ACCELERATED PUBLICATION
The ARG Tyrosine Kinase Interacts with Siva-1 in the
Apoptotic Response to Oxidative Stress*
Cheng
Cao,
Xinping
Ren,
Surender
Kharbanda,
Anthony
Koleske
,
K. V. S.
Prasad§, and
Donald
Kufe
Dana-Farber Cancer Institute, Harvard Medical School, Boston,
Massachusetts 02115 and
Department of Molecular Biophysics and
Biochemistry, Yale University, New Haven, Connecticut 06520, and
§ Department of Microbiology and Immunology, University of Illinois at
Chicago, Chicago, Illinois 60612
Received for publication, January 30, 2001
 |
ABSTRACT |
The Abl family of mammalian nonreceptor tyrosine
kinases consists of c-Abl and ARG (Abl-related gene). Certain insights
are available regarding the involvement c-Abl in the response of cells to stress. ARG, however, has no known function in cell signaling. The
present studies demonstrate that ARG associates with the proapoptotic Siva-1 protein. The functional significance of the ARG-Siva-1 interaction is supported by the finding that ARG is activated by
oxidative stress and that this response involves ARG-mediated phosphorylation of Siva-1 on Tyr48. The proapoptotic
effects of Siva-1 are accentuated in cells stably expressing ARG and
are inhibited in ARG-deficient cells. Moreover, the proapoptotic
effects of Siva-1 are abrogated by mutation of the Tyr48
site. We also show that the apoptotic response to oxidative stress is
attenuated in ARG-deficient cells and that this defect is corrected by
reconstituting ARG expression. These findings support a model in which
the activation of ARG by oxidative stress induces apoptosis by a
Siva-1-dependent mechanism.
 |
INTRODUCTION |
The mammalian c-Abl and
ARG1 nonreceptor tyrosine
kinases are ubiquitously expressed in adult tissues (1, 2). These
proteins contain N-terminal SH3, SH2, and kinase domains that share
~90% identity. The C-terminal regions of c-Abl and ARG share
29% identity and are distinguished from other nonreceptor tyrosine
kinases by the presence of globular (G) and filamentous (F)
actin-binding domains (3). The c-Abl protein is expressed in the
nucleus and cytoplasm, whereas ARG has been detected predominately in the cytoplasm (4). In addition, the C-terminal region of c-Abl differs
from ARG by the presence of a nuclear localization signal (5), sites
for phosphorylation by the Cdc2 kinase (6), and DNA binding sequences
(7). The structural differences of the C-terminal regions have
suggested that c-Abl and ARG may share only certain cellular functions.
Mice with targeted disruption of the c-abl gene are
born runted with head and eye abnormalities and succumb as neonates to defective lymphopoiesis (8, 9). Mice deficient in ARG develop normally
but exhibit behavioral abnormalities (10). Embryos deficient in both
c-Abl and ARG exhibit defects in neurolation and die before 11 days
postcoitum (10). These findings and the observation that
abl
/
,
arg
/
neuroepithelial cells
exhibit an altered actin cytoskeleton have supported roles for c-Abl
and ARG in the regulation of actin microfilaments (10).
Other studies have demonstrated that c-Abl is involved in the cellular
response to stress (11). Nuclear c-Abl associates with the
DNA-dependent protein kinase (DNA-PK) complex (12, 13) and
with the product of the gene mutated in ataxia telangiectasia (14, 15). Activation of c-Abl by DNA-PK and ataxia telangiectasia mutated gene product in cells exposed to genotoxic agents contributes to DNA damage-induced apoptosis by mechanisms in part dependent on p53
and its homolog p73 (11, 16-19). In the cellular response to reactive
oxygen species (ROS), the cytoplasmic form of c-Abl is activated by
protein kinase C
(PKC
) (20). Activation of cytoplasmic c-Abl by
ROS transduces signals that induce release of mitochondrial cytochrome
c and thereby apoptosis (21).
