase (CaMK) II
(16). Early
reports showed that anti-CD5 mAb augment the intracellular
Ca2+, inositol triphosphate, IL-2 secretion, and IL-2R
expression induced by anti-CD3 mAbs (6, 7, 8). Recently,
phosphatidylinositol 3-kinase (PI 3-K), Vav, Rac1, Ras
GTPase-activating protein, c-Cbl, and CaMK type IV have been reported
to be involved in the CD5 signaling pathway in human T lymphocytes
(17, 18, 19, 20). The relevance of these associations for the physiological
function of CD5 is not well defined. Interestingly, data from
CD5-/- mice have shown hyper-reactivity of thymocytes
associated with increased tyrosine phosphorylation of various proteins
(Vav, ZAP-70, PLC-1
, and CD3) in response to CD3 stimulation
(10). Consistently, a preliminary study indicates that CD5 could
associate with the protein tyrosine phosphatase 1C in thymocytes
(21).
We have previously shown that some anti-CD5 mAbs induce protein
tyrosine phosphorylation and phosphoinositide turnover- and
Ca2+-independent protein kinase C (PKC) activation (9). The
latter is achieved through diacylglycerol (DAG), which is itself the
result of both phosphatidylcholine-specific phospholipase C (PC-PLC)
activation and de novo synthesis (22). This indicates that CD5 is an
accessory molecule with its own signaling pathway, which evokes that
used by some cytokine and cell surface receptors (TNF receptor I
(TNFRI), CD95/Apo-1/Fas ligand, CD28, and IL-1R) to modulate lymphocyte
activation (22). The DAG generated by PC-PLC has been implicated in the
activation of acidic sphingomyelinase (A-SMase) (23, 24). The resulting
sphingomyelin (SM) metabolites (ceramide) have been implicated in the
activation of other downstream signaling elements (PKC-, NF-B,
etc.) and the modulation of the pleiotropic cellular effects (from cell
proliferation and differentiation to growth arrest and apoptosis)
induced by a number of extracellular inducers (25). In this study we
demonstrate that the CD5 signaling pathway involves PC-PLC-dependent
A-SMase activation as well as the activation of PKC- and members of
the mitogen-activated protein kinase (MAPK) cascade, namely MAPK kinase
(MEK) and c-Jun NH2-terminal kinase (JNK), in the absence
of NF-B transcriptional activity. The relevance of these findings in
the context of the modulatory effects of CD5 on lymphocyte activation
is discussed.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
PMA and wortmannin were obtained from Sigma (St. Louis, MO). The xanthogenate tricyclodecan-9-yl (D609) and the calcium ionophore A23187 were purchased from Calbiochem (La Jolla, CA).
Antibodies
All mAbs were of mouse origin and were clustered in the
International Workshops on Human Leukocyte Differentiation Antigens.
The F145-GF3 (CD5, IgG1) and A50 (CD5, IgG2a) mAbs were gifts from D.
Carrière (Sanofi Recherche, Montpellier, France) and A. Bernard
(Institut National de la Santé et de la Recherche Médicale,
U343, Nice, France), respectively. Cris-1 (CD5, IgG2a) and 152-2E10
(CD28, IgG1) were produced in our laboratory by R. Vilella. The OKT3
(CD3) and Leu 1 (CD5) mAbs were obtained from American Type Culture
Collection (Manassas, VA). The rabbit polyclonal anti-PKC- was
raised against the last 16 amino acids. The Leu 19 (CD56) mAb was
purchased from Becton Dickinson (Mountain View, CA). Goat antiserum to
mouse Ig (GAMIg) was obtained from Dako (Copenhagen, Denmark).
Noncommercial mAbs were produced as ascites fluid and affinity purified
on protein A-Sepharose. The preparations were >90% pure as assessed
by SDS-PAGE.
Cells and transfectants
Jurkat JE6.1 cells were obtained from American Type Culture Collection. The isolation and the phenotypic characteristics of the CD5- Jurkat 2G5 clone have been previously reported (22). Thymocytes were obtained by teasing apart thymus specimens that had been removed from children undergoing cardiac surgery. Human PBMC were obtained by Ficoll-Hypaque density gradient centrifugation. B-CLL cells with >95% purity were obtained after two rounds of complement-mediated cell lysis of PBMC with anti-CD3, -CD56, and -CD14 mAbs.
