| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
ARTICLES |
Endocrinology and Reproduction Research Branch, National Institute of Child Health and Human Development, National Institutes of Health, Bethesda, Maryland 20892
Address all correspondence and requests for reprints to: Dr. K. J. Catt, ERRB, NICHD, National Institutes of Health, Building 49, Room 6A-36, 9000, Rockville Pike, Bethesda, Maryland 20892. E-mail: catt{at}helix.nih.gov
 |
Abstract |
|---|
 Top Abstract IntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
|
Introduction |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Ang II has been shown to influence several intracellular signaling pathways in its numerous target cells. The peptide can inhibit adenylate cyclase, activate guanylate cyclase, release prostaglandins and leukotrienes, regulate calcium channels, and induce the expression of transcription factors including c-fos, c-jun, junB, and Krox 24 (7, 8). However, the major signaling event activated by the AT1 receptor appears to be phospholipase C-dependent hydrolysis of phosphatidylinositol 4,5 bisphosphate (PtdInsP2). The cleavage of PtdInsP2 results in the generation of inositol 1,4,5-trisphosphate (which mobilizes Ca2+ from intracellular stores) and diacylglycerol [which activates protein kinase C (PKC)] (7). Ang II also stimulates the phosphorylation on tyrosine residues of several proteins in various target cells (9, 10, 11). However, despite detailed studies of these pathways in BAG and other cells, the signaling events that mediate Ang II-stimulated mitogenesis are not well defined.
Mitogen-activated protein kinases (MAPKs, p42MAPK and p44MAPK) are ubiquitous signaling intermediates that, when activated by phosphorylation, play a critical role in cellular proliferation (reviewed in Refs. 12–14). The best understood pathway to MAPK activation is that initiated by receptor tyrosine kinases, exemplified by the EGF receptor (EGF-R). Following activation, the EGF-R is autophosphorylated on tyrosine residues to create docking sites for the SH2 domains of adapter molecules such as shc and Grb2. After binding to the EGF-R, shc is tyrosine phosphorylated by the receptor, thereby creating a binding site for the SH2 domain of Grb2. The latter (which therefore binds to the EGF-R via both shc-dependent, and -independent mechanisms) recruits to the plasma membrane the guanine nucleotide exchange factor, m-sos, which promotes the exchange of GDP for GTP on membrane-anchored ras. GTP-bound ras recruits to the plasma membrane raf-1 kinase, which is then activated by a poorly understood mechanism. Raf-1, in turn, phosphorylates and activates MAPK kinase (Mek), which subsequently phosphorylates and activates MAPK. Following its activation, MAPK translocates to the nucleus where it phosphorylates various targets including transcription factors critical to the control of cellular proliferation.
In addition to this pathway of MAPK activation via receptor tyrosine
kinases, MAPK can also be activated via certain G protein-coupled
receptors (which lack intrinsic kinase activity). The pathway from
Gi-coupled receptors appears to be mediated by the release
of Gß
complexes from pertussis toxin-sensitive G
proteins (15, 16). In contrast, the mechanisms leading to MAPK
activation via Gq-coupled receptors are poorly defined.
Because the mitogenic action of Ang II is mediated via the
Gq-coupled AT1 receptor, we have investigated
the effects of the peptide on MAPK, and the upstream signaling pathways
leading to its activation, in BAG cells.
|
Materials and Methods |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
Bovine adrenal glomerulosa cell preparation
Primary cultures of glomerulosa cells were prepared from bovine
adrenal glands as previously described (6). Cells were plated at
1.5 x 106 cells per 60-mm plastic culture dish
(Becton Dickinson, Lincoln, NJ) in DMEM containing 10% (vol/vol) DHS,
2% (vol/vol) FBS, 100 µg/ml streptomycin, 100 IU/ml penicillin, 5
µg/ml fungizone, 25 µg/ml gentamicin, 8 µg/ml trimethoprim, and
40 µg/ml sulfamethoxazole. The cells were cultured for 4 days in a
humidified atmosphere of 5% CO2 in air at 37 C, after
which time they formed confluent monolayers. Cells were rendered
quiescent by the withdrawal of serum for 48 h before use. After
stimulation for the times indicated in the individual figures, cells
were washed with ice-cold PBS before lysing in the appropriate
buffer.
