© 2000 American Heart Association, Inc.
Molecular Medicine |
The Third Cytoplasmic Loop of the Angiotensin II Type 1 Receptor Exerts Differential Effects on Extracellular Signal–Regulated Kinase (ERK1/ERK2) and Apoptosis via Ras- and Rap1-Dependent Pathways
From the Center for Cardiovascular Research, University of Rochester, Rochester, NY. Present address of M.I. is Department of Clinical Laboratory, Hiroshima University School of Medicine, Japan; present address of L.H. is Department of Physiology, Semmelweis University of Medicine, Budapest, Hungary.
Correspondence to Bradford C. Berk, MD, PhD, Center for Cardiovascular Research, University of Rochester, 601 Elmwood Ave, Box 679, Rochester, NY 14642. E-mail bradford_berk{at}urmc.rochester.edu
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Abstract |
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Abstract—The third cytoplasmic loop of the angiotensin (Ang) II type 1 receptor (AT1) is important for receptor coupling to G proteins and activation of downstream events. Therefore, we determined whether specific AT1 sequences were required for kinase activation and inhibition of apoptosis by transfecting wild-type (AT1Rwt) and mutated AT1 into 293 cells. Ang II stimulated a 19.4-fold increase in extracellular signal–regulated kinase (ERK1/ERK2) activity in 293 cells transfected with AT1Rwt. However, in 293 cells that expressed a receptor in which amino acids 221 and 222 were deleted (AT1R[Del221/222]), Ang II–mediated ERK1/ERK2 activation was inhibited by >85%. In contrast, c-Jun NH2-terminal protein kinase (JNK) activation was similar in AT1Rwt- and AT1R(Del221/222)-transfected cells. Activation of ERK1/ERK2 by AT1Rwt was independent of Ca2+, whereas the low level of ERK1/ERK2 activation by AT1R(Del221/222) was completely Ca2+ dependent. Activation of ERK1/ERK2 in AT1Rwt required Ras, whereas AT1R(Del221/222) required Rap1. These results demonstrate the presence of 2 different pathways for ERK1/ERK2 activation by Ang II, which differ in their requirements for Ca2+ and small G proteins (Ras versus Rap1). Furthermore, Ang II prevented serum deprivation–induced apoptosis in cells transfected with AT1Rwt but not AT1R(Del221/222). AKT was only phosphorylated by Ang II in AT1Rwt-transfected cells. Overexpression of constitutively active AKT significantly reduced serum deprivation–induced apoptosis in cells transfected with AT1R(Del221/222). This study shows for the first time a direct link between kinase activation and inhibition of apoptosis dependent on amino acids 221 and 222 in the third cytoplasmic loop of the AT1.
Key Words: angiotensin II • apoptosis • AT1 • kinases
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Introduction |
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Angiotensin II (Ang II), an octapeptide pressor hormone, activates cellular events that may contribute to the pathogenesis of cardiovascular disease.1 The physiological actions of Ang II in adults are mediated largely via the Ang II type 1 receptor (AT1).2 AT1 is a G protein–coupled receptor (GPCR). GPCRs share a common basic structure of 7 transmembrane helices connected by alternating cytoplasmic and extracellular loops. Structure-function analysis of the AT1 has revealed important functional domains for signal transduction in the third cytoplasmic loop.3 AT1 couples signaling events via heterotrimeric G proteins, which occurs primarily through the Gq/11 group of G proteins and the third cytoplasmic loop. Recent studies revealed that a synthetic peptide representing the proximal part of the third cytoplasmic loop (residues 216 to 230) was able to activate purified G proteins, whereas a peptide composing the distal loop (residues 229 to 240) had no effect.4 In addition, the third cytoplasmic loop appears to be necessary for Ang II–mediated conformational changes in the AT1 that result in receptor activation.3
Activation of AT1 by Ang II stimulates protein synthesis and cell hypertrophy.5 6 7 Signaling events required for the growth-promoting effects of Ang II downstream of the AT1 include calcium mobilization and stimulation of kinases such as p38, c-Jun NH2-terminal protein kinase (JNK), and extracellular signal–regulated kinase (ERK1/ERK2).7 8 9 10 Furthermore, Ang II signaling through the AT1 also activates phosphatidylinositol 3-kinase (PI3K), which leads to activation of the serine/threonine kinase AKT, also known as protein kinase B (AKT).11 Activation of PI3K and AKT is associated with growth stimulation by Ang II.12 Recent studies have demonstrated the antiapoptotic and promitogenic functions of ERK1/ERK2 and AKT in different cells.13 14 In contrast, JNK is activated by inflammatory cytokines, reactive oxygen species, and Ang II.10 Activation of JNK is associated with proapoptotic effects.15 Therefore, the present study was performed to elucidate the signaling pathways that are dependent on the third cytoplasmic loop of the AT1 and the effect of mutations in the third loop on activation of kinases and inhibition of apoptosis.