Construction of cytoplasmic tail mutant CD5 molecules and transfection conditions
The procedure for the generation of constructs coding for
wild-type and cytoplasmic tail mutant CD5 molecules (see Fig. 1
) has been previously reported (15). All
plasmid constructions were checked by dsDNA sequencing in an ABI PRISM
377 DNA sequencer (Perkin-Elmer, Foster City, CA) and were purified by
cesium chloride density gradients. The constructs were stably expressed
in 2G5 Jurkat cells by cell electroporation and selection for CD5
surface expression of neomycin-resistant cell clones (22).
|
At the indicated times, stimulation of the cells was stopped by immersion in a methanol-dry ice bath. Cells were centrifuged for 5 min at 4°C and washed with ice-cold PBS. Neutral and acidic SMase activities were measured in cell solubilizates by monitoring the amount of phosphorylcholine produced from exogenous [14C]SM, according to a previously reported micellar assay system (23).
Assay of PKC- activity
Cell samples (20 x 106 cells) were incubated
for different times with anti-CD5 mAb (20 µg/ml) and then lysed
in a buffer containing 50 mM Tris (pH 7.5), 150 mM NaCl, 1% Triton
X-100, 2 mM EDTA, 1 mM EGTA, 10 µg/ml leupeptin, 10 µg/ml
aprotinin, 1 mM orthovanadate, and 1 mM PMSF. Equivalent lysate samples
(200 µg of total protein) were immunoprecipitated for 2 h with
an affinity-purified rabbit polyclonal Ab against PKC- plus protein
A-Sepharose. Immune complexes were extensively washed with lysis buffer
containing 0.5 M NaCl and then incubated (20 min at 30°C) in 20 µl
of kinase buffer (35 mM Tris-HCl (pH 7.5), 10 mM MgCl2, 0.5
mM EGTA, 0.1 mM CaCl2, and 1 mM phenylphosphate) containing
2 µg of myelin basic protein and 5–10 µCi (100 µM) of
[-32P]ATP). Reactions were stopped by the addition of
SDS sample buffer and were separated by SDS-PAGE. The gels were
autoradiographed, and the relative densities of the bands were
quantitated with a FluorS-MultiImager (Bio-Rad, Hercules, CA) and
MultiAnalyst software.
NF-B-dependent promoter activity assay
Cell samples (107 cells) were transfected by electroporation with 100 ng of 3EconAluc plasmid (26). The power settings were 960 µF and 220 V. After transfection, cells were left in culture (at 1 x 106 cells/ml) for 16 h with RPMI medium supplemented with 10% FCS. Transfected cells were then incubated with different stimuli for 6 h. Total cell extracts were prepared in a lysis buffer, and samples were analyzed in a luminometer. Data are expressed in terms of relative luciferase activity units.
Assay of MEK and JNK activities
Extracts from 107 stimulated Jurkat cells were
immunoprecipitated with polyclonal anti-MEK-1 or anti-JNK Abs
(Santa Cruz Biotechnology, Santa Cruz, CA) plus protein A-Sepharose
(Pharmacia Biotech, Uppsala, Sweden). Immunoprecipitates were incubated
for 20 min at 30°C with 2 µg of recombinant ERK2-GST or c-Jun-GST
proteins in kinase assay buffer containing 5–10 µCi of
[-32P]ATP. The assay buffer for MEK was 75 mM
ß-glycerolphosphate (pH 7.3), 3.75 mM EGTA, 0.15 mM orthovanadate,
1.5 mM DTT, 30 µM calmidazolium, 30 mM MgCl2, and 0.3 mM
ATP. The assay buffer for JNK was 20 mM MOPS (pH 7.2), 2 mM EGTA, 10 mM
MgCl2, 1 mM DTT, and 0.1% Triton X-100. The reaction was
stopped with SDS sample buffer and then run on SDS-PAGE. The gels were
autoradiographed, and the relative densities of the bands were
quantitated as indicated above.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Various studies have shown that DAG generated via PC-PLC
activation serves as an important factor for A-SMase activation (23, 24) and the subsequent generation of ceramide, a relevant lipid
messenger intermediate. Since CD5 engagement mediates PC-PLC activation
in Jurkat cells (22), we explored whether CD5 triggering couples to
increased A-SMase activity. For this purpose, Jurkat cells were
stimulated for different times with identical amounts (10 µg/ml) of
mAbs directed against CD5 and other surface receptors (CD3 and CD28).
