|
|
 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 10 (May 15), 2000:
pp. 3199-3203
IMMUNOBIOLOGY
RasGRP links T-cell receptor signaling to Ras
Julius O. Ebinu,
Stacey L. Stang,
Christine Teixeira,
Drell A. Bottorff,
Jonathan Hooton,
Peter M. Blumberg,
Michele Barry,
R. Chris Bleakley,
Hanne L. Ostergaard, and
James C. Stone
From the Departments of Biochemistry and Immunobiology, University
of Alberta, Edmonton, Alberta, Canada; and the Laboratory of
Cellular Carcinogenesis and Tumor Promotion, National Cancer Institute,
Bethesda, MD.
 |
Abstract |
Stimulation of the T-cell receptor (TCR) alters a number of
intracellular signaling pathways including one that involves protein tyrosine kinases, phospholipase C- 1 (PLC-1), diacylglycerol (DAG), and calcium messengers. By a divergent pathway, TCR-stimulated protein tyrosine kinase activity is thought to result independently in
recruitment of the Ras activator Sos to the plasma membrane, leading to
Ras activation. Here we show that RasGRP, a Ras activator that contains
calcium-binding EF hands and a DAG-binding domain, is expressed in T
cells. A PLC-1 inhibitor diminished activation of Ras following TCR
stimulation. Membranes from TCR-stimulated Jurkat T cells exhibited
increased RasGRP and increased Ras-guanyl nucleotide association
activity that was inhibited by antibodies directed against RasGRP.
Overexpression of RasGRP in T cells enhanced TCR-Ras-Erk signaling and
augmented interleukin-2 secretion in response to calcium ionophore plus
DAG analogues phorbol ester myristate or bryostatin-1. Thus, RasGRP
links TCR and PLC-1 to Ras-Erk signaling, a pathway amenable to
pharmacologic manipulation.
(Blood. 2000;95:3199-3203)
© 2000 by The American Society of Hematology.
| |
Introduction |
A key step in T-cell activation is the physical
interaction between the T-cell receptor (TCR) on the surface of the T
cells and peptide antigen presented in the context of a major
histocompatibility molecule on an antigen-presenting cell. This
interaction results in the rapid modulation of several biochemical
processes within the T cells that ultimately lead to T-cell
proliferation.1-3 TCR-proximal events include the
activation of cytoplasmic protein tyrosine kinases such as the
CD4-associated protein tyrosine kinase lck. Tyrosine phosphorylation of
the intracellular domains of the small TCR subunits by lck leads to the
recruitment to the TCR of a second protein tyrosine kinase,
ZAP-70.4-6 TCR-associated ZAP-70 phosphorylates adaptor
proteins such as LAT and SLP-76, which may be complexed at the plasma
membrane.7-10
Within minutes of TCR stimulation, several divergent signaling systems
are thought to come into play. Phospholipase C-1 (PLC-1) is
activated by a combination of tyrosine phosphorylation and recruitment
to the tyrosine phosphorylated adaptor proteins.11 Cleavage
of membrane phosphoinositides by PLC-1 generates membrane diacylglycerol (DAG) messenger, which activates protein kinase C (PKC).
PLC-1 also generates inositol triphosphate, which facilitates a rise
in free cytoplasmic calcium, stimulation of the calcium-activated phosphatase calcineurin, and engagement of the nuclear factor of
activated T cells (NF-AT) transcription system.12
Independently, early protein tyrosine kinase activity is thought to
activate the small GTPase Ras by promoting the formation of Ras bound
to GTP. Ras-GTP activates the Raf-Mek-Erk protein kinase cascade and
this pathway controls the level of the Jun/Fos dimeric transcription
factor known as AP1.13 The coordinated activation of AP1
transcription factors by the Ras-Erk signaling system and the NF-AT
transcription factor results in efficient transcription of the
interleukin-2 (IL-2) gene, the protein product of which drives T-cell
proliferation.12 Additional signaling systems contribute to
the synthesis of the IL-2 receptor, changes in cell shape, and other
aspects of T-cell activation.14-16
Despite considerable effort, the mechanism whereby Ras is activated
after TCR stimulation has not been fully elucidated. In principle, the
equilibrium between the GDP-bound "off" and GTP-bound "on"
states of Ras could be regulated by controlling the rates of GTP
hydrolysis and guanyl nucleotide exchange. The hydrolysis reaction is
controlled by GTPase activating proteins (GAPs). The exchange rate is
limited by the activity of guanyl nucleotide exchange factors (GEFs).
Early work with T cells indicated that Ras activation following TCR
stimulation involved a PKC-dependent inhibition of Ras
GAPs.17-19 The ability of the DAG analogue phorbol ester
myristate (PMA) to activate Ras in T cells has also been attributed to
PKC-dependent inhibition of Ras GAPs. However, in most cell types, Ras
is positively regulated by the recruitment of Ras GEFs such as Sos to
the plasma membrane through tyrosine phosphorylated adaptor
proteins.20,21 The results from a number of studies suggest
that Sos may activate Ras in T cells by such a
mechanism.22-24
We recently described a novel Ras GEF called RasGRP (Ras guanyl
nucleotide releasing protein25). In addition to the
catalytic domain responsible for catalyzing nucleotide release, RasGRP
contains a pair of calcium-binding EF hands and a DAG-binding domain.
Treatment of engineered fibroblasts with PMA resulted in increased
association of RasGRP with membranes and Ras activation.25
Although normal expression was initially detected only in brain,
subsequent studies revealed that RasGRP RNA was expressed in a variety
of blood cells including T cells.26,27 These observations
led to the hypothesis that TCR stimulation, PLC-1 activity, and DAG
and possibly calcium messengers are linked by RasGRP to Ras-Erk signaling.
| |
Materials and methods |
Antibodies and plasmids
H176 is derived from rabbits immunized with the amino-terminal rat
RasGRP peptide (residues 1-15). J32 was raised in rabbits by injecting
the catalytic domain of rat RasGRP (residues 49-473); these antibodies
react with both rat and human RasGRP in an immunoblot protocol.
Antibodies were purified by affinity selection using immobilized
recombinant rat RasGRP. Full-length human RasGRP complementary DNA
(cDNA) was cloned into the SalI site of
pBMGNeo.28 The plasmid was introduced into Jurkat T
cells by electroporation and Neo+ cells were selected in 1 mg/mL G418.
Detection of RasGRP by immunoblotting
Protein lysates were prepared from various cell lines and from
thymocytes freshly isolated from the thymus of a 6-week-old female
Balb/c mouse. H176 was used in an immunoblot protocol with goat
antirabbit IgG conjugated to horseradish peroxidase and enhanced chemiluminescence detection (ECL kit, Pierce, Rockford, IL) to detect
p90 RasGRP (100 µg/mL total cellular protein per sample).