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Materials and Methods |
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Cell Culture, cDNA Constructs, and Transfection
293 cells were maintained in DMEM containing 10% heat-inactivated FBS. The plasmids for the wild-type AT1 (AT1Rwt) and the deletion mutants were subcloned as described previously.16 Dominant-negative RasN17, Rap1N17, and CDC42N17 were generated as described previously.17 18 Plasmid DNAs were transfected into 293 cells using lipofectamine/Plus according to the manufacturer’s protocol. The final amount of transfected DNA for a 60-mm dish was adjusted to 1.3 µg by pcDNA3.1-LacZ.
[Sar,Ile]Ang II Binding to Intact Cells
To determine the expression level and structural integrity of
the mutant receptor, the number of Ang II binding sites was determined
as described previously.16
Immunoblotting
After incubation with the indicated stimuli, cells were lysed in
lysis buffer (in mmol/L, Tris-HCl 20 [pH 7.5], NaCl 150, KCl
2.5, Na3VO4 2, NaF 50, DTT
2, and benzamidine 2) for 20 minutes and scraped off the plates. After
removing the cell debris, equal amounts of protein were loaded on
SDS-PAGE and then transferred to polyvinylidene
difluoride membranes. Immunoblotting was
performed with monoclonal antibodies directed against
phospho-ERK1/ERK2, phospho-AKT, and phospho-JNK (New England Biolabs);
ERK1/ERK2 and AT1 (Santa Cruz Biotechnology); and
Ras and Rap1 (Transduction Laboratories). Antibodies were detected by
the enhanced chemiluminescence system (Amersham).
Preparation of Recombinant Proteins
The Raf1-RBD- or the RalGDS-RBD-construct was transformed
into Escherichia coli D5
. Protein production was
initiated by addition of 1 mmol/L isopropyl
ß-D-thiogalactopyranoside to the culture.
Fusion proteins were affinity purified on gluthathione Sepharose 4B to
obtain glutathione S-transferase (GST)–Raf1-Ras-binding
domain (RBD) to isolate RasGTP or GST-RalGDS-RBD
to isolate Rap1GTP.
Ras and Rap1 Activation Assays
Cells were lysed in lysis buffer containing 10 mmol/L
MgCl2. GST-Raf1-RBD or GST-RalGDS-RBD was added
to the supernatant and incubated overnight at 4°C with slight
agitation. After washing the beads 3 times with lysis buffer, Laemmli
sample buffer was added and samples were resolved on a 12%
SDS-PAGE.
JNK Activation Assay
JNK activity was measured with a commercially available kit
based on phosphorylation of recombinant c-Jun (New
England Biolabs).
Detection of Cell Death
Cells were cotransfected with 0.9 µg of
AT1 plasmids and 0.4 µg of pcDNA3.1-LacZ using
lipofectamine/Plus (GIBCO-BRL). After a 24-hour incubation, to allow
protein expression, apoptosis was induced by serum
deprivation for 24 hours. The dishes were
centrifuged to pellet-detached cells. Transfected living and
apoptotic cells were identified by ß-galactosidase staining.
Cells were fixed in 2% formaldehyde/0.2%
glutaraldehyde, and ß-galactosidase activity was
determined by incubation with 40 µg/mL X-gal for 24 hours at 37°C.