No functional role has been ascribed to ARG as a cell signaling
molecule. The present studies demonstrate that ARG interacts with the
proapoptotic Siva-1 protein (22, 23). ARG phosphorylates Siva-1 in the
cellular response to oxidative stress and induces apoptosis by a
Siva-1-dependent mechanism.
 |
MATERIALS AND METHODS |
Cell Culture and Transfections--
293, MCF-7, and mouse embryo
fibroblasts (MEFs, wild-type, and
arg
/
) were grown in Dulbecco's
modified Eagle's medium supplemented with 10% heat-inactivated fetal
bovine serum, 2 mM L-glutamine, 100 units/ml
penicillin, and 100 µg/ml streptomycin. Transient transfections were
performed with LipofectAMINE (Life Technologies, Inc.). MCF-7 cells
stably expressing ARG or ARG(K-R) were established by selection
in G418.
Vectors--
Flag-tagged ARG, ARG(K-R), and Siva-1 were
constructed by cloning into the pcDNA3.1-based Flag vector.
GFP-Siva constructs were obtained by cloning into pEGFPC1
(CLONTECH). Retrovirus-expressing Siva-1 was
prepared by cloning the human siva-1 gene into the pLXSN
vector (CLONTECH). The arg gene was
cloned into the retroviral vector pMSCV-IRES-GFP.
Immunoprecipitation and Immunoblot Analysis--
Cell lysates
were prepared in lysis buffer (50 mM Tris-HCl, pH 7.5, 1 mM phenylmethylsulfonyl fluoride, 1 mM
dithiothreitol, 10 mM sodium fluoride, and 10 µg/ml
aprotinin, leupeptin, and pepstatin A) containing 0.5% Nonidet P-40.
Soluble protein was subjected to immunoprecipitation with anti-Flag
(agarose-conjugated, M-2, Sigma). Immunoblot analysis was
performed with anti-GFP (CLONTECH) and anti-ARG
(rabbit antibody against ARG-specific C-terminal QVSSAAAGVPGTNPVLNNL
peptide). The antigen-antibody complexes were visualized by
chemiluminescence (ECL, Amersham Pharmacia Biotech).
Binding Assays--
Cell lysates were incubated with 5 µg of
GST, GST-ARG SH2-(162-259), GST-ARG SH3-(112-161), or GST-Siva-1 for
2 h at 4 °C. The adsorbates were washed with lysis buffer and
then subjected to immunoblotting with anti-Flag (M5, Sigma). An aliquot
of the total lysate (2% v/v) was included as a control. For direct
binding assays, purified GST fusion proteins were incubated with 15 µl of 35S-labeled Siva-1. The adsorbates were analyzed by
SDS-PAGE and autoradiography. An aliquot (0.5 µl) of the
35S-labeled protein was loaded as input.
ARG Kinase Assays--
Lysates from Flag-ARG- or
Flag-ARG(K-R)- transfected cells were subjected to
immunoprecipitation with anti-Flag-agarose. The protein complexes
were washed, normalized by immunoblot analysis with anti-Flag, and then
resuspended in kinase buffer (20 mM HEPES, pH 7.5, 75 mM KCl, 10 mM MgCl2, 10 mM MnCl2) containing 2.5 µCi of
[
-32P]ATP and 2 µg of GST-Siva-1 for 30 min at
30 °C. The reaction products were analyzed by SDS-PAGE and autoradiography.
Apoptosis Assays--
The DNA content was assessed by staining
ethanol-fixed and citrate buffer-permeabilized cells with propidium
iodide and monitoring by FACScan (Becton Dickinson). The numbers of
cells with sub-G1 DNA were determined with a MODFIT LT
program as described (24).
 |
RESULTS AND DISCUSSION |
To extend the findings in the yeast two-hybrid system that ARG
associates with the pro-apoptotic Siva-1 protein (data not shown),
lysates from MCF-7 cells expressing Flag-tagged ARG and GFP-tagged
human Siva-1 were subjected to immunoprecipitation with anti-Flag.
Analysis of the precipitates by immunoblotting with anti-GFP
demonstrated the presence of ARG-Siva-1 complexes (Fig.
1A, left). Analysis of
anti-Flag immunoprecipitates from cells expressing Flag-Siva-1 by
immunoblotting with anti-ARG provided further support for binding of
ARG and Siva-1 (Fig. 1A, right). To extend these findings,
lysates from cells expressing Flag-ARG were incubated with a GST-Siva-1
fusion protein. Analysis of the adsorbates with anti-Flag confirmed the
binding of ARG and Siva-1 (Fig. 1B). Other studies with GST
fusion proteins prepared from the ARG SH2 and ARG SH3 domains
demonstrated that both confer binding to Siva-1 (Fig. 1C).