Ras activation assay
Ras activation was assayed by comparing the amount of Ras-GTP that
could be precipitated using GST-Raf fusion protein and the amount of
total Ras in cell lysates as described,29 with minor
modification. Jurkat were grown to 1 × 106/mL in
RPMI containing 10% heat-inactivated fetal bovine serum plus
penicillin and streptomycin. Cells were incubated in herbimycin A (1.0 µg/mL) for 18 hours. Alternatively, cells were treated with U73343 or
U73122 (1.0 µmol/L) for the last 15 minutes of incubation. Cells were
then concentrated by centrifugation, suspended in 1.0 mL of the
original medium in a plastic centrifuge tube
(5 × 106 cells/assay), and incubated at 37°C
for 5 minutes. After addition of OKT3 at 10 µg/mL or 0.156 µg/mL
for a further 5 minutes, the cells were immediately centrifuged at
1400g for 2 minutes at 4°C. (Note that soluble OKT3 was
used throughout these experiments.) Cell pellets were then lysed in 25 mmol/L HEPES pH 7.5, 150 mmol/L NaCl, 1.0% NP40, 10% glycerol, 25 mmol/L NaF, 10 mmol/L MgCl2, 1.0 mmol/L EDTA, and 1.0 mmol/L sodium ortho-vanadate plus protease inhibitors. After
centrifugation to remove nuclei, 90% of each supernatant was incubated
with GST-RAF (Ras-binding domain) fusion protein bound to glutathione
beads to collect GTP-bound Ras. Bead-associated Ras was detected using
an anti-K-ras antibody (Santa Cruz no. F234, Santa Cruz, CA) in an
immunoblotting protocol. The remaining 10% of each lysate was probed
with the anti-Ras antibody to verify that similar amounts of total Ras
were present in each lysate and with phospho-Erk antibody (New England
Biolabs no. 9101, Beverly, MA) to assess the level of Erk activation.
Inhibitors were purchased from Calbiochem (San Diego, CA).
Subcellular fractionation
Jurkat T cells were suspended in hypotonic buffer and disrupted in a
glass homogenizer.25 After removing nuclei and unbroken cells by centrifugation at 2000g, cell homogenates were
separated into P100 and S100 by ultracentrifugation at
100 000g. For detection of RasGRP, samples were resolved by
sodium dodecyl sulfate-polyacrylamide gel electrophoresis (SDS-PAGE)
and immunoblotted with H176 IgG.
Membrane Ras-guanyl nucleotide association assay
To assay guanyl nucleotide association with membrane-bound Ras,
membrane fractions were suspended in 20 mmol/L Tris pH 7.5, 100 mmol/L
NaCl, 1 mmol/L MgCl2 (2.5 × 105 cell
equivalents/µL). Membranes (25 µL) were then incubated with 1 µL
[ 32P]GTP (3000 Ci/mmol final concentration 66 nmol/L)
in a final volume of 50 µL. After incubation at 30°C for 1 minute
to allow exchange of resident guanyl nucleotide with the radiolabeled
GTP, the reaction was diluted in ice-cold buffer (50 mmol/L Tris pH 7.5, 150 mmol/L NaCl, 20 mmol/L MgCl2, 0.5% v/v NP40)
containing 1 µg anti-Ras antibody Y13-259. After incubation at
0°C for 1 hour, Ras-guanyl nucleotide complexes were recovered
using protein A-Sepharose beads coated with rabbit antirat IgG. Guanyl
nucleotide was released by heating at 80°C in 1.0 mol/L potassium
phosphate (pH 3.4). Following chromatography of polyethylenimine
plates, total guanyl nucleotide (GTP plus GDP) was quantified by
phosphor-imager analysis. Background values obtained when no Y13-259
antibody was present were used to correct the experimental values. To
determine the maximal degree of Ras activation in these preparations,
membranes were exposed to 5.0 mmol/L EDTA for 5 minutes at 30°C
followed by addition of excess MgCl2, before lysis and
precipitation. To demonstrate the specificity of the above assay,
membrane preparations were preincubated with antibodies (J32) raised
against the catalytic domain of RasGRP (residues 49-473) or with
preimmune antibodies from the same rabbit. To demonstrate that J32
antibodies specifically inhibited RasGRP, exchange assays were
performed with purified proteins in buffer containing 20 mmol/L Tris pH
7.5, 100 mmol/L NaCl, 1.0 mmol/L DTT, 1.0 mmol/L MgCl2,
10% v/v glycerol, and either 1.6 pmol recombinant full-length Sos or
1.96 pmol RasGRP catalytic domain. These low amounts of Ras GEF were
used to increase the likelihood that the antibody was in molar excess.
Total IgG was 62 pmol/reaction but the amount of neutralizing antibody
is an unknown fraction of the total.
IL-2 assays
Where indicated, cells were incubated with 5.0 µmol/L
CdCl2 for 24 hours to induce RasGRP expression from the
metallothionein promoter. Cells (5 × 105) of each
type were then exposed in 1.0 mL fresh medium to calcium ionophore and
DAG agonist for a further 48 hours. IL-2 in supernatants was measured
using a colorimetric cell survival bioassay using the IL-2-dependent
HT2 mouse T-cell line and units were defined as
described.30,31
| |
Results |
Using an antibody (H176) directed against the amino-terminal peptide
sequence of RasGRP, we documented expression of this Ras activator in a
variety of human and mouse T-cell lines, but not in other cell types
(Figure 1). RasGRP was also detected in primary mouse thymocytes. As controls, we showed that p90 RasGRP was
present in rat2 cells engineered to express human RasGRP cDNA, but not
in parental rat2 cells.
View larger version (15K):
[in this window]
[in a new window]
| Fig 1.
RasGRP expressed in T cells.
Protein lysates were prepared from T-cell lines (T; Jurkat, human acute
T-cell leukemia; ADOH, mouse T-helper cell hybridoma; BW5147, mouse
T-cell lymphoma; SAKR, mouse T-cell lymphoma; EL4, mouse T-cell
lymphoma; CEM, human acute T-cell lymphoblastic leukemia; YT-INDY,
human NK-like T-cell leukemia; PEER, human T-cell lymphoblastic
leukemia; MOLT4, human acute lymphoblastic T-cell leukemia), and from
non-T-cell lines (non-T: FaDu, human pharynx squamous cell carcinoma;
B65, mouse neuroblastoma; ED27, human chroriocarcinoma; MCF10A, human
mammary epithelium; SK28 and WM39, human melanoma). Freshly isolated
mouse thymocyctes (Th) were also examined. As controls, we studied rat2
cells and rat2 cells engineered to express RasGRP. Protein extracts
were resolved by SDS/PAGE followed by immunoblotting with an antibody
(H176) directed against the amino-terminus of RasGRP.
|
|
Jurkat T cells can be stimulated with antibodies such as OKT3, which
recognizes the extracellular region of the  chain of CD3, a
component of TCR. Treatment with soluble OKT3 activates Ras within 5 minutes in Jurkat T cells. The tyrosine kinase inhibitor herbimycin A
interferes with early T-cell signaling events, including Ras
activation, probably by inhibiting lck and ZAP-70.32 We confirmed that herbimycin A strongly diminished Ras activation (Figure
2). The compound U73122 has been shown to
inhibit PLC-1 and to block the proliferative response in stimulated
T cells.33 We found that U73122 diminished OKT3-stimulated
Ras activation in Jurkat T cells. Inhibition was 2.8-fold when a
saturating concentration of OKT3 was used and 5.3-fold when a
suboptimal concentration of OKT3 was used. The specificity of this
inhibition was demonstrated by showing that the inert analogue U73343
had no effect.
View larger version (47K):
[in this window]
[in a new window]
| Fig 2.
TCR-stimulated Ras activation in Jurkat T cells and the
effects of pharmacologic inhibitors.
Jurkat T cells were preincubated with herbimycin A (protein tyrosine
kinase inhibitor), U73343 (inert analogue) or U73122 (PLC-1
inhibitor), and then stimulated with OKT3 at either a saturating
concentration (10 µg/mL) or at a suboptimal concentration (0.156 µg/mL). Cell lysates were assayed for Ras-GTP using GST-Raf affinity
selection followed by immunoblotting to detect precipitated Ras.
Phospho-Erk and total Ras in lysates were also detected using
immunoblot methods.
|
|
Using subcellular fractionation techniques, RasGRP from untreated cells
was found in both the soluble and particulate fractions. After TCR
stimulation, a reproducible (n = 7) decrease in the relative amount
of soluble RasGRP was detected. In a time-course experiment, this
change in RasGRP fractionation behavior paralleled the activation of
Ras (Figure 3A and 3B).