The transfection efficiency with 1.3 µg of pcDNA3.1-LacZ was 90±4%,
and the efficiency for the cotransfection was 71±5%. For
morphological staining of nuclei, cells were stained with DAPI as
described previously.19 Cell apoptosis was also
measured by terminal
deoxynucleotidyltransferase–mediated
dUTP nick end labeling (TUNEL) staining and DNA laddering as described
previously.20
Statistical Analysis
Data are expressed as mean±SEM from 
3 independent
experiments. Statistical analysis was performed with ANOVA
followed by modified least significant difference test.
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Results |
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Effect of Ang II on ERK1/ERK2 Activation in 293 Cells Transfected With AT1Rwt or AT1R(Del221/222)
We investigated the effect of a deletion in the third cytoplasmic loop of the AT1 on ERK1/ERK2 activation by Ang II. A series of experiments supports a critical role for a conserved apolar residue in the third cytoplasmic loop (Leu222) in agonist-induced activation of the AT1 and possibly many other GPCRs.21 There is also a conserved motif in the third cytoplasmic loop (amino acids 221 and 222) present in both AT1 and AT2, and absent in other GPCRs, suggesting important Ang II–specific effects.22 Therefore, we have chosen to determine the effects on Ang II signal transduction of deleting amino acids 221 and 222 in the AT1. We determined that the expression and binding capacity of AT1R(Del221/222) and AT1Rwt for Ang II were equivalent (93±12% for AT1R[Del221/222]) compared with AT1Rwt (data not shown).21 However, coupling to G proteins by AT1R(Del221/222) was altered, because Ang II failed to stimulate phospholipid hydrolysis.21 In the present experiments, AT1Rwt and AT1R(221/222) were transfected into 293 cells, which do not express AT1. Equivalent protein expression was verified by Western blot analysis (Figure 1A
). To prove that Ang II–induced
ERK1/ERK2 activation was due to activation of the
AT1, ERK1/ERK2 activation was blocked by
preincubation with losartan, an AT1
antagonist (Figure 1B).
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First, a time course was studied. Stimulation of both AT1Rwt and
AT1R(Del221/222) by Ang II caused maximal activation of ERK1/ERK2 at 3
minutes (Figures 1C
and 1D). However, the ERK1/ERK2 activation
by Ang II in cells transfected with AT1R(Del221/222) was significantly
less than in cells transfected with AT1Rwt (3.0±0.5–fold versus
19.4±3.2–fold, P<0.01).
Effect of Cytoplasmic Ca2+ on Ang II–induced
ERK1/ERK2 Activation
Cytoplasmic Ca2+ plays an important role in
Ang II–mediated signal transduction.23 24 25 26 To determine
the calcium requirement for Ang II–induced ERK1/ERK2 activation in
AT1Rwt- and AT1R(Del221/222)-transfected cells, we used BAPTA-AM, a
cytoplasmic Ca2+ chelator.24
ERK1/ERK2 activation by Ang II in AT1Rwt-transfected cells was almost
completely Ca2+ independent (Figure 2). In contrast, ERK1/ERK2 activation in
AT1R(Del221/222)-transfected cells was completely
Ca2+ dependent. As a positive control, tumor
necrosis factor- was used (Figure 2). These results suggest
that 2 different pathways exist for Ang II–induced ERK1/ERK2
activation by the AT1.
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Effect of Ras and Rap1 on ERK1/ERK2 Activation
To gain further insight into the upstream mechanisms responsible
for Ca2+-dependent and -independent ERK1/ERK2
activation, we studied the ability of Ang II to stimulate Ras and Rap1.
Previously, it has been shown that Ca2+ seemed to
be required for activation of Rap1.27 Ras was
activated by Ang II in AT1Rwt-transfected cells (Figure 3A) to a magnitude similar to that
observed in vascular smooth muscle cells.8 28 However, Ang
II failed to stimulate Ras activity in AT1R(Del221/222)-transfected
cells (Figure 3A). In contrast, Rap1 was activated in
AT1R(Del221/222)-transfected cells, but not in AT1Rwt-transfected cells
(Figure 3B). Chelation of Ca2+ by BAPTA-AM
completely abolished Rap1 activation by Ang II in
AT1R(Del221/222)-transfected cells (data not shown). Consistent
with these differences in activation of small G proteins,
cotransfection with RasN17, a dominant-negative mutant of Ras,
dramatically inhibited Ang II–induced ERK1/ERK2 activation in AT1Rwt,
but not in AT1R(Del 221/222) (Figure 3C). Furthermore,
cotransfection with Rap1N17, a dominant-negative mutant of Rap1, almost
completely abolished ERK1/ERK2 activation in AT1R(Del 221/222) (Figure 3D). On the basis of these results, we speculate that the major
pathway for ERK1/ERK2 activation by AT1Rwt occurs via Ras activation
and, in addition, a minor pathway exists via Rap1 that is independent
of amino acids 221 and 222.