By contrast, binding of GST-ARG SH2, but not GST-ARG SH3, was
detectable to the shorter, nonapoptotic Siva-2 protein (Fig.
1D). Human Siva-1, but not Siva-2, contains a proline-rich
PESP sequence (amino acids 82-85) for potential binding to ARG SH3.
Notably, however, the PESP site is not conserved in mouse Siva-1 (22,
23). In this regard, GST-ARG SH2, and not GST-ARG SH3, binds to mouse
Siva-1 (data not shown). These findings demonstrate that the ARG SH2
domain interacts with Siva-1 and Siva-2 of both human and mouse origin
and that binding of the ARG SH3 domain is also detectable with human
Siva-1.

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Fig. 1.
Association of ARG and Siva-1.
A, 293 cells were transfected with Flag-ARG and GFP-Siva-1.
Lysates prepared at 48 h after transfection were subjected to
immunoprecipitation (IP) with anti-Flag. The
immunoprecipitates were analyzed by immunoblotting (IB) with
anti-GFP (left panel). MCF-7 cells were transfected with the
empty Flag vector or Flag-Siva-1. Anti-Flag immunoprecipitates were
subjected to immunoblot analysis with anti-ARG and anti-Flag
(right panel). Lysates not subjected to immunoprecipitation
were analyzed by immunoblotting with the indicated antibodies
(left and right panels). B, lysates
from 293 cells expressing Flag-ARG were incubated with GST-Siva-1 or
GST. Adsorbates were analyzed by immunoblotting with anti-Flag. Total
lysate (TL) was used as a control. C and
D, lysates from 293 cells expressing GFP-Siva-1
(C) or GFP-Siva-2 (D) were incubated with GST-ARG
SH2, GST-ARG SH3, or GST. Adsorbates were subjected to immunoblotting
with anti-GFP.
|
|
To determine whether Siva-1 is a substrate for ARG, GST-Siva-1 was
incubated with kinase-active ARG (Fig.
2A, left) in the presence of
[
-32P]ATP. Analysis of the reaction products by
SDS-PAGE and autoradiography demonstrated phosphorylation of Siva-1
(Fig. 2A, right). As a control, there was no detectable
phosphorylation when Siva-1 was incubated with kinase-inactive ARG(K-R)
in which Lys337 in the ATP binding site was mutated to Arg
(Fig. 2A). There are two potential tyrosine phosphorylation
sites in Siva-1 that are located at Tyr48 and
Tyr67. Mutation of these sites to Phe and then incubation
of the mutant proteins with ARG demonstrated abrogation of
phosphorylation with GST-Siva-1(Y48F), but not with GST-Siva-1(Y67F)
(Fig. 2A, right). To assess whether ARG phosphorylates
Siva-1 in vivo, Flag-Siva-1 was coexpressed with ARG and
lysates were analyzed by immunoblotting with anti-P-Tyr. The results
show that Siva-1 is phosphorylated by ARG in cells (Fig.
2B). By contrast, there was no detectable tyrosine
phosphorylation of Flag-Siva-1 when this vector was coexpressed with
ARG(K-R) (data not shown). Although Flag-Siva-1(Y67F) was also
phosphorylated by ARG, there was no detectable tyrosine phosphorylation of Flag-Siva-1(Y48F) (Fig. 2B). In concert with these
findings and the presence of Tyr48 in Siva-2, coexpression
of Siva-2 with ARG, but not ARG(K-R), also resulted in detectable
tyrosine phosphorylation (Fig. 2B). These findings thus
provided support for ARG-mediated phosphorylation of Siva-1 and Siva-2
on Tyr48 in vitro and in vivo. To
determine whether ARG, like c-Abl (20, 21), is activated by ROS, cells
expressing Flag-ARG were treated with H2O2.
Analysis of anti-Flag immunoprecipitates for phosphorylation of
GST-Siva-1 demonstrated H2O2
concentration-dependent induction of ARG activity (Fig.
2C). As a control, the same anti-Flag immunoprecipitates failed to phosphorylate GST-Siva-1(Y48F) (Fig. 2C). In
studies of wild-type and arg
/
MEFs, expression of Flag-Siva-1 resulted in little if any detectable phosphorylation (Fig. 2D). Treatment of the wild-type cells
with H2O2, however, was associated with
tyrosine phosphorylation of Flag-Siva-1 (Fig. 2D). By
contrast, there was no detectable phosphorylation of Flag-Siva-1 in
H2O2-treated
arg
/
MEFs (Fig. 2D).