View larger version (27163220K):
[in this window]
[in a new window]
| Fig 3.
RasGRP in membranes of activated T cells.
(A) In a time-course experiment, Jurkat T cells were stimulated with
OKT3 for various times and aliquots were assayed for Ras-GTP and total
Ras using immunoblotting methods. (B) Homogenates of Jurkat T cells
from the various time points were separated into particulate (P) and
soluble (S) fractions and RasGRP was immunoblotted with the H176
anti-RasGRP peptide antibody. (C) Membranes from untreated cells, or
from cells treated for 10 minutes with OKT3, were assayed for their
ability to promote transfer of exogenous guanyl nucleotide to
membrane-bound Ras and the sensitivity of this reaction to antibodies
raised against the catalytic domain of RasGRP was determined. Membranes
were preincubated with IgG prepared from immune (I) or preimmune
(pre-I) serum for 12 minutes at 30°C, then
[32P]GTP was added for 1 minute. Ras was
then extracted with detergent and precipitated with an anti-Ras
monoclonal antibody. Coprecipitated, Ras-associated guanyl nucleotides
were resolved by chromatography and quantified. Representative
chromatographic data are shown. The graphed values are the average of
triplicate assays. Values were normalized to the value obtained when
full association was achieved by incubation with EDTA, followed by
addition of excess MgCl2 to stabilize the Ras-guanyl
nucleotide complex before immune-precipitation. (D) In vitro Ras guanyl
nucleotide exchange reactions were performed with recombinant Sos and
RasGRP in the presence of IgG to demonstrate the specificity of the J32
antibodies.
|
|
Stimulation of Jurkat T cells with OKT3 also resulted in a prompt
5.9-fold increase in the ability of subsequently isolated membranes to
support the transfer of [32P]GTP to
endogenous, membrane-bound Ras (Figure 3C). In both the stimulated and
untreated membranes, much of this newly associated guanyl nucleotide
was converted to GDP during the course of the reaction, a phenomenon
that we attribute to the presence of Ras GAPs in these membrane
preparations. Ras is constitutively associated with the plasma membrane
and we found TCR stimulation does not affect the amount of Ras in
T-cell membrane preparations (data not shown). Significantly, we found
that stimulated labeling of Ras could be blocked by adding purified
antibodies (J32) directed against RasGRP catalytic domain (Figure 3C).
In control experiments with purified proteins in vitro, we demonstrated
that J32 antibodies specifically inhibit the Ras GEF activity of
recombinant RasGRP but not that of Sos (Figure 3D).
To assess the effects of excess RasGRP on TCR signaling, Jurkat T cells
were engineered to overexpress the human RasGRP cDNA using a bovine
papilloma-based vector with an inducible promoter (Figure
4A). Overexpression of RasGRP resulted in
higher OKT3-induced levels of Ras-GTP and Ras activation was relatively
sustained, compared to the case with normal RasGRP levels (Figure 4B).
Overexpression also modestly enhanced acute activation of Ras by PMA.
The level of phospho-Erk closely paralleled the level of Ras-GTP in
this experiment. In a separate experiment, we examined the effects of
RasGRP overexpression on the level of Erk phosphorylation achieved at
various concentrations of OKT3. RasGRP overexpression increased the
absolute amount of phosphorylated Erk observed at a saturating concentration of stimulating antibody and it decreased the
concentration of OKT3 required to elicit a given level of Erk
phosphorylation (Figure 4C).
View larger version (33292014K):
[in this window]
[in a new window]
| Fig 4.
TCR-Ras-Erk signaling and agonist-induced IL-2 secretion
in Jurkat T cells overexpressing RasGRP.
(A) Jurkat cells transformed with either the empty vector pBMGNeo (Neo)
or the same vector containing full-length human RasGRP (GRP) were
induced with 5.0 µmol/L CdCl2 for 24 hours, as indicated,
then examined for RasGRP expression by immunoblotting using the H176
antibody. (B) Cells expressing BMGNeo or RasGRP were induced with
CdCl2 for 24 hours then stimulated with either 50 ng/mL PMA
for 10 minutes or 0.156 µg/mL OKT3 for various periods. Cells were
then harvested, lysed, and assayed for Ras-GTP, phospho-Erk and total
Erk. (C) Cells from the same cultures as in (A) were stimulated with
various concentrations of OKT3 for 15 minutes at 37°C and then
directly lysed in SDS sample buffer. The lysates were then probed for
phospho-Erk. The bands representing phospho-Erk were quantified by
densitometry and plotted versus the concentration of OKT3. Samples were
also probed with an anti-Erk antibody to verify that similar amounts of
total Erk protein were present (data not shown). (D) Cells were induced
with CdCl2 as indicated for 24 hours then stimulated for 48 hours with the calcium ionophore A23187 (A, 0.5 µmol/L) and either
PMA (24 nmol/L) or bryostatin-1 (Bryo, 10 nmol/L). IL-2 in the medium
was then measured. Values are the average of quadruplicate samples,
with the standard error of the mean indicated.
|
|
Although TCR signaling can lead to IL-2 synthesis and secretion in a
normal T-cell response, Jurkat T cells do not synthesize IL-2 after
treatment with soluble OKT3. Conventionally, a calcium ionophore and a
DAG analogue such as PMA, which are thought to activate calcineurin and
PKC, respectively, are used to stimulate IL-2 in Jurkat T cells. We
found that RasGRP overexpressing Jurkat T cells produced substantially
more IL-2 than the control cells on dual stimulation (Figure 4D). This
effect was also seen with the combination of calcium ionophore and
bryostatin-1, a heterocyclic lactone that also acts as a DAG
analogue.34-37 Note that for each DAG analogue, the levels
of IL-2 measured roughly correlate with the levels of RasGRP expressed
in these cells (Figure 4A). Negligible IL-2 was detected in the medium
when no agonist or only 1 agonist was used (data not shown).
| |
Discussion |
The presence of RasGRP in T cells leads to the hypothesis that it
positively regulates Ras during TCR signaling. This hypothesis is
supported by the following observations: (1) TCR-induced Ras activation
is diminished by a PLC-1 inhibitor, (2) RasGRP is differentially
associated with membranes after TCR stimulation, (3) the increased Ras
guanyl nucleotide association activity in membranes from TCR-stimulated
cells is inhibited by anti-RasGRP antibodies, and (4) Jurkat T cells
that overexpress RasGRP are hypersensitive to TCR-Ras-Erk signaling and
hypersensitive to agonist-induced IL-2 secretion. These studies support
a model of T-cell signaling whereby receptor stimulation leads to
activation of PLC-1 followed by the generation of membrane DAG,
RasGRP membrane recruitment, and Ras activation. Our model may help
explain several puzzling facts about TCR signaling including the
observation that stimulation of PLC-1 by ectopically expressed
G-protein-coupled receptors leads to T-cell activation.38
One could propose that PLC-1-generated free cytoplasmic calcium
regulates RasGRP through its EF hands. However, we observed that RasGRP
can activate Ras in vivo even in the presence of EGTA plus BAPTA/AM,
compounds that sequester extracellular and intracellular calcium,
respectively (data not shown).
Diacylglycerol is known to activate PKC and independent evidence
indicates that PKC function is required for TCR
signaling.39 Indeed, PMA-stimulated PKC probably activates
phospholipase D, which can indirectly generate DAG at later stages of T
cell activation.40 Regardless of this complexity, the
demonstration here that DAG analogues can also directly activate RasGRP
and thereby promote Ras signaling in T cells is exciting. Bryostatins
activate PKC, have potent growth inhibitory effects on certain cell
types, and are currently being tested in clinical trials as
antineoplastic agents.41 Like PMA, however, bryostatin-1
also activates Ras in Jurkat T cells and in rat2 cells that ectopically
express RasGRP (Stang and Stone, unpublished data). Furthermore, in
this latter situation, bryostatin-1 activates Ras-Erk by a mechanism
that depends on the DAG-binding domain of RasGRP. Taken together, our results suggest that DAG analogues could be exploited to regulate RasGRP and thereby modulate the immune response.