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Effect of AT1R(Del221/222) on AKT Activation by Ang
II
It has previously been shown that Ang II binding to the
AT1 stimulated AKT, and AKT activity was required
for vascular smooth muscle cell growth.12 Therefore, the
effects of AT1R(Del221/222) on Ang II–induced AKT-activation were
determined. Ang II activated AKT in cells transfected with
AT1Rwt, with peak at 10 minutes. No activation occurred in cells
transfected with AT1R(Del221/222) (Figure 4A). Preincubation with the PI3K
antagonist, LY294002, completely inhibited Ang II–induced
AKT activation in AT1Rwt-transfected cells (Figure 4B). In
contrast, LY294002 did not show any effect on ERK1/ERK2 activation
by Ang II (Figure 4B).
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Effect of AT1R(Del221/222) on JNK Activation by Ang II
Although AKT and ERK1/ERK2 are involved in cell growth, JNK,
another kinase activated by Ang II, has been suggested to play
a role in apoptosis.15 25 Therefore, we examined
Ang II–induced JNK activation in cells transfected with
AT1R(Del221/222). As expected, JNK was activated by Ang II in
AT1Rwt-transfected cells, with a maximal increase at 15 minutes (Figure 5A). In AT1R(Del221/222)-transfected
cells, JNK was stimulated to a similar magnitude (Figure 5A). To
determine whether activation of JNK via the AT1Rwt and the
AT1R(Del221/222) required the same upstream mediators, we studied the
role of CDC42, a known upstream activator of JNK. CDC42N17,
a dominant-negative mutant of CDC42, was cotransfected with AT1Rwt or
AT1R(Del221/222), and JNK activity was measured.18
Activation of JNK was completely abolished in 293 cells cotransfected
with CDC42N17 and AT1Rwt or AT1R(Del221222) (Figure 5B). Cells
cotransfected with LacZ or RasN17 and AT1Rwt or AT1R(Del221/222) had no
effect on Ang II–induced jun phosphorylation (Figure 5B).
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Effect of Ang II on Serum Deprivation–Induced
Apoptosis in AT1Rwt- and AT1R(Del221/222)-Transfected
Cells
To gain further insight into the physiological
role of amino acids 221 and 222 in the third cytoplasmic loop of the
AT1, we examined the effect of Ang II on serum
deprivation–induced apoptosis in 293 cells
transfected with AT1Rwt or AT1R(Del221/222. Apoptosis was
induced by removing serum for 24 hours in the presence or absence of
Ang II. Ang II significantly decreased apoptosis induced by
serum deprivation in cells transfected with AT1Rwt (Figures 6A through 6C). However, in cells
transfected with AT1R(Del221/222), Ang II had no effect on
apoptosis induction (Figures 6A through 6C). To ensure
that the morphological changes observed with DAPI staining were due to
apoptosis, we also measured apoptosis with TUNEL
staining and DNA laddering and obtained results similar to those with
DAPI stain (Figure 6B and data not shown). To verify that the
effect of Ang II on serum deprivation–induced
apoptosis was not a nonspecific feature of
AT1R(Del221/222)-transfected cells, we determined the ability of
thrombin to prevent apoptosis. Serum
deprivation–induced apoptosis in AT1Rwt- and
AT1R(Del221/222)-transfected cells was significantly inhibited by
thrombin to the same extent (Figure 6C). Furthermore, we
investigated H2O2-induced
apoptosis, which was also inhibited by Ang II in
AT1Rwt-transfected cells, but not in cells transfected with
AT1R(Del221/222) (data not shown).
