New Signaling Pathways for Hormones and Cyclic Adenosine 3',5'-Monophosphate Action in Endocrine Cells
JoAnne S. Richards
Department of Molecular and Cellular Biology Baylor College of
Medicine Houston, Texas 77030
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ABSTRACT
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The glycoprotein hormones, ACTH, TSH, FSH, and LH
regulate diverse functions in endocrine cells. Although cAMP and PKA
have long been shown to mediate specific intracellular signaling events
including the transcription of specific genes via the CREB-CBP complex,
recent observations have indicated that PKA does not account for all of
the intracellular targets of cAMP. For example, TSH stimulation of
thyroid cell proliferation is not completely blocked by PKA inhibitors.
TSH and FSH can stimulate PKB phosphorylation by a PKAindependent
but PI3-K/PDK1-dependent pathway. An FSH inducible kinase, Sgk, has
recently been shown to be a close relative of PKB. Sgk is also a target
of PI3-K-PDK1 pathway, indicating that some effects previously ascribed
to PKB may be mediated by this inducible kinase. The
identification of novel cAMP-binding proteins that exhibit guanine
nucleotide exchange (GEF) activity (cAMP-GEFS; Epacs) has open new
doors for cAMP action that include activation of small GTPases such
as Rap1a, Rap2, and possibly Ras. These GTPases are known activators of
downstream kinase cascades, including p38MAPK and Erk1/2 as well as
PI3-K. Thus, FSH and TSH activation of PKB and Sgk may occur via this
alternative cAMP pathway that involves cAMP-GEFs and the activation of
the PI3-K/PDK1 pathway.
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INTRODUCTION
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The molecular mechanisms by which pituitary hormones (ACTH, FSH,
LH, and TSH) control the function of target cells in the adrenal gland,
gonads, and thyroid have been analyzed extensively. A specific pattern
of activation has been documented for each, and models of these
intracellular signaling systems are in all endocrine and biochemical
textbooks (Fig. 1A
). In brief, these
glycoprotein hormones bind ligandspecific, cell surface G
protein-coupled receptors (GPCRs) and activate adenylyl cyclase (AC)
leading to the production of cAMP. cAMP, first discovered as an
intracellular second messenger in 1959 (1), was by 1968 teamed up with
a protein kinase, cAMP-dependent protein kinase (2, 3, 4), establishing a
prototype for many intracellular signaling cascades. This
nucleotide-kinase pair has been universally accepted as a first tier of
reactions by which pituitary hormones control cell functions of
proliferation, differentiation, and cell survival. This model is so
well established that when one hears the word cAMP, protein kinase A
(PKA) or A-kinase immediately springs to mind. More recently, this
cascade has been expanded to include various isoforms of AC (5),
phosphodiesterases (PDEs)(6), and PKAs (7) as well as A-kinase anchor
proteins (AKAPs) (8, 9, 10). In addition, the nuclear transcription factor
cAMP regulatory element-binding protein (CREB) (11, 12, 13) and the
coregulatory molecule CREB-binding proteins (CBP/p300) (14, 15) have
been shown to mediate some of the effects of cAMP (Fig. 1A
).

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Figure 1. Classical and Expanding Views of GPCR-Activated
Pathways in Endocrine Cells
Panel A summarizes the classical, linear pathway that describes how
glycoprotein hormones act in most, if not all, endocrine cells. Panel B
depicts how the classical pathway has been modified. New factors
regulate the activation/deactivation of GPCR. The ß -subunits
now have functions beyond regulating G -subunit. CREB and CBP are no
longer the sole transcription factors regulated by cAMP. Many others
are either activated, induced, or induced and activated by cAMP.
Conversely, CBP is a coregulator of transcription factors in addition
to CREB. Other kinases have now been shown to impact CREB and CBP. In
addition, PKA has been shown to activate other kinase cascades such as
the MAPKs.
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Despite the appealing linearity and apparent simplicity of this
cascade, recent observations have challenged the model (Fig. 1
, A and
B). CREB is not the only transcription factor activated by elevated
levels of intracellular cAMP. In the ovary, for example, stimulatory
protein 1 (Sp1), upstream stimulatory factor (USF), and estrogen
receptor
/ß (ER
/ß) are activated (16, 17, 18, 19, 20). Others, such as
early growth response protein 1 (Egr-1), activator protein 1 (AP1)
factors (Fra2, JunD), and C/EBPß are induced and functionally active
based on promoter studies and gene knockout studies (21, 22).