The A-SMase activity was measured in cell solubilizates following a
previously reported micellar assay with exogenous radiolabeled SM (23).
CD5 stimulation of Jurkat cells resulted in a rapid and transient
increase in A-SMase activity regardless of the anti-CD5 mAb
(Cris-1, A50, or F145-GF3) used (data not shown). As illustrated in
Fig. 2A, this increase reached
maximal values 1–2 min after stimulation and declined to basal levels
by 5 min. This kinetics closely paralleled those of CD5-mediated DAG
production (22). As previously reported, CD28 stimulation resulted in
A-SMase activation, and CD3 triggering failed to induce the activation
of A-SMase (27). Human PBMC and thymocytes were also assayed for
CD5-mediated A-SMase activity. In PBMC the CD5-mediated A-SMase
activity was relatively low, but was greatly improved by the addition
of secondary cross-linking Abs (Fig. 2B). In thymocytes, the
CD5-induced A-SMase activity was detectable only under
cross-linking conditions with GAMIg (Fig. 2B). Similar
results were obtained when purified B-CLL cells were subjected to CD5
cross-linking (Fig. 2C). These results indicates that
CD5-mediated A-SMase activity is a property not only of lymphoblastoid
cells but also of normal cells. Notably, the activation of neutral
SMase was explored on CD5 cross-linked normal and leukemic cells, and
we could not detect products of SM breakdown (data not shown).
|
The need for PC-PLC activation for CD5-mediated A-SMase
activity was explored by using the xanthogenate tricyclodecan-9-yl
(D609), which is an specific inhibitor of PC-PLC (28). As shown in Fig. 3A, pretreatment of Jurkat
cells with D609 (50 µg/ml) resulted in a complete blockade of
CD5-mediated A-SMase activation. A-SMase activity was
unaffected by pretreatment of Jurkat cells with wortmannin, a PI
3-kinase inhibitor. These findings indicate that CD5-induced activation
of PC-PLC probably couples to the production of the second messenger
ceramide by activation of A-SMase. To further explore this functional
coupling we mapped the CD5 cytoplasmic region involved in A-SMase
activation by using Jurkat 2G5 (CD5-) cell transfectants
stably expressing cytoplasmic tail mutant CD5 molecules (Fig. 1
). As
expected, the analysis of transfectants expressing wild-type CD5
(CD5.WT) showed that they display the ability to activate A-SMase (Fig. 3B), with kinetics and magnitude similar to those of Jurkat
JE6.1 cells (see Fig. 2A). In contrast, 2G5 transfectants
expressing CD5 molecules devoid of either most of their
cytoplasmic domain (CD5.K384stop) or only a C-terminal
23-amino acid region (CD5.H449stop) failed to induce
A-SMase activity. This is in line with our previous findings
on PC-PLC activation (22) and indicates that the C-terminal
23-amino acid region is not only necessary but is also
sufficient to activate the A-SMase pathway. To further narrow
this region we analyzed CD5 mutant molecules carrying either single
(Y463
A) or double (S459A and S461G) amino acid substitutions
(CD5.Y463A and CD5.S459A,S461G, respectively). The Y463 residue is
phosphorylated in response to CD3 and CD5 cross-linking (our
unpublished observations), and this may allow src homology
domain 2-containing proteins to bind to and subsequently activate the
PC-PLC/A-SMase pathway. The S459 and S461 residues are the sites for
CKII-mediated constitutive phosphorylation of CD5 and are critical for
CD5-mediated PC-PLC activation (15). As shown in Fig. 3B,
the CD5.Y463A transfectant retained its ability to signal CD5-dependent
A-SMase activity, although it was reduced compared with that of CD5.WT.