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Because AKT and ERK1/ERK2 are both known to have antiapoptotic
functions, and our data demonstrate that AKT- and ERK1/ERK2-activation
occur via 2 independent pathways (Figure 4B), we used
pharmacological inhibitors to determine their relative
roles in the antiapoptotic effect of Ang II. The PI3K
inhibitor LY294002 blocked the antiapoptotic effect
of Ang II in AT1Rwt-transfected cells to a greater extent than the
mitogen-activated protein kinase (MEK)/ERK1
inhibitor PD98059 (Figure 6D). When used in
combination, PD98059 and LY294002 completely abolished the
antiapoptotic effect of Ang II in AT1Rwt-transfected cells
(Figure 6D). In cells transfected with AT1R(Del221/222), the
inhibitors showed no effect (Figure 6D).
Effect of Constitutively Active AKT on Serum
Deprivation–Induced Apoptosis
We further investigated the role of Ang II in the signal
transduction pathways dependent on amino acids 221 and 222. We
cotransfected constitutively active AKT13 and
AT1R(Del221/222) to show that we could rescue cells from serum
deprivation–induced apoptosis. Indeed, as shown in
Figure 7, overexpression of
constitutively active AKT significantly inhibited serum
deprivation–induced apoptosis in
AT1R(Del221/222)-transfected cells (Figure 7).
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Discussion |
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In the present study, we demonstrated that binding of Ang II to AT1 activates ERK1/ERK2 via 2 pathways and that activation of ERK1/ERK2 and AKT by Ang II via the third cytoplasmic loop of the AT1 is necessary for serum deprivation–induced apoptosis inhibition (Figure 8
). The major pathway (as defined
by the magnitude of ERK1/ERK2 activation) stimulates Ras, is
independent of cytoplasmic Ca2+, and requires the
presence of amino acids 221 and 222 in the third cytoplasmic loop,
whereas the minor pathway activates Rap1 and is dependent on
cytoplasmic Ca2+ and not on amino acids 221 and
222. In contrast, the third cytoplasmic loop is not required for Ang
II–mediated activation of CDC42 and the downstream kinase, JNK.
Finally, the activation of AKT and ERK1/ERK2 that is dependent on amino
acids 221 and 222 in the third cytoplasmic loop is required for Ang
II–mediated inhibition of serum deprivation–induced
apoptosis. These data provide evidence for the first time that
ERK1/ERK2 activation by Ang II occurs via 2 distinct pathways (via Ras
and via Rap1), as well as a direct link between activation of several
kinases by the third cytoplasmic loop of the AT1
and inhibition of apoptosis by Ang II.
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The "minor" pathway for ERK1/ERK2 activation by the AT1, which requires Rap1 activity and cytoplasmic Ca2+, was revealed by deletion of 2 amino acids (221 and 222) in the third cytoplasmic loop. The fact that Rap1 activation was not observed in cells transfected with AT1Rwt has 2 possible explanations. The most likely explanation is that signals stimulated by Ang II binding to the AT1Rwt inhibit Rap1 activity. A less likely explanation is that the AT1R(Del 221/222) has acquired a novel function (ie, a receptor metamorphosis) that results in altered coupling to downstream mediators. Given that the deletion of amino acids 221 and 222 in the AT1 abolishes phosphoinositide turnover,21 it seems that RAP1 activation requires an ambient level of intracellular calcium. The fact that the 2 AT1-stimulated ERK1/ERK2 pathways are characterized by a difference in their requirement for Ca2+ may provide an explanation for reports that have found varying degrees of calcium dependence for ERK1/ERK2 activation by Ang II in multiple cell types.23 26 29 30 It is possible that differences in the relative expression of the mediators responsible for the 2 pathways identified in the present study may explain these findings. If such differences occurred in vivo, there would be potentially significant physiological effects in tissue responses to Ang II.