Immunoblot analysis of MAPK and Raf-1 proteins
Following stimulation, cells were drained, scraped into 0.5 ml
of Laemmli sample buffer (17), and sonicated for 5 sec. After boiling
for 5 min, equal quantities of cell lysates were subjected to SDS-PAGE,
and the separated proteins were transferred to PVDF membranes. For MAPK
and raf-1 immunoblotting, the membranes were probed with mouse
monoclonal anti-p42MAPK (1 µg/ml; UBI, Lake Placid, NY)
or rabbit polyclonal anti-raf-1 antibody (0.5 µg/ml; Santa Cruz
Biotechnology, Santa Cruz, CA) respectively. Immunoreactive bands were
detected using horseradish peroxidase-conjugated secondary antibodies
(Kirkegaard & Perry, Gaithersburg, MD) at a dilution of 1 in 3000 and
enhanced chemiluminescence (LumiGlo, Kirkegaard & Perry).
MAPK activity assay
Following stimulation, cells were scraped into lysis buffer (137
mM NaCl, 25 mM NaF, 1 mM EGTA, 1.5
mM MgCl2, 1% (vol/vol) Triton X-100, 10%
(vol/vol) glycerol, 20 mM Tris, pH 8.0) containing freshly
added 100 µM Na3VO4, 200
µM phenylmethylsulfonylfluoride, aprotinin (1 µg/ml),
leupeptin (1 µg/ml), and pepstatin (1 µg/ml) and frozen immediately
on dry ice. After thawing, lysates were centifuged at 10,000 x
g for 20 min at 4 C, and equal amounts of supernatant were
immunoprecipitated with the anti-p42MAPK antibody. Immune
complexes were collected on GammaBind Plus sepharose (Pharmacia,
Uppsala, Sweden) and washed three times with lysis buffer lacking
inhibitors. The sepharose beads were resuspended in 60 µl of reaction
buffer (0.5 mM EGTA, 2.4 mM EDTA, 20
mM MgCl2, 50 µM NaF, 20
mM Tris, pH 7.5) in the presence of 2 µCi
[-32P]ATP, 50 µM unlabeled ATP, and 50
µg of the synthetic peptide, APRTPGGRR (synthesized by Dr. H. C.
Chen), which contains amino acids 95–98 of bovine myelin basic
protein, as substrate. After 30 min incubation at 30 C, the reaction
was terminated by addition of ice-cold trichloroacetic acid (TCA) to a
final concentration of 6% (wt/vol). Following removal of sepharose
beads by centrifugation, the supernatant was applied to
phosphocellulose filters (Whatman, Clifton, NJ), washed with 75
mM phosphoric acid, and radioactivity incorporated into the
peptide substrate was measured by liquid scintillation
spectrometry.
Raf-1 kinase assay
Following stimulation, cells were scraped into 0.5 ml of lysis
buffer (150 mM NaCl, 2 mM EDTA, 1% (wt/vol)
sodium deoxycholate, 1% (vol/vol) Nonidet P-40, 0.1% (wt/vol) SDS, 50
mM NaF, 10 mM sodium phosphate, pH 7.0)
containing freshly added aprotinin (1 µg/ml),
Na3VO4 (200 µM),
ß-mercaptoethanol (14 mM) and
phenylmethylsulfonylfluoride (1 mM). After centrifugation
at 10,000 x g for 20 min, equal amounts of supernatant
were immunoprecipitated with 2 µg of anti-raf-1 antibody. Immune
complexes were collected on GammaBind Plus sepharose, washed three
times in PAN buffer (10 mM
piperazine-N,N'-bis[2-ethanesulfonic acid), pH
7.0, 20 µg/ml aprotinin, 100 mM NaCl), and resuspended in
100 µl total volume of PAN buffer containing 20 µCi
[-32P]ATP, 50 µM unlabeled ATP, and 2.5
µg of a catalytically inactive mutant GST-[K97A]-Mek-1 fusion
protein (UBI, Lake Placid, NY) as substrate. After a 30-min incubation
at 30 C, the reaction was terminated by the addition of ice-cold TCA to
a final concentration of 6% (wt/vol). Precipitation of proteins was
facilitated by the addition of 20 µg ovalbumin; the precipitates were
collected by centrifugation and solubilized in Laemmli sample buffer
(17). Samples were then boiled for 10 min, subjected to SDS-PAGE, and
visualized in a PhosphorImager (Molecular Dynamics, Sunnyvale, CA).