Furthermore, CREB itself is phosphorylated and activated by kinases in
addition to PKA, such as calmodulin kinase IV and RSKB (11, 13, 23).
The coregulator CBP/p300 not only binds CREB but is highly promiscuous
and binds to a plethora of other transcription factors, including
members of the nuclear receptor superfamily (24), nuclear factor
B
(NF
B) (25) and others (26, 27). PKA itself has now been shown to
activate as well as inhibit other cell signaling cascades such as the
mitogen-activated protein kinases (MAPKs) in a cell- specific manner
(28, 29, 30, 31). Even the G protein ß
-subunits have functions beyond the
regulation of G
s and the activation of AC (32, 33, 34, 35). Additionally, a
newly identified family of activators of G protein signaling (AGSs) can
stimulate G proteins in the absence of receptor activation (32, 33, 34, 35).
Conversely, regulators of GPCR signaling (RGSs) serve as negative
regulatory GTPase-activating proteins (GAPs) (36, 37, 38) for the specific
G
-subunits, thereby turning off G protein activation. In this light,
the GPCRs may be viewed as a type of G
guanine nucleotide exchange
factor (G
-GEF) that is activated by external stimuli.
These are just a few examples of the multiplicity of signaling by GPCR
and cAMP. What is the moral of this? There is still more to know about
cAMP, the proteins with which it interacts, and the cell functions that
it controls. The linear model may give way to a mosaic with multiple
intersecting lines of interactions (39). Furthermore, functions
previously ascribed solely to cAMP activation of PKA may need to be
reevaluated. This includes the transcriptional regulation of many
genes.
The purpose of this minireview is to present some of the recent, novel
evidence for how hormones and cAMP control such diverse functions as
cell proliferation and differentiation in endocrine cells.
Specifically, this minireview will focus on the activation of a second
cAMP-dependent pathway and show how it may regulate hormone -induced
signaling cascades in endocrine cells without the need for activation
of PKA. Part of this alternative pathway is comprised of a new class of
cAMP-binding proteins, the cAMP-guanine nucleotide exchange factors
(cAMP-GEFs) or exchange protein activated by cAMP (Epac). This pathway
appears to activate a phosphoinositide- regulated kinase cascade in
which phosphoinositol 3-kinase (PI3-kinase) and
phosphoinositide-dependent kinase (PDK1) have been identified and shown
to mediate the activation of two downstream related kinases, protein
kinase B (PKB/Akt) and serum and glucocorticoid induced kinase (Sgk).
This cascade is a preeminent survival pathway involved in cell growth
and metabolism and likely mediates some of the trophic effects of the
gonadotropins. Due to space constraints, other parts of the pathway and
other important pathways in endocrine cells are presented only briefly
or not at all. This is not intended to show lack of interest or
importance.
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DISCUSSION
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Evidence suggesting that there are alternate pathways by which
cAMP regulates cell function has come primarily from two systems.
First, cAMP can activate specific ion-gated channels (40). Second, and
of particular relevance to this review, TSH and cAMP regulate
proliferation in thyroid cells by mechanisms independent of PKA
(41, 42, 43, 44, 45). In 1993, Kupperman et al. (41) showed that the
proliferative response of thyroid cells to TSH required not only cAMP
but also the small GTPase Ras commonly associated with proliferation.
Additionally, they showed that the PKA inhibitor PKI did not block the
actions of Ras and decreased the proliferative effect of TSH by only
50%. Full inhibition of proliferation required the presence of both a
dominant negative Ras and PKI. Although CREB appears to be required to
mediate some of the effects of PKA on thyroid cell function and
proliferation (46), the effects of Ras were not mediated by the
Raf-dependent kinase cascade (47). Studies by Dremier et al.
in 1997 (44) reported that the catalytic (C)-subunit of PKA could alter
the morphology of thyroid cells but did not mimic the proliferative
effects of TSH. These observations led Dremier et al. (44)
to entertain the notion that TSH/cAMP acted by mechanisms in addition
to PKA but might involve activation of GTPases other than Ras (48). In
1998 and 1999, Cass, Meinkoth, and colleagues (42, 43) extended their
observations to show that TSH, forskolin, or the cAMP analog CT-cAMP
phosphorylated and thereby activated p70S6K as well as PKB by
mechanisms that were not blocked by H89, a highly selective PKA
inhibitor. Nor were the effects of TSH or forskolin blocked by
PKI. Rather, TSH-induced phosphorylation of p70S6K and PKB was blocked
by specific inhibitors of PI3-K, wortmannin and LY294002. Increased
thyroid cell proliferation in the presence of a constitutively active
PI3-K was also blocked by wortmannin and LY294002, as well as by the
specific inhibitor of p70S6K, rapamycin. Based on these observations,
Cass, Meinkoth and colleagues (42, 43) suggested that cAMP might
activate alternative signaling pathways in thyroid cells, including
PKB.