It should be noted that Ras-Erk signaling is thought to play important
roles at a number of stages in the life of a T cell. Early growth and
maturation in the thymus are dependent on a pre-TCR complex42 and on Ras-Erk signaling.43,44 After
T-cell maturation, autocrine and paracrine action of IL-2 is thought to
contribute to Ras activation.45,46 RasGRP could facilitate
Ras activation during these stages, as well.
Our findings do not address the role of Sos in TCR signaling, nor do
they preclude a role for PKC down-regulation of Ras GAPs. Multiple
forms of Ras regulation might allow a common Ras switch to
differentially respond to diverse external stimuli and developmental cues, and thereby orchestrate distinct biochemical changes and biologic
responses. For example, the amplitude or duration of Ras signaling
might be varied according to the combination of regulatory mechanisms deployed.
| |
Acknowledgments |
We thank Gideon Bollag for recombinant Sos, Ed Chan for useful
suggestions, and Nancy Dower for careful reading of the manuscript.
| |
Footnotes |
Submitted November 10, 1999; accepted January 21, 2000.
Supported by grants to J.C.S., H.L.O., and R.C.B. from the Medical
Research Council and the National Cancer Institute of Canada.
Reprints: James C. Stone, Department of Biochemistry,
University of Alberta, Edmonton, Alberta, Canada T6G 2H7; e-mail jim.stone{at}ualberta.ca.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
References |
1.
Alberola-Ila J, Takaki S, Kerner JD, Perlmutter RM.
Differential signaling by lymphocyte antigen receptors.
Annu Rev Immunol.
1997;15:125-154[Medline]
[Order article via Infotrieve].
2.
Berridge MJ.
Lymphocyte activation in health and disease.
Crit Rev Immunol.
1997;17:155-178[Medline]
[Order article via Infotrieve].
3.
Henning SW, Cantrell DA.
GTPases in antigen receptor signaling.
Curr Opin Immunol.
1998;10:322-329[Medline]
[Order article via Infotrieve].
4.
Letourneur F, Klausner RD.
Activation of T cells by a tyrosine kinase activation domain in the cytoplasmic tail of CD3 .
Science.
1992;255:79-82[Abstract/Free Full Text].
5.
Chan AC, Iwashima M, Turck CW, Weiss A.
ZAP-70: a 70 kd protein-tyrosine kinase that associates with the TCR  chain.
Cell.
1992;71:649-662[Medline]
[Order article via Infotrieve].
6.
Iwishima M, Irving BA, van Oers NSC, Chan AC, Weiss A.
Sequential interactions of the TCR with two distinct cytoplasmic tyrosine kinases.
Science.
1994;263:1136-1139[Abstract/Free Full Text].
7.
Wardenburg JB, Fu C, Jackman JK, et al.
Phosphorylation of SLP-76 by the ZAP-70 protein-tyrosine kinase is required for T-cell receptor function.
J Biol Chem.
1996;271:19,641-19,644[Abstract/Free Full Text].
8.
Yablonski D, Kuhne MR, Kadlecek T, Weiss A.
Uncoupling of nonreceptor tyrosine kinases from PLC-1 in an SLP-76-deficient T cell.
Science.
1998;281:413-415[Abstract/Free Full Text].
9.
Clements JL, Yang B, Ross-Barta SE, et al.
Requirement for the leukocyte-specific adapter protein SLP-76 for normal T cell development.
Science.
1998;281:416-419[Abstract/Free Full Text].
10.
Zhang W, Sloan-Lancaster J, Kitchen J, Trible RP, Samelson LE.
LAT: the ZAP-70 tyrosine kinase substrate that links T cell receptor to cellular activation.
Cell.
1998;92:83-92[Medline]
[Order article via Infotrieve].
11.
Noh DY, Shin SH, Rhee SG.
Phosphoinositide-specific phospholipase C and mitogenic signaling.
Biochim. Biophys Acta.
1995;1242:99-113[Medline]
[Order article via Infotrieve].
12.
Crabtree GR.
Contingent genetic regulatory events in T lymphocyte activation.
Science.
1989;243:355-361[Abstract/Free Full Text].
13.
Su B, Karin M.
Mitogen-activated protein kinase cascades and regulation of gene expression.
Curr Opin Immunol.
1996;8:402-411[Medline]
[Order article via Infotrieve].
14.
Lowin-Kropf B, Shapiro VS, Weiss A.
Cytoskeletal polarization of T cells is regulated by an immunoreceptor tyrosine-based activation motif-dependent mechanism.
J Cell Biol.
1998;140:861-871[Abstract/Free Full Text].
15.
Stowers L, Yelon D, Berg LJ, Chant J.
Regulation of the polarization of T cells toward antigen-presenting cells by Ras-related GTPase CDC42.
Proc Natl Acad Sci U S A.
1995;92:5027-5031[Abstract/Free Full Text].
16.
Welte T, Leitenberg D, Dittel BN, et al.
STAT5 interaction with the T cell receptor complex and stimulation of T cell proliferation.
Science.
1999;283:222-225[Abstract/Free Full Text].
17.
Downward J, Graves JD, Warne PH, Rayter S, Cantrell DA.
Stimulation of p21ras upon T-cell activation.
Nature.
1990;346:719-723[Medline]
[Order article via Infotrieve].
18.
Bollag G, McCormick F.
Differential regulation of rasGAP and neurofibromatosis gene product activities.
Nature.
1991;351:576-579[Medline]
[Order article via Infotrieve].
19.
Izquierdo M, Downward J, Graves JD, Cantrell DA.
Role of protein kinase C in T-cell antigen receptor regulation of p21ras: evidence that two p21ras regulatory pathways coexist in T cells.
Mol Cell Biol.
1992;12:3305-3312[Abstract/Free Full Text].
20.
Buday L, Downward J.
Epidermal growth factor regulates p21ras through the formation of a complex of receptor, Grb2 adapter protein, and Sos nucleotide exchange factor.
Cell.
1993;73:611-620[Medline]
[Order article via Infotrieve].
21.
Egan SE, Giddings BW, Brooks MW, Buday L, Sizeland AM, Weinberg R.
Association of Sos Ras exchange protein with Grb2 is implicated in tyrosine kinase signal transduction and transformation.
Nature.
1993;363:45-51[Medline]
[Order article via Infotrieve].
22.
Ravichandran KS, Lee KK, Songyang Z, Cantley LC, Burn P, Burakoff SJ.
Interaction of Shc with the chain of the T cell receptor upon T cell activation.
Science.
1993;262:902-905[Abstract/Free Full Text].
23.
Li B-Q, Subleski M, Fusaki N, et al.
Catalytic activity of the mouse guanine nucleotide exchanger mSOS is activated by Fyn tyrosine protein kinase and the T-cell antigen receptor in T cells.
Proc Natl Acad Sci U S A.
1996;93:1001-1005[Abstract/Free Full Text].
24.
Nel AE, Gupta S, Lee L, Ledbetter JA, Kanner SB.
Ligation of the T-cell antigen receptor (TCR) induces association of hSos1, ZAP-70, phospholipase C-1, and other phosphoproteins with Grb2 and the -chain of the TCR.
J Biol Chem.
1995;270:18,428-18,436[Abstract/Free Full Text].
25.