Ras activation assay
Serum-deprived cells were incubated for 16 h in
phosphate-free DMEM containing 100 µCi/ml
32Pi. After washing, the cells were incubated
in a buffered salt solution (123 mM NaCl, 2.4
mM KCl, 1.8 mM CaCl2, 10
mM glucose, 20 mM HEPES, pH 7.4) containing
0.1% (wt/vol) BSA for 10 min at 37 C. Following the addition Ang II
(30 nM) for the required times, cells were washed with
ice-cold PBS, drained, and scraped into lysis buffer (150
mM NaCl, 16 mM MgCl2, 1% (vol/vol)
Nonidet P-40, 25 mM Tris, pH 7.5) containing 2 µg/ml
Y13–259 rat monoclonal anti-v-Ha-ras antibody (Oncogene Science,
Uniondale, NY). Insoluble material was removed by centrifugation and 20
µl of a 50% slurry of GammaBind Plus sepharose were added to the
supernatants for 1 h at 4 C. The sepharose-bound immune complexes
were collected, washed extensively with lysis buffer, and aspirated to
dryness. Radiolabeled guanine nucleotides were extracted into 12 µl
of elution buffer (0.2% (wt/vol) SDS, 2 mM DTT, 0.5
mM GTP, 0.5 mM GDP, 2 mM EDTA, pH
7.4) for 20 min at 68 C and resolved by ion-exchange TLC on
PEI-cellulose plates containing a fluorescent indicator (EM Science,
Gibbstown, NJ) with 0.75 M KH2PO4
(pH 3.4) as running buffer. Radioactivity migrating at the positions of
GDP and GTP standards was visualized and quantitated by analysis with a
PhosphorImager. The percentage of GTP was calculated using the formula:
(GTP x 2/3)/(GDP + GTP x 2/3) x 100.
|
Results |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
), reflecting its phosphorylation
on tyrosine and threonine residues (18, 19). Ang II-induced MAPK
phosphorylation was evident after a lag time of 1 min, increased to a
maximum between 5 and 10 min, and returned to the basal state by 60
min.
|
). Ang II was a potent stimulus of MAPK
activity in BAG cells, with a half-maximal effect at 3–10
pM and maximal activation by peptide concentrations as low
as 300 pM (Fig. 2B).
Similarly, maximal phosphorylation of MAPK was elicited by 500
pM Ang II (Fig. 2A).
|
). Hence, Ang II induces phosphorylation
(and, therefore, activation) of MAPK via the AT1 receptor
subtype.
|
), indicating that an increase in
cytoplasmic [Ca2+] alone is insufficient to activate the
kinase in BAG cells.
|
. 100 µM La3+
(a nonspecific inhibitor of Ca2+ entry pathways) had no
effect, and removal of external Ca2+ had only a minor
effect on Ang II-induced MAPK activity (Fig. 4). Similarly, the
dihydropyridine agonist, BayK (30 nM), and antagonist,
nifedipine (2 µM), each had no effect on the Ang
II-induced response (Fig. 5). However, removal of external
Ca2+ combined with the addition of 0.1 mM EGTA
significantly reduced the effect of Ang II on MAPK (Fig. 4). Taken
together, these data suggest that elevation of intracellular
[Ca2+], resulting either from Ca2+ influx or
due to its release from intracellular stores, is not a major component
of Ang II-induced MAPK activation. However, the impaired MAPK
activation observed in the presence of Ca2+-free medium
containing EGTA (which would deplete intracellular Ca2+)
suggest a permissive role for Ca2+ in this response.
|
). Maximal MAPK phosphorylation
and activation occurred at 5–10 min, which correlated with the time
required for maximal activation of MAPK in response to Ang II (Fig. 1B). However, in contrast to the transient effect of Ang II on MAPK
activity, which returned to the basal level 60 min after addition of
the ligand (Fig. 1B), the effect of PMA on MAPK activity was still
evident (3.5-fold increase over control) at 60 min (Fig. 6B).