But how might cAMP impact PKB without a need for PKA? To address this
question, it is necessary to review what is known about the activation
of PKB (Fig. 2
). It is well established
that PKB is expressed constitutively in all cell types examined.
However, the phosphorylation, activation, and cellular functions of PKB
remain an area of intense investigation (49). PKB is a terminal kinase
in a cascade that controls critical events in cell survival (50). It
has been best characterized as a downstream target of the insulin and
insulin-like growth factor I (IGF-I) pathways (50, 51) although the
downstream effects of these two hormones are not entirely identical
(52). In general, PI3-K generates specific phosphoinositides critical
for the activation of PDK1, which then phosphorylates PKB, p70S6K, Sgk
and other kinases (Fig. 2
).

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Figure 2. The GPCR Pathway Ventures Toward the IGF-I,
PI3-K/PDK1 Pathway
IGF-I and other growth factors can activate the PI3-K, PDK1, and PKB
pathway leading to cell proliferation and cell survival. This pathway
has been highly conserved from worms (C. elegans) to
man. Importantly, some components of this pathway have been shown to be
highly related to reproductive functions and viability in yeast and the
worm. This pathway also appears to be stimulated by cAMP. As discussed
in the text, TSH acts on thyroid cells to stimulate phosphorylation and
activation of p70S6K and PKB by mechanisms that do not involve PKA. The
question is how? By ß -subunits or by the newly described
cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs).
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Some of these kinases have been shown recently to have homologs in
yeast and in the worm, Caenorhabditis elegans (50, 53). In
budding yeast, genetic and functional equivalents of PDK (PKH1 and
PKH2) are essential for viability (54). In C. elegans daf 2,
daf 18, Age 1, and akt/PKB are the functional and structural
equivalents of the IGF-I receptor, the tumor suppressor PTEN, PI3-K,
and PKB, respectively (50, 53). In C. elegans
this pathway is highly related to the reproductive system, the nervous
system, and longevity (55, 56, 57). For example, worms lacking germ cells
and the germline signals, such as IGF-I, live longer (58). In order for
germ cell-ablated worms to live longer, the forkhead transcription
factor DAF 16 is required (58). That components of this signaling
cascade have been highly conserved in worms and man, and that some
components impact growth and viability in yeast and C.
elegans, indicate that PDK1 and its targets play key roles in cell
proliferation and function. Moreover, these appear to play a key role
in reproductive functions, at least in C. elegans.
Several conserved substrates for PKB have been identified. These
include glycogen synthase kinase-3 (GSK-3), 6-phosphofructo 2-kinase,
and other components (GLUT 1, 3, 4) of the glucose metabolic pathway.
Other substrates are the forkhead transcription factor DAF 16, an
orphan nuclear receptor DAF 12, and components of the apoptotic pathway
such as BAD (50, 53, 58, 59). Members of the forkhead family have been
shown to regulate transcription of p27KIP1,
providing one link to the cell cycle (60, 61, 62) that may be relevant in
endocrine cells as well (63, 64). Other pathways may control the levels
of p27KIP1 protein (65). In mammalian cells PKB
(via PDK1) appears to be phosphorylated and thereby activated not only
in response to IGF-I and insulin but also in response to numerous
growth factors (50) and other cell surface proteins, including
integrins (66, 67). Importantly, the responses of cells to PKB may be
cell cycle and stage specific, thus requiring cautious interpretations
of data obtained with cell culture and in vivo experiments
(68). These observations are consistent with a central role of PI3-K
and PDK1 in controlling cell function and the response of cells to
environmental and hormonal cues (53, 69, 70, 71).
Do the glycoprotein hormones and cAMP impact the PKB pathway? The
answer that is emerging from recent studies appears to be, yesat
least in some cell types (Fig. 2
). The pioneering studies of Meinkoth
and Dremier in thyroid cells have been confirmed in the ovary where FSH
leads to the rapid phosphorylation and activation of PKB in granulosa
cells (31). PKB may also be activated by
MSH and the Ras pathway in
melanocytes (72). Are these effects of hormones and cAMP restricted to
endocrine cells? The answer to this is not yet known, but is probably
no. What is the mechanism and what are the factors that mediate this
alternate response of cells to glycoprotein hormones and cAMP? As
already mentioned, one pathway may be via the ß
-subunits (32, 33, 34, 35).