Ebinu JO, Bottorff DA, Chan EYW, Stang SL, Dunn RJ, Stone JC.
RasGRP, a Ras guanyl nucleotide-releasing protein with calcium- and diacylglycerol-binding motifs.
Science.
1998;280:1082-1086[Abstract/Free Full Text].
26.
Kawasaki H, Springett GM, Toki S, et al.
A Rap guanine nucleotide exchange factor enriched highly in the basal ganglia.
Proc Natl Acad Sci U S A.
1998;95:13,278-13,283[Abstract/Free Full Text].
27.
Tognon CE, Kirk HE, Passmore LA, Whitehead IP, Der CJ, Kay RJ.
Regulation of RasGRP via a phorbol ester-responsive C1 domain.
Mol Cell Biol.
1998;18:6995-7008[Abstract/Free Full Text].
28.
Karasuyama H, Melcher F.
Establishment of mouse cell lines which constitutively secrete large quantities of interleukin 2, 3, 4 or 5, using modified cDNA expression vectors.
Eur J Immunol.
1988;18:97-104[Medline]
[Order article via Infotrieve].
29.
Taylor SJ, Shalloway D.
Cell cycle-dependent activation of Ras.
Curr Biol.
1996;6:1621-1627[Medline]
[Order article via Infotrieve].
30.
Mossman T.
Rapid colorimetric assay for cellular growth and survival: application to proliferation and cytotoxicity assays.
J Immunol Methods.
1983;65:55-63[Medline]
[Order article via Infotrieve].
31.
Hooton JWL, Gibbs C, Paetkau V.
Interaction of interleukin 2 with cells: quantitative analysis of effects.
J Immunol.
1985;135:2464-2473[Abstract].
32.
Ohtsuka T, Kaziro Y, Satoh T.
Analysis of the T-cell activation signaling pathway mediated by tyrosine kinases, protein kinase C, and Ras protein, which is modulated by intracellular cyclic AMP.
Biochim Biophys Acta.
1996;1310:223-232[Medline]
[Order article via Infotrieve].
33.
Vassilopoulos D, Smallridge RC, Tsokos GC.
Effects of an aminosteroid inhibitor of phospholipase C-dependent processes on the TCR-mediated signal transduction pathway in human T cells.
Clin Immunol Immunopathol.
1995;77:59-68[Medline]
[Order article via Infotrieve].
34.
Pettit GR, Herald CL, Doubek DL, Herald DL.
Isolation and structure of bryostatin 1.
J Am Chem Soc.
1982;104:6846-6848.
35.
Berkow RL, Kraft AS.
Bryostatin, a non-phorbol macrocyclic lactone, activates intact human polymorphonuclear leukocytes and binds to the phorbol ester receptor.
Biochem Biophys Res Commun.
1985;131:1109-1116[Medline]
[Order article via Infotrieve].
36.
Smith JB, Smith L, Pettit GR.
Bryostatins: potent, new mitogens that mimic phorbol ester tumor promoters.
Biochem Biophys Res Commun.
1985;132:939-945[Medline]
[Order article via Infotrieve].
37.
Kraft AS, Smith JB, Berkow RL.
Bryostatin, an activator of the calcium phospholipid-dependent protein kinase, blocks phorbol ester-induced differentiation of human promyelocytic leukemia cells HL-60.
Proc Natl Acad Sci U S A.
1986;83:1334-1338[Abstract/Free Full Text].
38.
Desai DM, Newton ME, Kadlecek T, Weiss A.
Stimulation of the phosphatidylinositol pathway can induce T-cell activation.
Nature.
1990;348:66-69[Medline]
[Order article via Infotrieve].
39.
Szamel M, Appel A, Schinzer R, Resch K.
Different protein kinase C isoenzymes regulate IL-2 receptor expression or IL-2 synthesis in human lymphocytes stimulated via the TCR.
J Immunol.
1998;160:2207-2214[Abstract/Free Full Text].
40.
Mollinedo F, Gajate C, Flores I.
Involvement of phospholipase D in the activation of transcription factor AP-1 in human T lymphoid Jurkat cells.
J Immunol.
1994;153:2457-2469[Abstract].
41.
Pluda JM, Chelson BD, Philips PH.
Clinical trials referral resource: clinical trials using bryostatin-1.
Oncology (Huntington).
1996;10:740-742[Medline]
[Order article via Infotrieve].
42.
Malissen B, Malissen M.
Functions of TCR and pre-TCR subunits: lessons from gene ablation.
Curr Opin Immunol.
1996;8:383-393[Medline]
[Order article via Infotrieve].
43.
Crompton T, Gilmour KC, Owen MJ.
The MAP kinase pathway controls differentiation from double-negative to double-positive thymocyte.
Cell.
1996;86:243-251[Medline]
[Order article via Infotrieve].
44.
Swan KA, Alberola-Ila J, Gross JA, et al.
Involvement of p21ras distinguishes positive and negative selection in thymocytes.
EMBO J.
1995;14:276-285[Medline]
[Order article via Infotrieve].
45.
Graves JD, Downward J, Izquierdo PM, Rayter S, Warne PH, Cantrell DA.
The growth factor IL-2 activates p21ras proteins in normal human T lymphocytes.
J Immunol.
1992;148:2417-2422[Abstract].
46.
Gomez J, Martinez-AC, Fernandez B, Garcia A, Rebollo A.
Ras activation leads to cell proliferation or apoptotic cell death upon interleukin-2 stimulation or lymphokine deprivation, respectively.
Eur J Immunol.
1997;27:1610-1618[Medline]
[Order article via Infotrieve].
 CiteULike  Connotea  Del.icio.us  Digg  Reddit  Technorati What's this?