These findings demonstrate that activation of ARG by
H2O2 is associated with phosphorylation of
Siva-1 on Tyr48.

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Fig. 2.
ARG phosphorylation of Siva-1 in response to
oxidative stress. A, Flag-ARG and Flag-ARG(K-R)
(left panel) were incubated with GST-Siva-1,
GST-Siva-1(Y67F), or GST-Siva-1(Y48F). GST-Crk-(120-225) was used as a
positive control. Reaction products were analyzed by SDS-PAGE and
autoradiography (right panel). B, 293 cells were
cotransfected with ARG and Flag-Siva-1, Flag-Siva-1(Y48F),
Flag-Siva-1(Y67F), or Flag-Siva-2. Lysates were subjected to
immunoblotting (IB) with anti-P-Tyr and anti-Flag.
C, 293 cells were transfected to express Flag-ARG. At
36 h after transfection, the cells were treated with the indicated
concentrations of H2O2 for 2 h. Anti-Flag
immunoprecipitates (IP) were subjected to ARG kinase assays
using Siva-1 or Siva-1(Y48F) as substrate. D, wild-type
(arg+/+) and
arg / MEFs expressing Flag-Siva-1
were treated with 1 mM H2O2 for
2 h. Anti-Flag immunoprecipitates were analyzed by immunoblotting
with anti-P-Tyr and anti-Flag.
|
|
To assess the functional significance of the ARG-Siva-1 interaction,
MCF-7 cells were prepared that stably express ARG or the ARG(K-R)
mutant. There was no detectable effect of ARG or ARG(K-R) expression on
MCF-7 cell growth (data not shown) or cell cycle distribution (Fig.
3A). Expression of Siva-1 in
the wild-type MCF-7 cells was associated with the appearance of
apoptotic cells containing sub-G1 DNA (Fig. 3A).
Whereas Siva-1-induced apoptosis was more pronounced in MCF-7/ARG
cells, expression of Siva-1 had little if any effect on MCF-7/ARG(K-R)
cells (Fig. 3A). As a control, expression of Siva-2 resulted
in substantially less apoptosis in MCF-7/ARG cells as compared with
that obtained with Siva-1, and had no effect on the wild-type MCF-7 and
MCF-7/ARG(K-R) cells (Fig. 3A). To extend these findings,
Siva-1 was expressed in the wild-type and
arg
/
MEFs. The results
demonstrate that, although Siva-1 induces apoptosis in wild-type cells,
there was little effect of Siva-1 in the absence of ARG expression
(Fig. 3B). In concert with the finding that ARG
phosphorylates Siva-1 on Tyr48, the expression of
Siva-1(Y48F) had little effect on the induction of apoptosis, whereas
the proapoptotic effects of Siva-1(Y67F) were similar to those obtained
with wild-type Siva-1 (Fig. 3C). These findings demonstrate
that Siva-1-induced apoptosis is dependent on the ARG kinase function
and that ARG-mediated phosphorylation of Siva-1 on Tyr48 is
a proapoptotic signal.

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Fig. 3.
Interaction of ARG and Siva-1 in the
apoptotic response to oxidative stress. A, MCF-7,
MCF-7/ARG, and MCF-7/ARG(K-R) cells were transfected to express
GFP-Siva-1 or GFP-Siva-2. At 36 h after transfection, GFP-positive
cells were analyzed for sub-G1 DNA (left
panels). Cells with sub-G1 DNA are depicted in the
shaded profiles. GO/G1 and
G2/M cells are shown in the dark profiles and S
phase cells in the hatched profiles. Cells were subjected to
immunoblot analysis (IB) with the indicated antibodies
(right panels). B, wild-type
(arg+/+) and
arg / MEFs were infected with
empty or Siva-1 retroviral vectors for 24 h. The cells were
analyzed by flow cytometry (left panels) and immunoblotting
(right panels). C, MCF-7 (open bars),
MCF-7/ARG (hatched bars), and MCF-7/ARG(K-R) (solid
bars) were transfected with GFP-Siva-1, GFP-Siva-2,
GFP-Siva-1(Y48F), or GFP-Siva-1(Y67F). GFP-positive cells were analyzed
for DNA content. The results are expressed as the percentage (mean ± S.E. of two independent experiments each performed in duplicate) of
GFP-positive cells with sub-G1 DNA.