However, cAMP itself can mediate specific effects.
New doors to the actions of cAMP sprang wide open in 1998 with papers
published by deRooij, Bos, and colleagues (73) and Kawasaki et
al. (74) (Fig. 3
). Bos and
colleagues were searching the genomic database for additional genes
with cAMP binding domains. Kawasaki et al. isolated a novel
gene by differential display RT-PCR. Both groups identified genes
encoding proteins that bound cAMP with affinities similar to that of
the regulatory (RI) subunit of type I PKA. In addition, these papers
showed that the novel cAMP binding proteins had regions of homology and
functional activity corresponding to GEFs that exchange high-energy GTP
for GDP to activate Ras-related small GTPases. Hence they were called
cAMP-GEF or Exchange proteins activated by cAMP (Epac). These cAMP-GEFs
were first shown to be an exchange factor for the small GTPase, Rap1
(73, 74). GTP-bound Rap1 activates kinases (Raf-1, B-Raf or c-Raf)
leading into the ERK1/2 or p38MAPK pathways. Subsequent papers have
shown the cAMP-GEFI can activate Rap2 (75, 76) and possibly Ras (77).
The latter is particularly relevant to this review since Ras can
activate yet additional kinase cascades, such as PI3-K/PDK1 pathway.
Another structural feature of the cAMP-GEFs is that they also contain a
DEP (disheveled, Egl-10, Pleckstrin) domain that targets them to the
membrane (76), thus positioning them in proximity to other
membrane-localized enzymes such as PI3-K, PDK1, and PKB (78). cAMP
GEFII has recently been implicated in controlling exocytosis and
therefore may provide one means for the effects of cAMP in enhancing
secretion in specific cell types (79). cAMP-activated GEFs have also
been identified in C. elegans (74, 80) adding credence to
the universality of this pathway in mediating specific actions of
cAMP.

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Figure 3. A Working Model to Help Explain the Diversity and
Complexity of cAMP Action in Endocrine Cells
This model has been developed to integrate the induction and activation
of Sgk-1 and the activation of PKB in endocrine cells by TSH, FSH, MSH,
and other glycoproteins that activate GPCR and AC. Based on the recent
information, we propose that cAMP can activate a second pathway in
endocrine cells that lead to the phosphorylation of PKB and thereby the
phosphorylation and regulation of its known targets such as the
transcription factors forkhead and Daf 12. In addition, the inducible
kinase Sgk-1 is a target of PDK1, indicating that some functions
ascribed to PKB may be the functions of Sgk-1. In addition, the
cAMP-GEFs provide a mechanism in addition to PKA by which cAMP can also
activate the MAPK pathways. It is important to emphasize that this is
only a working model and that the effects of cAMP on PKA, MAPKs, and
PKB/Sgk need not be mutually exclusive. However, some do appear to be
antagonisticat least in some cells. Obviously caution is advised in
all interpretations. But at least now we have additional options for
understanding the diversity and complexity of cAMP action in endocrine
cells.
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With so many GEFs now being identified (81) it is likely there will be
more. Most of these pioneering studies were done with cell lines and
the overexpression of the interacting proteins. The importance of these
interactions need to be addressed in normal cells where rapid changes
in response to hormones and elevated levels of cAMP occur. It will be
critical to know how endogenous levels or activities of cAMP-GEFs,
small GTPases (Rap1, Rap2, Ras, Rim-2), and their presumed target
kinases (c-Raf, B-raf, raf-1) change in these situations. Some hints on
the horizon indicate that cAMP-GEFs do have important physiological
roles in some cells at specific stages of development. The
relative roles of cAMP-GEF activation of Rap-Ras proteins and
downstream kinases (73, 74, 76) as well as PKAs reported activation
and inhibition of Rap1and B-Raf (28, 30) need to be analyzed
in different cell types and at defined stages of development.