This article has been cited by other articles:
|
|
|
|
 
S. Shen, M. Zhu, J. Lau, M. Chuck, and W. Zhang
The Essential Role of LAT in Thymocyte Development during Transition from the Double-Positive to Single-Positive Stage
J. Immunol.,
May 1, 2009;
182(9):
5596 - 5604.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
U. Schenk, A. M. Westendorf, E. Radaelli, A. Casati, M. Ferro, M. Fumagalli, C. Verderio, J. Buer, E. Scanziani, and F. Grassi
Purinergic Control of T Cell Activation by ATP Released Through Pannexin-1 Hemichannels
Sci. Signal.,
September 30, 2008;
1(39):
ra6 - ra6.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Jongstra-Bilen, A. Puig Cano, M. Hasija, H. Xiao, C. I. E. Smith, and M. I. Cybulsky
Dual Functions of Bruton's Tyrosine Kinase and Tec Kinase during Fc{gamma} Receptor-Induced Signaling and Phagocytosis
J. Immunol.,
July 1, 2008;
181(1):
288 - 298.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Ko, L. M. Joshi, L. L. Cooke, N. Vazquez, M. W. Musch, S. C. Hebert, G. Gamba, and R. S. Hoover
Phorbol ester stimulation of RasGRP1 regulates the sodium-chloride cotransporter by a PKC-independent pathway
PNAS,
December 11, 2007;
104(50):
20120 - 20125.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. T. Luke, C. E. Oki-Idouchi, J. M. Cline, and P. S. Lorenzo
RasGRP1 Overexpression in the Epidermis of Transgenic Mice Contributes to Tumor Progression during Multistage Skin Carcinogenesis
Cancer Res.,
November 1, 2007;
67(21):
10190 - 10197.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Yasuda, R. L. Stevens, T. Terada, M. Takeda, T. Hashimoto, J. Fukae, T. Horita, H. Kataoka, T. Atsumi, and T. Koike
Defective Expression of Ras Guanyl Nucleotide-Releasing Protein 1 in a Subset of Patients with Systemic Lupus Erythematosus
J. Immunol.,
October 1, 2007;
179(7):
4890 - 4900.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. S. Winter, Z. Jiang, H. M. Khawaja, T. Griffin, M. Devidas, B. L. Asselin, and R. S. Larson
Identification of genomic classifiers that distinguish induction failure in T-lineage acute lymphoblastic leukemia: a report from the Children's Oncology Group
Blood,
September 1, 2007;
110(5):
1429 - 1438.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Beaulieu, B. Zahedi, R. E. Goulding, G. Tazmini, K. V. Anthony, S. L. Omeis, D. R. de Jong, and R. J. Kay
Regulation of RasGRP1 by B Cell Antigen Receptor Requires Cooperativity between Three Domains Controlling Translocation to the Plasma Membrane
Mol. Biol. Cell,
August 1, 2007;
18(8):
3156 - 3168.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Qi and A. August
Keeping the (Kinase) Party Going: SLP-76 and ITK Dance to the Beat
Sci. Signal.,
July 24, 2007;
2007(396):
pe39 - pe39.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. DeBell, L. Graham, I. Reischl, C. Serrano, E. Bonvini, and B. Rellahan
Intramolecular Regulation of Phospholipase C-{gamma}1 by Its C-Terminal Src Homology 2 Domain
Mol. Cell. Biol.,
February 1, 2007;
27(3):
854 - 863.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Han, S. M. Knoepp, M. A. Hallman, and K. E. Meier
RasGRP1 Confers the Phorbol Ester-Sensitive Phenotype to EL4 Lymphoma Cells
Mol. Pharmacol.,
January 1, 2007;
71(1):
314 - 322.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. B. Graham, M. P. Bell, C. J. Huntoon, M. D. Griffin, X. Tai, A. Singer, and D. J. McKean
CD28 Ligation Costimulates Cell Death but Not Maturation of Double-Positive Thymocytes due to Defective ERK MAPK Signaling
J. Immunol.,
November 1, 2006;
177(9):
6098 - 6107.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. Choi, S.-Y. Cho, R. H. Schwartz, and K. Choi
Dual Effects of Sprouty1 on TCR Signaling Depending on the Differentiation State of the T Cell
J. Immunol.,
May 15, 2006;
176(10):
6034 - 6045.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. H. Wabnitz, G. Nebl, M. Klemke, A. J. Schroder, and Y. Samstag
Phosphatidylinositol 3-Kinase Functions as a Ras Effector in the Signaling Cascade That Regulates Dephosphorylation of the Actin-Remodeling Protein Cofilin after Costimulation of Untransformed Human T Lymphocytes
J. Immunol.,
February 1, 2006;
176(3):
1668 - 1674.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Kumar, S. Feske, A. Rao, and R. S. Geha
A 10-aa-long sequence in SLP-76 upstream of the Gads binding site is essential for T cell development and function
PNAS,
December 27, 2005;
102(52):
19063 - 19068.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. J. Coughlin, S. L. Stang, N. A. Dower, and J. C. Stone
RasGRP1 and RasGRP3 Regulate B Cell Proliferation by Facilitating B Cell Receptor-Ras Signaling
J. Immunol.,
December 1, 2005;
175(11):
7179 - 7184.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. J. S. Stork and T. J. Dillon
Multiple roles of Rap1 in hematopoietic cells: complementary versus antagonistic functions
Blood,
November 1, 2005;
106(9):
2952 - 2961.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Alonso, M. C. Rodriguez, J. Pindado, E. Merino, I. Merida, and M. Izquierdo
Diacylglycerol Kinase {alpha} Regulates the Secretion of Lethal Exosomes Bearing Fas Ligand during Activation-induced Cell Death of T Lymphocytes
J. Biol. Chem.,
August 5, 2005;
280(31):
28439 - 28450.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Pu, N. A. Perry, D. Yang, N. E. Lewin, N. Kedei, D. C. Braun, S. H. Choi, P. M. Blumberg, S. H. Garfield, J. C. Stone, et al.
A Novel Diacylglycerol-lactone Shows Marked Selectivity in Vitro among C1 Domains of Protein Kinase C (PKC) Isoforms {alpha} and {delta} as Well as Selectivity for RasGRP Compared with PKC{alpha}
J. Biol. Chem.,
July 22, 2005;
280(29):
27329 - 27338.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
K. K. Hoyer, M. Herling, K. Bagrintseva, D. W. Dawson, S. W. French, M. Renard, J. G. Weinger, D. Jones, and M. A. Teitell
T Cell Leukemia-1 Modulates TCR Signal Strength and IFN-{gamma} Levels through Phosphatidylinositol 3-Kinase and Protein Kinase C Pathway Activation
J. Immunol.,
July 15, 2005;
175(2):
864 - 873.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. P. Roose, M. Mollenauer, V. A. Gupta, J. Stone, and A. Weiss
A Diacylglycerol-Protein Kinase C-RasGRP1 Pathway Directs Ras Activation upon Antigen Receptor Stimulation of T Cells
Mol. Cell. Biol.,
June 1, 2005;
25(11):
4426 - 4441.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. J. Dillon, K. D. Carey, S. A. Wetzel, D. C. Parker, and P. J. S. Stork
Regulation of the Small GTPase Rap1 and Extracellular Signal-Regulated Kinases by the Costimulatory Molecule CTLA-4
Mol. Cell. Biol.,
May 15, 2005;
25(10):
4117 - 4128.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Zheng, H. Liu, J. Coughlin, J. Zheng, L. Li, and J. C. Stone
Phosphorylation of RasGRP3 on threonine 133 provides a mechanistic link between PKC and Ras signaling systems in B cells
Blood,
May 1, 2005;
105(9):
3648 - 3654.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Wang and P. Johnson
Expression of CD45 Lacking the Catalytic Protein Tyrosine Phosphatase Domain Modulates Lck Phosphorylation and T Cell Activation
J. Biol. Chem.,
April 8, 2005;
280(14):
14318 - 14324.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Sommers, J. Lee, K. L. Steiner, J. M. Gurson, C. L. DePersis, D. El-Khoury, C. L. Fuller, E. W. Shores, P. E. Love, and L. E. Samelson
Mutation of the phospholipase C-{gamma}1-binding site of LAT affects both positive and negative thymocyte selection
J. Exp. Med.,
April 4, 2005;
201(7):
1125 - 1134.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
R. Gonen, D. Beach, C. Ainey, and D. Yablonski
T Cell Receptor-induced Activation of Phospholipase C-{gamma}1 Depends on a Sequence-independent Function of the P-I Region of SLP-76
J. Biol. Chem.,
March 4, 2005;
280(9):
8364 - 8370.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. M. Roberts, A. L. Anderson, M. Hidaka, R. L. Swetenburg, C. Patterson, W. L. Stanford, and V. L. Bautch
A Vascular Gene Trap Screen Defines RasGRP3 as an Angiogenesis-Regulated Gene Required for the Endothelial Response to Phorbol Esters
Mol. Cell. Biol.,
December 15, 2004;
24(24):
10515 - 10528.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. N. Johnson, E. R. Appelbaum, D. C. Carptenter, R. F. Cox, J. Disa, J. J. Foley, S. K. Ghosh, D. P. Naselsky, M. A. Pullen, H. M. Sarau, et al.