Similarly, PMA-induced MAPK phosphorylation was still apparent at 60
min (Fig. 6A), at which time AngII-induced MAPK phosphorylation had
returned to the basal level (Fig. 1A). Hence, stimulation of PKC alone
is sufficient to activate MAPK in BAG cells.
|
), and the basal level of MAPK activity
was increased by about 60% in PKC-depleted (compared with PKC-replete)
cells (Fig. 7B). However, the magnitude of Ang II-induced MAPK
activation in PKC-depleted cells was greatly reduced (110% increase
over PKC-replete control; 40% increase over PKC-depleted control)
compared with PKC-replete cells (300% increase over PKC-replete
control). Consistent with these findings, PKC depletion partially
attenuated Ang II-stimulated MAPK phosphorylation (Fig. 7A). Hence, PKC
participates in a major (but not exclusive) pathway to MAPK activation
in AngII-stimulated BAG cells.
|
). In terms of absolute magnitude,
therefore, PTX had no effect on MAPK activation. However, if MAPK
activation is evaluated as a fold increase over unstimulated (but PTX
treated) cells, PTX inhibited the Ang II-stimulated increase in MAPK
activation by 47% (from 3.4-fold to 1.8-fold). Hence, although a major
component of the Ang II-induced MAPK activation is clearly insensitive
to PTX, these data do not exclude a possible minor PTX-sensitive
component in this response.
|
), an effect that correlates with
hyperphosphorylation of the kinase (25). However, this mobility shift
was considerably delayed in comparison to the effect of Ang II on MAPK
phosphorylation in the same experiment. Whereas MAPK phosphorylation
was detected as early as 1 min after addition of the peptide, no
mobility shift of raf-1 was apparent before 5 min. Furthermore, whereas
MAPK phosphorylation decreased from its peak at 5–10 min to the basal
level by 60 min, the mobility shift of raf-1 was sustained and was
still maximal at 60 min (Fig. 9A).
|
).
Thus, the time-course of Ang II-induced raf-1 phosphorylation and the
consequent shift in its electrophoretic mobility do not correlate with
activation, but rather with inactivation, of the kinase.
We next investigated the role of PKC in raf-1 phosphorylation.
Short-term (5 min) treatment of BAG cells with PMA caused a shift in
raf-1 mobility (Fig. 10A), indicating
that activation of PKC alone is sufficient to phosphorylate raf-1.
Furthermore, depletion of PKC by prolonged PMA treatment completely
abrogated the raf-1 mobility shift induced by Ang II (Fig. 10A). These
results indicate that the raf-1 phosphorylation (which causes a shift
in its electrophoretic mobility) induced by Ang II is mediated by
PKC.
|
). These data indicate
that, although PKC activation is sufficient to activate raf-1 kinase,
the pathway by which Ang II activates raf-1 does not require PKC.
Ang II activates ras
Because ras acts as an upstream regulator of raf-1 kinase in
growth factor-stimulated cells, we investigated the effect of Ang II on
ras activation in BAG cells. As ras is activated by the exchange of
bound GDP for GTP, the percentage of radiolabeled GTP (as a proportion
of GTP + GDP) bound to p21ras immunoprecipitated from
32Pi-labeled BAG cells was measured. The basal
%GTP bound to ras varied from 5.3% to 9.3% (n = 3). Ang II (30
nM) stimulated a rapid but transient exchange of ras-bound
GDP for GTP that reached a maximum (mean 70% increase over control,
n = 3) at 5–10 min and declined thereafter to near the
prestimulation level by 30 min (Fig. 11). The time-course of Ang
II-induced ras activation therefore correlates with both raf-1 and MAPK
activation in BAG cells.
|
|
Discussion |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
We found that Ang II activates the major mitogenic signaling intermediate, MAPK, in BAG cells, thus providing a probable mechanistic explanation for the mitogenic effects of the peptide in these cells. Although the pathway from receptor tyrosine kinases to MAPK activation is well characterized, the mechanisms whereby G protein-coupled receptors (which lack intrinsic kinase activity) activate MAPK are not well defined. In contrast to the ras-dependent pathway activated by receptor tyrosine kinases, G protein-coupled receptors appear to activate multiple ras-dependent and -independent pathways to MAPK (12, 13, 14). Receptors that couple via Gq to phosphoinositide hydrolysis (such as the AT1 receptor) stimulate the formation of diacylglycerol and elevate intracellular [Ca2+] (7). In several cell types, the resultant activation of PKC plays an important role in MAPK activation (12, 13, 14), although elevated intracellular [Ca2+] also appears to be sufficient to activate MAPK in some cell types (21).