In contrast, the CD5.S459A,S461G transfectant was completely defective
in signaling CD5-mediated A-SMase activation. These results
indicate that S459 and S461, but not Y463, are critical residues for
CD5-mediated A-SMase activation.
|
activation
Ceramide generated by SMase activation has been reported to be a
positive regulator of PKC- activity (29, 30). This fact prompted us
to analyze whether PKC- is also involved in CD5 signaling. Jurkat
cells were stimulated for different times with the anti-CD5 Cris-1
mAb, and PKC- was immunoprecipitated from the extracts and assayed
for in vitro kinase activity. As shown in Fig. 4A, CD5 triggering increased
the basal activity of PKC- in Jurkat JE6.1 cells. The activity
peaked at 5 min and declined by 10 min. Stimulation of
transfectants carrying CD5.WT induced a CD5-dependent activation of
PKC-, with similar kinetics (not shown). These kinetics are
compatible with a model in which the PC-PLC/A-SMase pathway
(peaks at 2 min) activates PKC- (peaks at 5 min). To further address
the role played by the PC-PLC/A-SMase pathway in the activation of
PKC-, we performed kinase assays on different Jurkat 2G5 cell
transfectants. The analysis of transfectants expressing
CD5.H449stop, which is missing the C-terminal region
critical for A-SMase activation, also showed PKC- activation similar
to that found in JE6.1 cells and CD5.WT transfectants (Fig. 4B). This indicates that the C-terminal cytoplasmic region
of CD5 involved in PC-PLC/A-SMase activation is dispensable to
CD5-induced activation of PKC-. This was further supported by the
analysis of CD5.WT transfectants pretreated with D609 at doses (50
µg/ml) that completely inhibited the PC-PLC/A-SMase pathway (see
above). Consistently, the presence of D609 did not abolish the
CD5-induced PKC- activation. These findings indicate that other
upstream biochemical events are involved in CD5-induced PKC-
activation.
|
B
Ceramide and PKC- have been shown to be critically involved in
the activation of NF-B and some members of the MAPK family (25). To
determine whether CD5 triggering leads to activation of NF-B, we
stimulated Jurkat JE6.1 cells transfected with a luciferase reporter
plasmid harboring three copies of the B enhancer from the long
terminal repeat of HIV (26). Our results show that CD5 stimulation,
either alone or in combination with CD3 and CD28 stimulation, does not
result in B-dependent promoter activity (Fig. 5). Similarly, CD5 stimulation does not
increase the B-dependent promoter activity induced by PMA plus the
calcium ionophore A23187 (Fig. 5). Identical results were obtained
regardless of the anti-CD5 mAb used (data not shown). As expected
from previous reports, CD28 stimulation of Jurkat cells did not result
in NF-B activation, either alone or in combination with CD3
stimulation, but clearly increased the NF-B activation induced by
PMA plus A23187 (27).
|
A,
CD5 stimulation resulted in ERK2 phosphorylation, which was maximal at
5 min and declined at 15 min. Stimulation of Jurkat cells with PMA (10
ng/ml) for 5 min served as a positive control. Similarly, increased JNK
activity was observed following CD5 stimulation, either alone or in
combination with simultaneous CD3 stimulation (Fig. 6B).
Taken together, these results indicate that different MAPK cascades are
involved in the CD5-induced signaling pathway.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
, and members of the MAPK family, namely MEK and JNK. This
represents the first reported evidence for the involvement of these
enzymatic activities in the CD5 signaling pathway. The CD5-mediated
activation of A-SMase and PKC- reported here is consistent with our
earlier finding that CD5 triggering induces phosphoinositide turnover-
and Ca2+-independent PKC activation (9), as well as DAG
release via PC-PLC and de novo synthesis (22). DAG generated through
PC-PLC is known to trigger activation of A-SMase (23, 24). In turn,
ceramide generated by A-SMase contributes to the activation of both
PKC- (29, 30), a Ca2+-, DAG-, and phorbol
ester-independent atypical PKC isoform, and members of the MAPK
cascades (25). Because TCR/CD3 triggering does not induce PC-PLC and
A-SMase activation, our data confirm CD5 as a signal transducing
molecule with its own second messenger cascade that collaborates with
the TCR/CD3 complex in eliciting optimal T cell responses.