Neuromedin Elicits Cytokine Release in Murine Th2-Type T Cell Clone D10.G4.1
J. Immunol.,
December 15, 2004;
173(12):
7230 - 7238.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Aiba, M. Oh-hora, S. Kiyonaka, Y. Kimura, A. Hijikata, Y. Mori, and T. Kurosaki
Activation of RasGRP3 by phosphorylation of Thr-133 is required for B cell receptor-mediated Ras activation
PNAS,
November 23, 2004;
101(47):
16612 - 16617.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-Y. Fan, L. H. Ly, R. Barhoumi, D. N. McMurray, and R. S. Chapkin
Dietary Docosahexaenoic Acid Suppresses T Cell Protein Kinase C{theta} Lipid Raft Recruitment and IL-2 Production
J. Immunol.,
November 15, 2004;
173(10):
6151 - 6160.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. S. Chin, C. H.T. Miller, L. Graham, M. Parviz, S. Zacur, B. Patel, A. Duong, and H. D. Bear
Bryostatin 1/ionomycin (B/I) ex vivo stimulation preferentially activates L-selectinlow tumor-sensitized lymphocytes
Int. Immunol.,
September 1, 2004;
16(9):
1283 - 1294.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Ehrhardt, M. D. David, G. R. A. Ehrhardt, and J. W. Schrader
Distinct Mechanisms Determine the Patterns of Differential Activation of H-Ras, N-Ras, K-Ras 4B, and M-Ras by Receptors for Growth Factors or Antigen
Mol. Cell. Biol.,
July 15, 2004;
24(14):
6311 - 6323.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. A. Walker and P. J. Lockyer
Visualizing Ras signalling in real-time
J. Cell Sci.,
June 15, 2004;
117(14):
2879 - 2886.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. F. Fierro, G. A. Wurth, and A. Zweifach
Cross-talk with Ca2+ Influx Does Not Underlie the Role of Extracellular Signal-regulated Kinases in Cytotoxic T Lymphocyte Lytic Granule Exocytosis
J. Biol. Chem.,
June 11, 2004;
279(24):
25646 - 25652.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. N. Wu, M. S. Jordan, M. A. Silverman, E. J. Peterson, and G. A. Koretzky
Differential Requirement for Adapter Proteins Src Homology 2 Domain-Containing Leukocyte Phosphoprotein of 76 kDa and Adhesion- and Degranulation-Promoting Adapter Protein in Fc{epsilon}RI Signaling and Mast Cell Function
J. Immunol.,
June 1, 2004;
172(11):
6768 - 6774.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Carrasco and I. Merida
Diacylglycerol-dependent Binding Recruits PKC{theta} and RasGRP1 C1 Domains to Specific Subcellular Localizations in Living T Lymphocytes
Mol. Biol. Cell,
June 1, 2004;
15(6):
2932 - 2942.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Guilbault and R. J. Kay
RasGRP1 Sensitizes an Immature B Cell Line to Antigen Receptor-induced Apoptosis
J. Biol. Chem.,
May 7, 2004;
279(19):
19523 - 19530.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. J. Caloca, J. L. Zugaza, M. Vicente-Manzanares, F. Sanchez-Madrid, and X. R. Bustelo
F-actin-dependent Translocation of the Rap1 GDP/GTP Exchange Factor RasGRP2
J. Biol. Chem.,
May 7, 2004;
279(19):
20435 - 20446.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. F. Reynolds, C. de Bettignies, T. Norton, A. Beeser, J. Chernoff, and V. L. J. Tybulewicz
Vav1 Transduces T Cell Receptor Signals to the Activation of the Ras/ERK Pathway via LAT, Sos, and RasGRP1
J. Biol. Chem.,
April 30, 2004;
279(18):
18239 - 18246.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
I. Perez de Castro, T. G. Bivona, M. R. Philips, and A. Pellicer
Ras Activation in Jurkat T cells following Low-Grade Stimulation of the T-Cell Receptor Is Specific to N-Ras and Occurs Only on the Golgi Apparatus
Mol. Cell. Biol.,
April 15, 2004;
24(8):
3485 - 3496.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Davidson, A. J. Pawson, R. L. de Maturana, S. H. Freestone, P. Barran, R. P. Millar, and S. Maudsley
Gonadotropin-releasing Hormone-induced Activation of Diacylglycerol Kinase-{zeta} and Its Association with Active c-Src
J. Biol. Chem.,
March 19, 2004;
279(12):
11906 - 11916.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Madani, A. Hichami, M. Charkaoui-Malki, and N. A. Khan
Diacylglycerols Containing Omega 3 and Omega 6 Fatty Acids Bind to RasGRP and Modulate MAP Kinase Activation
J. Biol. Chem.,
January 9, 2004;
279(2):
1176 - 1183.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Oh-hora, S. Johmura, A. Hashimoto, M. Hikida, and T. Kurosaki
Requirement for Ras Guanine Nucleotide Releasing Protein 3 in Coupling Phospholipase C-{gamma}2 to Ras in B Cell Receptor Signaling
J. Exp. Med.,
December 15, 2003;
198(12):
1841 - 1851.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-P. Zhong, J. S. Maltzman, E. A. Hainey, and G. A. Koretzky
Transcriptional Regulation of Src Homology 2 Domain-Containing Leukocyte Phosphoprotein of 76 kDa: Dissection of Key Promoter Elements
J. Immunol.,
December 15, 2003;
171(12):
6621 - 6629.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Ge, O. Li, P. Wilder, A. Rizzino, and T. W. McKeithan
NF-{kappa}B Regulates BCL3 Transcription in T Lymphocytes Through an Intronic Enhancer
J. Immunol.,
October 15, 2003;
171(8):
4210 - 4218.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
H. M. Wilcox and L. J. Berg
Itk Phosphorylation Sites Are Required for Functional Activity in Primary T Cells
J. Biol. Chem.,
September 26, 2003;
278(39):
37112 - 37121.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S.-i. Saitoh, S. Odom, G. Gomez, C. L. Sommers, H. A. Young, J. Rivera, and L. E. Samelson
The Four Distal Tyrosines Are Required for LAT-dependent Signaling in Fc{varepsilon}RI-mediated Mast Cell Activation
J. Exp. Med.,
September 2, 2003;
198(5):
831 - 843.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. M. Barry, D. G. Zisoulis, J. W. Neal, N. A. Clipstone, and G. S. Kansas
Induction of FucT-VII by the Ras/MAP kinase cascade in Jurkat T cells
Blood,
September 1, 2003;
102(5):
1771 - 1778.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. Teixeira, S. L. Stang, Y. Zheng, N. S. Beswick, and J. C. Stone
Integration of DAG signaling systems mediated by PKC-dependent phosphorylation of RasGRP3
Blood,
August 15, 2003;
102(4):
1414 - 1420.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y. Kawakami, J. Kitaura, L. Yao, R. W. McHenry, Y. Kawakami, A. C. Newton, S. Kang, R. M. Kato, M. Leitges, D. J. Rawlings, et al.