|
|
As the findings demonstrate that ARG is activated by ROS,
H2O2-induced apoptosis was assessed in the
MCF-7, MCF-7/ARG, and MCF-7/ARG(K-R) cells. The results demonstrate
that the apoptotic effects of H2O2 are
attenuated in MCF-7/ARG(K-R) as compared with wild-type MCF-7 cells
(Fig. 4A). Notably, however,
there was a marked increase in H2O2-induced
apoptosis in MCF-7/ARG cells (Fig. 4A). The apoptotic
effects of H2O2 were attenuated in
arg
/
(two separate embryos) as
compared with wild-type MEFs (Fig. 4B). Moreover, expression
of ARG in arg
/
cells corrected
the defect in H2O2-induced apoptosis (Fig.
4C).

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Fig. 4.
Apoptotic response to oxidative stress is ARG
kinase-dependent. A C, the indicated cells
were left untreated (open bars) or treated with 1 mM H2O2 for 2 h (hatched
bars), washed, and then cultured for 18 h. In C,
arg+/ cells were prepared by transduction of
arg / MEFs with a retroviral
vector expressing ARG (transduction efficiency, >95% as determined by
GFP expression). Cells were analyzed for DNA content. The results are
expressed as the percentage (mean ± S.E. of two independent
experiments performed in duplicate) of cells with sub-G1
DNA.
|
|
The ARG tyrosine kinase has, like c-Abl, been associated with the
development of leukemia (25, 26). Despite the relatedness to c-Abl and
a role in neurolation as defined in
arg
/
mice (10), a function for
ARG in cell signaling has remained obscure. Genetic studies in
Drosophila have indicated that Abl family kinases regulate
cellular morphology through interactions with the cytoskeleton (27,
28). The identification of actin-binding domains in the C-terminal
region of ARG (3) and localization of ARG with actin microfilaments
(10) have supported a role in regulation of the actin cytoskeletion.
The present results provide evidence for involvement of ARG in the
cellular response to oxidative stress. Moreover, the induction of
apoptosis by oxidative stress is attenuated in ARG-deficient cells.
These findings indicate that, in addition to regulating the actin
cytoskeleton, ARG functions in ROS-mediated signals that induce an
apoptotic response.
Siva-1 interacts with members of the tumor necrosis factor receptor
family and induces apoptosis in diverse cells (22). Siva-1 has also
been implicated in the induction of Coxsackievirus-induced apoptosis
(29). Full-length Siva-1 but not Siva-2, which lacks sequences encoded
by exon 2, induces the apoptotic response (23). The present studies
demonstrate that ARG phosphorylates both Siva-1 and Siva-2. By
contrast, the interaction between ARG and Siva-1, but not Siva-2, is
associated with the induction of apoptosis. Our results also
demonstrate that mutation of the Siva-1 Tyr48 site
abrogates the apoptotic function of Siva-1 and that apoptosis induced
by Siva-1 is dependent on expression of kinase-active ARG. These
findings thus define ARG as an upstream effector of Siva-1 in the
apoptotic response to oxidative stress.
 |
FOOTNOTES |
*
This investigation was supported by Grant CA42802 awarded by
the NCI, National Institutes of Health.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.
To whom correspondence should be addressed: Dana-Farber
Cancer Institute, Harvard Medical School, 44 Binney St., Boston, MA 02115. Tel.: 617-632-3141; Fax: 617-632-2934; E-mail:
donald_kufe@dfci.harvard.edu.
Published, JBC Papers in Press, February 23, 2001, DOI 10.1074/jbc.C100050200
 |
ABBREVIATIONS |
The abbreviations used are:
ARG, Abl-related
gene;
DNA-PK, DNA-dependent protein kinase;
ROS, reactive
oxygen species;
PKC, protein kinase C;
GST, glutathione
S-transferase;
GFP, green fluorescence protein;
PAGE, polyacrylamide gel electrophoresis;
MEF, mouse embryo fibroblast;
SH2/SH3, Src homology 2 and 3 (domains).
 |
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