Ceramide accumulation has been reported for a number of extracellular
inducers, including 1,25-dihydroxyvitamin D3, TNF-
,
endotoxin, IFN-, IL-1, Fas ligands, CD28, dexamethasone, retinoic
acid, progesterone, ionizing irradiation, chemotherapeutic agents,
heat, and nerve growth factor (25). From now on, CD5 should be added to
this list. Ceramide appears to be involved in the diverse outcomes
(from cell proliferation and differentiation to apoptosis and growth
arrest) reported for some of these inducers (25). Ceramide can be
generated by the activation of two forms of sphingomyelinases, a
membrane-bound neutral SMase and a DAG-dependent endo/lysosomal A-SMase
(23). These two forms are triggered independently from each other and
lead to different signaling pathways (23). The simultaneous, albeit
independent, activation of both A-SMase and N-SMase has been reported
following engagement of CD95, TNF receptor I (TNFRI), and IL-1R (23, 24, 31). The activation of A-SMase in the absence of neutral SMase
activation has been reported for CD28 (27) and is also shown here for
CD5. This indicates that signaling through the CD5 and CD28 receptors
differ from that of other inducers of ceramide release.
The coupling of PC-PLC and A-SMase activation has been reported for the signaling pathways of TNFRI, CD95, and IL-1R (23, 24, 31), but not other receptors that also induce PC-PLC activation, such as IL-4R (32). The data presented here point to the functional coupling of these two phospholipases in the CD5 signaling pathway: 1) the kinetics of CD5-mediated A-SMase activation closely parallel those of DAG production (22); 2) D609, a specific inhibitor of PC-PLC, completely abrogates CD5-mediated A-SMase activation; and 3) the CD5 cytoplasmic residues critical for A-SMase activation are the same as those previously reported for PC-PLC activation (15, 22). In this regard, it is surprising that only partial effects in abrogating PC-PLC/A-SMase activation induced by Y463 replacement are found compared with the dramatic effects seen after replacement of the C-terminal serine cluster (S458, S459, and S461). It can be hypothesized that constitutive phosphorylation of serine residues by CKII (14, 15) provides the C-terminal region of CD5 with the optimal conformation for PC-PLC/A-SMase activation to proceed. The inducible phosphorylation of Y463 may also assist in optimizing this activation.
Our data indicate that PKC- activation following CD5 engagement is
not fully dependent on PC-PLC/A-SMase activation. PKC- activation
can still be achieved either in the presence of D609 or by CD5
molecules lacking the C-terminal region critical for PC-PLC/A-SMase
activation. This is not surprising, since the remarkable complexity of
PKC- regulation is achieved through a delicate balance involving
different modulators: 1) ceramide (29, 30), PI 3-K (33), and
phosphatidic acid (34), which activate PKC-; and 2) arachidonic acid
(29) and the product of the par-4 gene (35), which inhibit
PKC-. Therefore, the identification of upstream activators of
PKC- different from ceramide should be investigated in the CD5
signaling pathway. Although controversial, the recently reported
involvement of PI 3-K in signaling through CD5 (18, 20, 36) could be
claimed as an alternative mechanism for PKC- activation. This would
involve a CD5 cytoplasmic region different from the C-terminal and,
very likely, encompassing the immunoreceptor tyrosine-based activation
motif-like motif (18). Based on its bifunctional modulation by lipid
second messengers, it has been suggested that PKC- acts as a
molecular switch between mitogenic and apoptotic signals (29). However,
the role of PKC- in T cell activation remains controversial. PKC-
has been reported to control IL-2-mediated T cell proliferation and
cytoskeleton organization (37). Experiments in oocytes and fibroblasts
have suggested a role for PKC- in NF-B induction and mitogenic
signals (26, 38), but the expression of constitutively active PKC-
or the overexpression of PKC-wt was not sufficient for NF-B,
AP-1, and NF-AT-1 trans-activation in T cells (39). This
could reflect the fact that the mechanisms to regulate the activity of
these transcriptional factors in T cells and fibroblast differ. In the
present study we could not detect NF-B-dependent transcriptional
activity following CD5 stimulation of Jurkat cells. However, we
detected MEK activity, another event downstream of PKC- (26).