Insight into the roles of the 2 AT1-dependent ERK1/ERK2 activation pathways may be derived from consideration of the specific functions of Ras and Rap1. Ras is activated by Grb2 adaptor proteins and the guanine nucleotide exchange factor SOS, whereas Rap1 is activated by CRK adaptor proteins and the guanine-nucleotide-exchange factor C3G. Two 2 nonexclusive roles for Rap1 have been proposed, as follows31 : (1) as a negative regulator of Ras-dependent signal events and (2) as an upstream Ras-like small G protein that couples to downstream kinases.30 32 In support of Rap1 inhibiting Ras are the data of Okada et al,33 which showed a "competition" between Ras and Rap1 for binding to Raf1. These authors showed that insulin stimulation of the human insulin receptor inactivated Rap1 and decreased the amount of Rap1 bound to Raf1, whereas association of Raf1 with Ras was increased. In contrast, Franke et al27 showed in platelets that Rap1 was activated by GPCRs, which required a rise in cytoplasmic Ca2+ and was induced by agents that increase cytoplasmic Ca2+. Finally, York et al32 reported that activation of ERK1/ERK2 by nerve growth factor in PC12 cells required both Ras and Rap1. Initial activation of ERK1/ERK2 required Ras, but sustained ERK1/ERK2 activation required Rap1 via stimulation of the downstream B-Raf/MEK/ERK cascade. Thus, our data provide evidence that in cells expressing both B-Raf and Raf1, Ang II may regulate ERK1/ERK2 via these parallel pathways.
The nature of the interaction between signal mediators and the AT1 third cytoplasmic loop remains undefined. However, it is clear that Ang II binding induces a conformational change in the AT1 that, in the presence of GTP-bound G proteins, confers an additional conformational change to yield a high-affinity state of the receptor.34 Our findings now indicate further that a critical conformational change in the AT1 is mediated by the third cytoplasmic loop. When this interaction is disrupted, alternative pathways such as the Rap1-dependent pathway described in the present study are revealed.
The signaling pathways that determine cell death versus cell survival via the AT1 are poorly understood. It is known that binding of Ang II to the AT1 activates AKT and ERK1/ERK2 and both kinases participate in inhibition of apoptosis. An important physiological property of Ang II is its ability to regulate cell growth and apoptosis.19 35 Recently, it has been found that Ang II can exert both antiapoptotic and proapoptotic effects in a cell- and receptor-specific manner. Binding of Ang II to the AT1 inhibits apoptosis of vascular smooth muscle cells35 and 293 cells (as shown in the present study). In contrast, in endothelial cells, the AT1 promotes apoptosis by activation of caspases via the AT1 as well as via the AT2.19 However, the regulatory mechanisms by which Ang II inhibits apoptosis via the AT1 in smooth muscle cells or other cell lines are poorly defined. Pollman et al35 showed that Ang II inhibited NO-induced apoptosis in vascular smooth muscle cells. Furthermore, it is well known that PI3K, AKT, and ERK1/ERK2 are involved in cell survival and in apoptosis suppression.8 14 Thus, our data for the first time connect the antiapoptotic functions of the AT1 with the activation of kinases AKT and ERK1/ERK2 because of amino acids 221 and 222 of the third cytoplasmic loop of the AT1.
Consistent with our findings that the third cytoplasmic loop is important for G protein coupling are recent studies demonstrating that G proteins play a role in mitogenesis and cell growth.36 Furthermore, JNK, which seems to have a proapoptotic function, is not activated by events dependent on amino acids 221 and 222. The effects of Ang II on growth and apoptosis mediated by ERK1/ERK2, AKT, and JNK in vitro are likely to be important in vivo, as shown by studies in the rat carotid balloon injury model.37 Together with the present study, these results suggest that the AT1 third cytoplasmic loop is critical in determining the nature of Ang II effects on cell growth and apoptosis. Moreover, mutations in the third cytoplasmic loop of the AT1 or alterations in G proteins that couple to the third cytoplasmic loop may be pathogenic in vascular diseases such as hypertension, atherosclerosis, and restenosis after balloon angioplasty.
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Acknowledgments |
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This study was supported by NIH/National Heart, Lung, and Blood Institute Grants R01HL491921 and HL 59975 (to B.C.B.). J.H. was supported by Deutsche Forschungsgemeinschaft Grant HA 2868/1-1. We thank Dr Shalloway (Cornell University, Ithaca, NY) for providing the Raf-RBD, Dr Meinkoth (University of Pennsylvania, Philadelphia, Pa) for the RalGDS-RBD construct, and Dr S. Dimmeler (University of Frankfurt, Frankfurt, Germany) for the AKT construct.
Received October 13, 1999; accepted January 27, 2000.
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