Ang II increases intracellular [Ca2+] in BAG cells, both via the release of Ca2+ from intracellular stores and by the activation of Ca2+ influx (7). However, neither blockade nor activation of Ca2+ channels had any effect on Ang II-stimulated MAPK activation. Also, the release of Ca2+ from intracellular stores by thapsigargin failed to activate MAPK. Hence, elevation of intracellular [Ca2+] does not appear to contribute significantly to Ang II-induced MAPK activation. However, Ca2+ does appear to play a permissive role in this response because incubation of cells in Ca2+-free medium containing EGTA (which depletes intracellular Ca2+) significantly reduced Ang II-stimulated MAPK activation.
We examined the role of PKC in Ang II-induced MAPK activation by down-regulating the kinase with a high dose of PMA. Because PKC depletion attenuated, but did not abolish, Ang II-induced MAPK activation, the peptide appears to activate at least two pathways to MAPK: a major, PKC-dependent pathway and a minor, PKC-independent pathway. In contrast to its partial inhibitory effect on MAPK activation, PKC depletion had no effect on Ang II-induced raf-1 activation. Because raf-1 kinase lies immediately downstream of ras, it is reasonable to assume, therefore, that the ras/raf-1 activation pathway represents the PKC-independent limb of the Ang II-induced MAPK response in BAG cells.
Previous studies of the role of PKC in ras activation are conflicting. For example, the expression of a dominant-negative ras mutant failed to block PMA-stimulated MAPK phosphorylation in fibroblasts (36), whereas phorbol ester-induced MAPK activation was dependent on ras in T cells (37). Because ras/raf-1 activation is independent of PKC in BAG cells, the site(s) of PKC action in these cells probably lies downstream of raf-1 at the level of Mek and/or MAPK itself. However, because PKC appears unable to directly activate either of these kinases in some cells (14), it is possible that it may act on alternative (non-raf) Mek activators such as Mek kinase or mos (12, 13, 14).
The reported effects of PKC on raf-1 phosphorylation and its relationship to raf-1 activity are contradictory. In fibroblasts, PKC phosphorylated and directly activated raf-1 (38, 39) and the expression of a dominant-negative raf-1 mutant blocked PMA-induced gene transcription (40). Conversely, mutation of the raf-1 site phosphorylated by PKC was found to have no effect on raf-1 activation in T cells (41). In BAG cells, Ang II stimulated a raf-1 phosphorylation event that was detectable as a shift in the electrophoretic mobility of the kinase, but this mobility shift did not correlate temporally with raf-1 activation. Furthermore, whereas raf-1 activation was independent of PKC, its phosphorylation was PKC dependent. It is apparent, therefore, that the raf-1 phosphorylation event induced by Ang II that causes a mobility shift cannot be responsible for activating the kinase but correlates at least temporally with its deactivation. Nevertheless, it remains to be determined whether delayed PKC-mediated raf-1 phosphorylation is causally related to deactivation of the kinase.
One group of G protein-coupled receptors capable of activating MAPK
operate independently of PKC via PTX-sensitive G proteins (22, 23, 24). The
resultant liberation of Gß complexes is believed to
mediate a sequence of events similar to that activated by receptor
tyrosine kinases (15, 16). These include the tyrosine phosphorylation
of shc and its association with Grb2, and also involve the
participation of a hitherto unidentified component(s) presumed to
contain pleckstrin homology domains (which are capable of interaction
with liberated Gß complexes) (42). In BAG cells, PTX
had no major effect on Ang II-stimulated MAPK activation, and both the
mitogenic and early gene responses of BAG cells to Ang II appear to be
mediated by PTX-insensitive pathways (6). However, because we cannot
rule out a minor PTX-sensitive component to MAPK activation, it will be
interesting to determine the sensitivity to PTX of signaling
intermediates upstream of MAPK activated by Ang II in BAG cells.