It has been reported that the CD5 signaling pathway up-regulates the
DNA binding activity of AP-1 but not that of NF-B (17). AP-1 is a
heterodimer composed of different Fos and Jun family members that can
bind to the IL-2 promoter alone or complexed with NF-AT. The AP-1
activity is regulated at both transcriptional and post-translational
levels by members of the MAPK family (JNK, ERK, and p38), the Janus
kinase family, CaMK, and protein kinase A. Based on results obtained
with specific kinase inhibitors, the above-mentioned report claims that
CaMK IV, but not the MAP kinases ERK, JNK, and p38, play a role in the
CD5-mediated induction of AP-1 activity (17). This contradicts our
results and the previously reported ability of CaMK IV to activate JNK,
ERK, and p38 (40). Furthermore, JNK and p38 are downstream effectors of
Rac1, which have bee recently reported to be essential to the CD5
costimulatory signal pathway leading to up-regulation of the IL-2
promoter activity (20). In fact, we show that JNK is activated during
CD5 stimulation of Jurkat cells. Ceramide, either directly or
indirectly, is known to activate JNK, thereby affecting the activity of
c-Jun (25), and its possible contribution should be taken into
consideration. The reported conflicting results may reflect the use of
different cell systems (purified peripheral T cells vs Jurkat T cells),
stimulation conditions (PHA, anti-CD28, and anti-CD5 vs
anti-CD5 alone), and parameters to evaluate kinase activity (IL-2
secretion or IL-2 promoter activity vs in vitro kinase assays).
The lymphocyte surface receptor CD5, first considered as a
costimulatory molecule in mature T cells, is now known to also be a
negative regulator of Ag receptor-mediated signals in thymocytes and
B1a cells (10, 11). Therefore, CD5 seems to behave as a dual receptor,
providing either positive or negative signals depending on the cell
type and the maturational stage. The CD5 signaling pathway is only
beginning to be understood, and the molecular basis for its ability to
modulate TCR and BCR signals has not yet been defined. The work
reported here shows that activation of A-SMase, PKC-, and MAPK
cascade members are components of the intracellular signaling pathway
initiated by CD5 ligation. These enzymatic activities are triggered by
a number of cell receptors and have been largely implicated as key
elements in the control of cellular processes as diverse as
differentiation, proliferation, and apoptosis (25). The final outcome
of these enzyme activities depends on factors such as the cell type and
their integration with other signals originating from the same receptor
or other receptors concurrently engaged. Thus, the involvement of
A-SMase, PKC-, and MAPK family members in the CD5 signaling pathway
could also be on the basis of the modulatory effects of CD5 on
lymphocyte activation and differentiation. The dynamic balance between
the opposing effects attributed to the ERK and JNK pathways (41) may be
of special relevance.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
2 Address correspondence and reprint requests to Dr. Francisco Lozano, Servei d’Immunologia, Institut D’Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Villarroel 170, 08036 Barcelona, Spain. E-mail address:
3 Abbreviations used in this paper: CKII, casein kinase II; CaMK, Ca2+/calmodulin-dependent kinase; PI 3-K, phosphatidylinositol 3-kinase; PKC, protein kinase C; DAG, 1,2-diacylglycerol; PC-PLC, phosphatidylcholine-dependent phospholipase C; TNFRI, TNF receptor I; A-SMase, acidic sphingomyelinase; SM, sphingomyelin; MAPK, mitogen-activated protein kinase; MEK, MAPK kinase; JNK, c-Jun NH2-terminal kinase; D609, xanthogenate tricyclodecan-9-yl; GAMIg, goat antiserum to mouse Ig; ERK, extracellular signal-regulated kinase.