A Ras activation pathway dependent on Syk phosphorylation of protein kinase C
PNAS,
August 5, 2003;
100(16):
9470 - 9475.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
E. Diaz-Flores, M. Siliceo, C. Martinez-A., and I. Merida
Membrane Translocation of Protein Kinase C{theta} during T Lymphocyte Activation Requires Phospholipase C-{gamma}-generated Diacylglycerol
J. Biol. Chem.,
August 1, 2003;
278(31):
29208 - 29215.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Li, Y. Yang, G. W. Wong, and R. L. Stevens
Mast Cells in Airway Hyporesponsive C3H/HeJ Mice Express a Unique Isoform of the Signaling Protein Ras Guanine Nucleotide Releasing Protein 4 That Is Unresponsive to Diacylglycerol and Phorbol Esters
J. Immunol.,
July 1, 2003;
171(1):
390 - 397.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Y.-Y. Fan, D. N. McMurray, L. H. Ly, and R. S. Chapkin
Dietary (n-3) Polyunsaturated Fatty Acids Remodel Mouse T-Cell Lipid Rafts
J. Nutr.,
June 1, 2003;
133(6):
1913 - 1920.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Koike, H. Yamagishi, Y. Hatanaka, A. Fukushima, J.-w. Chang, Y. Xia, M. Fields, P. Chandler, and M. Iwashima
A Novel ERK-dependent Signaling Process That Regulates Interleukin-2 Expression in a Late Phase of T Cell Activation
J. Biol. Chem.,
April 25, 2003;
278(18):
15685 - 15692.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. D. Wells, Q.-H. Liu, B. Hondowicz, J. Zhang, L. A. Turka, and B. D. Freedman
Regulation of T Cell Activation and Tolerance by Phospholipase C{gamma}-1-Dependent Integrin Avidity Modulation
J. Immunol.,
April 15, 2003;
170(8):
4127 - 4133.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Kettner, V. Pivniouk, L. Kumar, H. Falet, J.-S. Lee, R. Mulligan, and R. S. Geha
Structural Requirements of SLP-76 in Signaling via the High-Affinity Immunoglobulin E Receptor (Fc{varepsilon}RI) in Mast Cells
Mol. Cell. Biol.,
April 1, 2003;
23(7):
2395 - 2406.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. M. Norment, L. Y. Bogatzki, M. Klinger, E. W. Ojala, M. J. Bevan, and R. J. Kay
Transgenic Expression of RasGRP1 Induces the Maturation of Double-Negative Thymocytes and Enhances the Production of CD8 Single-Positive Thymocytes
J. Immunol.,
February 1, 2003;
170(3):
1141 - 1149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. Zhu, E. Janssen, K. Leung, and W. Zhang
Molecular Cloning of a Novel Gene Encoding a Membrane-associated Adaptor Protein (LAX) in Lymphocyte Signaling
J. Biol. Chem.,
November 22, 2002;
277(48):
46151 - 46158.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
G. W. Reuther, Q. T. Lambert, J. F. Rebhun, M. A. Caligiuri, L. A. Quilliam, and C. J. Der
RasGRP4 Is a Novel Ras Activator Isolated from Acute Myeloid Leukemia
J. Biol. Chem.,
August 16, 2002;
277(34):
30508 - 30514.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X.-P. Zhong, E. A. Hainey, B. A. Olenchock, H. Zhao, M. K. Topham, and G. A. Koretzky
Regulation of T Cell Receptor-induced Activation of the Ras-ERK Pathway by Diacylglycerol Kinase zeta
J. Biol. Chem.,
August 16, 2002;
277(34):
31089 - 31098.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
T. Santos, S. Carrasco, D. R. Jones, I. Merida, and A. Eguinoa
Dynamics of Diacylglycerol Kinase zeta Translocation in Living T-cells. STUDY OF THE STRUCTURAL DOMAIN REQUIREMENTS FOR TRANSLOCATION AND ACTIVITY
J. Biol. Chem.,
August 9, 2002;
277(33):
30300 - 30309.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
S. Pisegna, A. Zingoni, G. Pirozzi, B. Cinque, M. G. Cifone, S. Morrone, M. Piccoli, L. Frati, G. Palmieri, and A. Santoni
Src-Dependent Syk Activation Controls CD69-Mediated Signaling and Function on Human NK Cells
J. Immunol.,
July 1, 2002;
169(1):
68 - 74.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
C. L. Sommers, C.-S. Park, J. Lee, C. Feng, C. L. Fuller, A. Grinberg, J. A. Hildebrand, E. Lacana, R. K. Menon, E. W. Shores, et al.
A LAT Mutation That Inhibits T Cell Development Yet Induces Lymphoproliferation
Science,
June 14, 2002;
296(5575):
2040 - 2043.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. G. Kazanietz
Novel "Nonkinase" Phorbol Ester Receptors: The C1 Domain Connection
Mol. Pharmacol.,
April 1, 2002;
61(4):
759 - 767.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
B. Albrecht, C. D. D'Souza, W. Ding, S. Tridandapani, K. M. Coggeshall, and M. D. Lairmore
Activation of Nuclear Factor of Activated T Cells by Human T-Lymphotropic Virus Type 1 Accessory Protein p12I
J. Virol.,
March 7, 2002;
76(7):
3493 - 3501.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
N. Brose and C. Rosenmund
Move over protein kinase C, you've got company: alternative cellular effectors of diacylglycerol and phorbol esters
J. Cell Sci.,
January 12, 2002;
115(23):
4399 - 4411.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
A. Takesono, L. D. Finkelstein, and P. L. Schwartzberg
Beyond calcium: new signaling pathways for Tec family kinases
J. Cell Sci.,
January 8, 2002;
115(15):
3039 - 3048.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. M. Morgan, C. M. Labno, G. A. Van Seventer, M. F. Denny, D. B. Straus, and J. K. Burkhardt
Superantigen-Induced T Cell:B Cell Conjugation Is Mediated by LFA-1 and Requires Signaling Through Lck, But Not ZAP-70
J. Immunol.,
November 15, 2001;
167(10):
5708 - 5718.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
X. Shan, R. Balakir, G. Criado, J. S. Wood, M.-C. Seminario, J. Madrenas, and R. L. Wange
ZAP-70-Independent Ca2+ Mobilization and Erk Activation in Jurkat T Cells in Response to T-Cell Antigen Receptor Ligation
Mol. Cell. Biol.,
November 1, 2001;
21(21):
7137 - 7149.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
Q. Gong, X. Jin, A. M. Akk, N. Foger, M. White, G. Gong, J. B. Wardenburg, and A. C. Chan
Requirement for Tyrosine Residues 315 and 319 within {zeta} Chain-associated Protein 70 for T Cell Development
J. Exp. Med.,
August 20, 2001;
194(4):
507 - 518.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
D. Yablonski, T. Kadlecek, and A. Weiss
Identification of a Phospholipase C-{gamma}1 (PLC-{gamma}1) SH3 Domain-Binding Site in SLP-76 Required for T-Cell Receptor-Mediated Activation of PLC-{gamma}1 and NFAT
Mol. Cell. Biol.,
July 1, 2001;
21(13):
4208 - 4218.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J.-G. Nemorin, P. Laporte, G. Berube, and P. Duplay
p62dok Negatively Regulates CD2 Signaling in Jurkat Cells
J. Immunol.,
April 1, 2001;
166(7):
4408 - 4415.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
M. K. Topham and S. M. Prescott
Diacylglycerol Kinase {zeta} Regulates Ras Activation by a Novel Mechanism
J. Cell Biol.,
March 12, 2001;
152(6):
1135 - 1144.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
P. S. Lorenzo, J. W. Kung, D. A. Bottorff, S. H. Garfield, J. C. Stone, and P. M. Blumberg
Phorbol Esters Modulate the Ras Exchange Factor RasGRP3
Cancer Res.,
February 1, 2001;
61(3):
943 - 949.
[Abstract]
[Full Text]
|
|
|
|
|
|
|
L. G. Puente, J. C. Stone, and H. L. Ostergaard
Evidence for Protein Kinase C-Dependent and -Independent Activation of Mitogen-Activated Protein Kinase in T Cells: Potential Role of Additional Diacylglycerol Binding Proteins
J. Immunol.,
December 15, 2000;
165(12):
6865 - 6871.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
J. Lin and A. Weiss
Identification of the Minimal Tyrosine Residues Required for Linker for Activation of T Cell Function
J. Biol. Chem.,
July 27, 2001;
276(31):
29588 - 29595.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
|
|
L. Kumar, V. Pivniouk, M. A. de la Fuente, D. Laouini, and R. S. Geha
Differential role of SLP-76 domains in T cell development and function
PNAS,
January 22, 2002;
99(2):
884 - 889.
[Abstract]
[Full Text]
[PDF]
|
|
|
|
|
Top
Abstract
Introduction