Activation of MAPK by Ang II has previously been demonstrated in several cell types including rat vascular smooth muscle cells (43, 44, 45), cardiac myocytes (46), bovine adrenal fasciculata/reticularis cells (34), CHO cells stably transfected with the human AT1 receptor (47), and H295R human adrenal cells (48). However, reports of the role of PKC in MAPK activation are conflicting. Unlike BAG cells, PKC depletion had no effect on MAPK activation in cardiac myocytes (46) or vascular smooth muscle cells (44), whereas (like BAG cells) PKC depletion significantly reduced MAPK activation in AT1-expressing CHO cells (47) and abolished it in bovine adrenal fasciculata/reticularis cells (34). Ang II activated ras in vascular smooth muscle cells (43, 44, 45, 49), ras (50), and raf-1 (46) in cardiac myocytes, and raf-1 in AT1-expressing CHO cells (47). However, in contrast to the PKC-independence of raf-1 activation in BAG cells, raf-1 activation was dependent on PKC in cardiac myocytes (46) and AT1-expressing CHO cells (47). In vascular smooth muscle cells, ras activation was independent of PKC (44). Where tested, PTX had no effect on MAPK activation by Ang II in any of these cells, although both PTX-sensitive (43) and -insensitive (44) ras activation by Ang II have been reported in vascular smoooth muscle cells. The causal relationship between ras/raf-1 activation and MAPK activation in some Ang II-stimulated cells has been addressed by expressing dominant-negative mutants of each factor, with conflicting results: whereas ras was not required for MAPK activation in vascular smooth muscle cells (43, 45) and AT1-expressing CHO cells (47), dominant-negative ras reduced c-fos and cyclin D1 transcription in H295R adrenal cells (48). Similarly, dominant-negative raf-1 abolished, and manumycin (an inhibitor of ras farnesyl transferase) reduced MAPK activation in cardiac myocytes (46). Taking all these findings together, it is apparent that the pathways leading to MAPK activation from the AT1 receptor, and the role played by PKC in these pathways, vary considerably between different cell types, consistent with multiple mechanisms converging on MAPK.
In summary, we have demonstrated that Ang II activates multiple pathways to MAPK in BAG cells: a major, PKC-dependent pathway and a minor PKC-independent pathway which appears to operate via ras and raf-1 kinase. Further analysis of the upstream signaling pathways to MAPK should facilitate our understanding of the mechanisms underlying the mitogenic effects of Ang II in BAG cells.
|
Acknowledgments |
|---|
|
Footnotes |
|---|
Received May 27, 1997.
|
References |
|---|
|
TopAbstractIntroductionMaterials and MethodsResultsDiscussionReferences |
|---|
-mediated MAP kinase activation by
a common signaling pathway. Nature 376:781–784[CrossRef][Medline]
subunits. Nature 369:418–420[CrossRef][Medline]
2-adrenergic
receptors expressed in fibroblasts. J Biol Chem 268:22235–22238 activates RAF-1 by direct phosphorylation. Nature 363:249–252
interactions with PH domains and ras-MAPK signaling pathways.
Trends Biochem Sci 20:151–156[CrossRef][Medline]
This article has been cited by other articles:
 |
|
 |
|
  A. J. Casal, S. Ryser, A. M. Capponi, and C. F. Wang-Buholzer Angiotensin II-Induced Mitogen-Activated Protein Kinase Phosphatase-1 Expression in Bovine Adrenal Glomerulosa Cells: Implications in Mineralocorticoid Biosynthesis Endocrinology, November 1, 2007; 148(11): 5573 - 5581. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Liu, J. A. Enyeart, and J. J. Enyeart Angiotensin II inhibits native bTREK-1 K+ channels through a PLC-, kinase C-, and PIP2-independent pathway requiring ATP hydrolysis Am J Physiol Cell Physiol, August 1, 2007; 293(2): C682 - C695. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Otis and N. Gallo-Payet Differential Involvement of Cytoskeleton and Rho-Guanosine 5'-Triphosphatases in Growth-Promoting Effects of Angiotensin II in Rat Adrenal Glomerulosa Cells Endocrinology, November 1, 2006; 147(11): 5460 - 5469. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. Inagaki, F. Otsuka, J. Suzuki, Y. Kano, M. Takeda, T. Miyoshi, H. Otani, Y. Mimura, T. Ogura, and H. Makino Involvement of Bone Morphogenetic Protein-6 in Differential Regulation of Aldosterone Production by Angiotensin II and Potassium in Human Adrenocortical Cells Endocrinology, June 1, 2006; 147(6): 2681 - 2689. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. Gambaryan, E. Butt, P. Tas, A. Smolenski, B. Allolio, and U. Walter Regulation of aldosterone production from zona glomerulosa cells by ANG II and cAMP: evidence for PKA-independent activation of CaMK by cAMP Am J Physiol Endocrinol Metab, March 1, 2006; 290(3): E423 - E433. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J.-G. LeHoux and A. Lefebvre Novel protein kinase C-epsilon inhibits human CYP11B2 gene expression through ERK1/2 signalling pathway and JunB J. Mol. Endocrinol., February 1, 2006; 36(1): 51 - 64. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Hus-Citharel, X. Iturrioz, P. Corvol, J. Marchetti, and C. Llorens-Cortes Tyrosine Kinase and Mitogen-Activated Protein Kinase/Extracellularly Regulated Kinase Differentially Regulate Intracellular Calcium Concentration Responses to Angiotensin II/III and Bradykinin in Rat Cortical Thick Ascending Limb Endocrinology, January 1, 2006; 147(1): 451 - 463. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. H. Shah, A. Yesilkaya, J. A. Olivares-Reyes, H.-D. Chen, L. Hunyady, and K. J. Catt Differential Pathways of Angiotensin II-Induced Extracellularly Regulated Kinase 1/2 Phosphorylation in Specific Cell Types: Role of Heparin-Binding Epidermal Growth Factor Mol. Endocrinol., August 1, 2004; 18(8): 2035 - 2048. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Ohashi, H. Takagi, H. Oh, K. Suzuma, I. Suzuma, N. Miyamoto, A. Uemura, D. Watanabe, T. Murakami, T. Sugaya, et al. Phosphatidylinositol 3-Kinase/Akt Regulates Angiotensin II-Induced Inhibition of Apoptosis in Microvascular Endothelial Cells by Governing Survivin Expression and Suppression of Caspase-3 Activity Circ. Res., April 2, 2004; 94(6): 785 - 793. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. SPAT and L. HUNYADY Control of Aldosterone Secretion: A Model for Convergence in Cellular Signaling Pathways Physiol Rev, April 1, 2004; 84(2): 489 - 539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 J. Li, R. E. Feltzer, K. L. Dawson, E. A. Hudson, and B. J. Clark Janus Kinase 2 and Calcium Are Required for Angiotensin II-dependent Activation of Steroidogenic Acute Regulatory Protein Transcription in H295R Human Adrenocortical Cells J. Biol. Chem., December 26, 2003; 278(52): 52355 - 52362. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
N. Cherradi, B. Pardo, A. S. Greenberg, F. B. Kraemer, and A. M. Capponi Angiotensin II Activates Cholesterol Ester Hydrolase in Bovine Adrenal Glomerulosa Cells through Phosphorylation Mediated by p42/p44 Mitogen-Activated Protein Kinase Endocrinology, November 1, 2003; 144(11): 4905 - 4915. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 H. Wei, S. Ahn, S. K. Shenoy, S. S. Karnik, L. Hunyady, L. M. Luttrell, and R. J. Lefkowitz Independent {beta}-arrestin 2 and G protein-mediated pathways for angiotensin II activation of extracellular signal-regulated kinases 1 and 2 PNAS, September 16, 2003; 100(19): 10782 - 10787. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
C. Suarez, G. Diaz-Torga, A. Gonzalez-Iglesias, J. Vela, A. Mladovan, A. Baldi, and D. Becu-Villalobos Angiotensin II phosphorylation of extracellular signal-regulated kinases in rat anterior pituitary cells Am J Physiol Endocrinol Metab, September 1, 2003; 285(3): E645 - E653. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. El Bekay, M. Alvarez, J. Monteseirin, G. Alba, P. Chacon, A. Vega, J. Martin-Nieto, J. Jimenez, E. Pintado, F. J. Bedoya, et al. Oxidative stress is a critical mediator of the angiotensin II signal in human neutrophils: involvement of mitogen-activated protein kinase, calcineurin, and the transcription factor NF-{kappa}B Blood, July 15, 2003; 102(2): 662 - 671. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