Received for publication November 4, 1998. Accepted for publication February 8, 1999.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
chain/CD3 and protein-tyrosine kinases p56lck and p59fyn. Proc. Natl. Acad. Sci. USA 89:9311. molecules in human CD3+ thymocytes. J. Immunol. 159:3739.[Abstract]
. Eur. J. Immunol. 28:2167.[Medline]
. EMBO J. 14:6157.[Medline]
is a molecular switch in signal transduction of TNF-, bifunctionally regulated by ceramide and arachidonic acid. EMBO J. 14:1961.[Medline]
isoform is critical for B-dependent promoter activation by sphingomyelinase. J. Biol. Chem. 269:19200. isozyme of protein kinase C by phosphatidylinositol 3,4,5-triphosphate. J. Biol. Chem. 268:13. overexpressed in COS cells: comparison with other protein kinase C isotypes and other acidic lipids. Biochem. J. 304:1001.
-like protein family, phosphatidylinositol 3-kinase, and protein kinase C-. J. Immunol. 158:1516.[Abstract]
isoform is critical for mitogenic transduction. Cell 74:555.[Medline]
, -
, and - in T cell activation. J. Biol. Chem. 270:9833.This article has been cited by other articles:
|
|
 |
|
  E. Gulbins and P. L. Li Physiological and pathophysiological aspects of ceramide Am J Physiol Regulatory Integrative Comp Physiol, January 1, 2006; 290(1): R11 - R26. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Arman, J. Calvo, M. E. Trojanowska, P. N. Cockerill, M. Santana, M. Lopez-Cabrera, J. Vives, and F. Lozano Transcriptional Regulation of Human CD5: Important Role of Ets Transcription Factors in CD5 Expression in T Cells J. Immunol., June 15, 2004; 172(12): 7519 - 7529. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tierens, J. Delabie, A. Malecka, J. Wang, A. Gruszka-Westwood, D. Catovsky, and E. Matutes Splenic Marginal Zone Lymphoma with Villous Lymphocytes Shows On-Going Immunoglobulin Gene Mutations Am. J. Pathol., February 1, 2003; 162(2): 681 - 689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. Zhou, C. M. Lauderback, T. Yu, S. A. Brown, D. A. Butterfield, and J. S. Thompson D609 Inhibits Ionizing Radiation-Induced Oxidative Damage by Acting as a Potent Antioxidant J. Pharmacol. Exp. Ther., July 1, 2001; 298(1): 103 - 109. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. H. Cantor, S. M. Pritchard, F. Dequiedt, L. Willems, R. Kettmann, and W. C. Davis CD5 Is Dissociated from the B-Cell Receptor in B Cells from Bovine Leukemia Virus-Infected, Persistently Lymphocytotic Cattle: Consequences to B-Cell Receptor-Mediated Apoptosis J. Virol., February 15, 2001; 75(4): 1689 - 1696. [Abstract] [Full Text]
|
|
|
|
|
|
J. M. Vila, J. Calvo, L. Places, O. Padilla, M. Arman, I. Gimferrer, C. Aussel, J. Vives, and F. Lozano Role of Two Conserved Cytoplasmic Threonine Residues (T410 and T412) in CD5 Signaling J. Immunol., January 1, 2001; 166(1): 396 - 402. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Menne, J. P. H. Lauritsen, J. Dietrich, J. Kastrup, A.-M. K. Wegener, N. Odum, and C. Geisler Ceramide-Induced TCR Up-Regulation J. Immunol., September 15, 2000; 165(6): 3065 - 3072. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Gary-Gouy, P. Bruhns, C. Schmitt, A. Dalloul, M. Daeron, and G. Bismuth The Pseudo-immunoreceptor Tyrosine-based Activation Motif of CD5 Mediates Its Inhibitory Action on B-cell Receptor Signaling J. Biol. Chem., January 7, 2000; 275(1): 548 - 556. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. Kirschnek, F. Paris, M. Weller, H. Grassme, K. Ferlinz, A. Riehle, Z. Fuks, R. Kolesnick, and E. Gulbins CD95-mediated Apoptosis in Vivo Involves Acid Sphingomyelinase J. Biol. Chem., August 25, 2000; 275(35): 27316 - 27323. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Grassme, A. Jekle, A. Riehle, H. Schwarz, J. Berger, K. Sandhoff, R. Kolesnick, and E. Gulbins CD95 Signaling via Ceramide-rich Membrane Rafts J. Biol. Chem., June 1, 2001; 276(23): 20589 - 20596. [Abstract] [Full Text] [PDF]
|
|
| ||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