H. Osman, C. Murigande, A. Nadakal, and A. M. Capponi Repression of DAX-1 and Induction of SF-1 Expression. TWO MECHANISMS CONTRIBUTING TO THE ACTIVATION OF ALDOSTERONE BIOSYNTHESIS IN ADRENAL GLOMERULOSA CELLS J. Biol. Chem., October 18, 2002; 277(43): 41259 - 41267. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
I. Startchik, D. Morabito, U. Lang, and M. F. Rossier Control of Calcium Homeostasis by Angiotensin II in Adrenal Glomerulosa Cells through Activation of p38 MAPK J. Biol. Chem., June 28, 2002; 277(27): 24265 - 24273. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 B. H. Shah and K. J. Catt Calcium-Independent Activation of Extracellularly Regulated Kinases 1 and 2 by Angiotensin II in Hepatic C9 Cells: Roles of Protein Kinase Cdelta , Src/Proline-Rich Tyrosine Kinase 2, and Epidermal Growth Factor Receptor trans-Activation Mol. Pharmacol., February 1, 2002; 61(2): 343 - 351. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Otani, H. Takagi, H. Oh, S. Koyama, and Y. Honda Angiotensin II Induces Expression of the Tie2 Receptor Ligand, Angiopoietin-2, in Bovine Retinal Endothelial Cells Diabetes, April 1, 2001; 50(4): 867 - 875. [Abstract] [Full Text]
|
|
|
|
|
|
L. Xu and J. J. Enyeart Properties of ATP-dependent K+ channels in adrenocortical cells Am J Physiol Cell Physiol, January 1, 2001; 280(1): C199 - C215. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. Thibonnier, D. M. Conarty, and C. L. Plesnicher Mediators of the mitogenic action of human V1 vascular vasopressin receptors Am J Physiol Heart Circ Physiol, November 1, 2000; 279(5): H2529 - H2539. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 K. C. Corbit, J.-W. Soh, K. Yoshida, E. M. Eves, I. B. Weinstein, and M. R. Rosner Different Protein Kinase C Isoforms Determine Growth Factor Specificity in Neuronal Cells Mol. Cell. Biol., August 1, 2000; 20(15): 5392 - 5403. [Abstract] [Full Text]
|
|
|
|
|
|
P. G. Andreis, A. Markowska, H. C. Champion, G. Mazzocchi, L. K. Malendowicz, and G. G. Nussdorfer Adrenomedullin Enhances Cell Proliferation and Deoxyribonucleic Acid Synthesis in Rat Adrenal Zona Glomerulosa: Receptor Subtype Involved and Signaling Mechanism Endocrinology, June 1, 2000; 141(6): 2098 - 2104. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
A. Chorvatova, L. Gendron, L. Bilodeau, N. Gallo-Payet, and M. D. Payet A Ras-Dependent Chloride Current Activated by Adrenocorticotropin in Rat Adrenal Zona Glomerulosa Cells Endocrinology, February 1, 2000; 141(2): 684 - 692. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
L. Gendron*, L. Laflamme*, N. Rivard, C. Asselin, M. D. Payet, and N. Gallo-Payet Signals from the AT2 (Angiotensin Type 2) Receptor of Angiotensin II Inhibit p21ras and Activate MAPK (Mitogen-Activated Protein Kinase) to Induce Morphological Neuronal Differentiation in NG108-15 Cells Mol. Endocrinol., September 1, 1999; 13(9): 1615 - 1626. [Abstract] [Full Text]
|
|
|
|
 |
|
 G. G. Nussdorfer, G. P. Rossi, L. K. Malendowicz, and G. Mazzocchi Autocrine-Paracrine Endothelin System in the Physiology and Pathology of Steroid-Secreting Tissues Pharmacol. Rev., September 1, 1999; 51(3): 403 - 438. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. C. Corbit, D. A. Foster, and M. R. Rosner Protein Kinase Cdelta Mediates Neurogenic but Not Mitogenic Activation of Mitogen-Activated Protein Kinase in Neuronal Cells Mol. Cell. Biol., June 1, 1999; 19(6): 4209 - 4218. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. D. Smith, A. J. Baukal, P. Dent, and K. J. Catt Raf-1 Kinase Activation by Angiotensin II in Adrenal Glomerulosa Cells: Roles of Gi, Phosphatidylinositol 3-Kinase, and Ca2+ Influx Endocrinology, March 1, 1999; 140(3): 1385 - 1391. [Abstract] [Full Text]
|
|
| |||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||||
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
| Endocrinology | Endocrine Reviews | J. Clin. End. & Metab. |
| Molecular Endocrinology | Recent Prog. Horm. Res. | All Endocrine Journals |