Since the original studies by Meinkoth, Dremier, and their colleagues,
other investigators have shown that cAMP can regulate the
phosphorylation of PKB in normal cells. In particular, not only IGF-I
but also FSH, forskolin, and 8-bromo-cAMP have been shown to increase
rapidly PKB phosphorylation in ovarian granulosa cells (31, 82, 83, 84, 85). In
rat granulosa cells, PKB phosphorylation in response to FSH is biphasic
with an initial peak at 12 h followed by a decline at 6 h and
then a secondary increase at 2448 h. Inhibitors of PI3-K (LY294002
and wortmannin) antagonized FSH (and IGF-I)-induced phosphorylation of
PKB whereas the PKA inhibitor, H89, caused a small but consistent
increase. Interestingly, phorbol myristate acetate (PMA) failed
to stimulate PKB phosphorylation and even blocked FSH (but not
IGF-I)-stimulated phosphorylation of PKB. Thus, either C-kinase or the
calcium-diacylglycerol-GEF (CalDAG-GEFs) (86) may block the activity of
cAMP-GEFs. These observations suggest that FSH and cAMP activate
signaling pathways that impact components of the IGF-I pathway,
possibly IGF-I itself (85, 87), without the need for PKA
activation.
In the ovary, the phosphorylation of PKB by FSH was associated with
increased phosphorylation of GSK-3, a known substrate for PKB (31). It
is likely that FSH via PKB alters the functional activity of other
proteins, especially the inhibition of those involved in the apoptotic
process. Alternatively, PKB may exert additional cell survival roles in
granulosa cells including the regulation of steroidogenesis. It is of
particular interest that FSH via PKB can mimic some actions of IGF-I
whereas IGF-I cannot mimic the cAMP-mediated actions of FSH, such as
the induction of genes involved in steroidogenesis (aromatase) (88, 89), the LH receptor (90), or the PKB-related kinase, Sgk (31).
Conversely, IGF alone induces the expression of specific proteoglycans
in the ovary (91, 92). Thus, each pathway brings distinct but also
overlapping functions to ensure appropriate progression of
proliferation and differentiation in granulosa cells of developing
follicles. The distinct but overlapping functions of IGF-I and FSH are
supported by phenotypes of IGF-I, IGF-R, IRS-2, and FSH-R knockout
mice (93, 94). In each mutant mouse, follicles can grow to the
small antral stage but never complete final differentiation.
As already indicated, FSH also induces Sgk (16, 95), a kinase first
cloned by Webster et al. (96, 97) as a serum- and
glucocorticoid-induced gene (96, 97). More recently, Sgk has been shown
to be most closely related to PKB and can be phosphorylated by PDK1
(98). Thus, Sgk like PKB is a downstream target of PI3-K and PDK1. In
this regard some functions previously ascribed to PKB may be mediated
by one of the three known isoforms of Sgk (Sgk13) (99). This seems
particularly important in cells where Sgk-1 is selectively expressed,
induced, and phosphorylated. Despite the fact that PKB and Sgk-1 are
both targets of PKD1, there are some important differences in these two
terminal kinases. Sgk-1, but not Sgk3 (99), is inducible in many cell
types by a variety of agonists, such as glucocorticoids (96),
aldosterone (100, 101), serum (96), hyperosmotic stress (102),
transforming growth factor-ß (TGF-ß) (103), and FSH (16). Sgk-2 is
selectively expressed in a limited number of tissues examined (99). In
contrast, PKB is constitutively expressed in all cells. Whereas PKB has
a pleckstrin homology (PH) domain that targets it to the cell membrane,
Sgk does not (98). Importantly, Sgk-1 is nuclear in proliferating cells
and cytoplasmic in terminally differentiated nondividing cells. These
observations on the nuclear to cytoplasmic localization of Sgk-1 during
proliferation have been made in mammary epithelial cells (104) as well
as granulosa cells (89, 95). Thus, although PKB and Sgk-1 have a common
upstream activator and may have some overlapping functions, they appear
to respond to different factors and, therefore, likely phosphorylate
different substrates and control different functions. In support of
these data, human Sgk-1, but not PKB or p70S6K, can substitute for
mutated yeast kinases Ypk1and Ypk2 and restore viability to otherwise
inviable yeast (54). Despite this critical role of Sgk-1 in yeast, its
roles in mammalian cells are not yet clear. Sgk-1 has been shown to
phosphorylate and activate an epithelial sodium channel (100) and has
recently been proposed to regulate the translocation of the
Na+ channels to the plasma membrane in a manner
analogous to the translocation of GLUT4 (78) and thereby facilitate ion
transport. Perhaps relevant to this is the presence of
voltage-activated Na+-channels in ovarian cells
(105). Most recently, Sgk-1 but not PKB, has been shown to
transactivate a serum-response element in the promoter of the
c-fos-luciferase transgene (106). In light of these
observations, FSH via cAMP integrates multiple functions in granulosa
cells such as the induction of Sgk-1 as well as the activation of PDK1,
PKB, and Sgk-1 via a putative cAMP-GEF pathway (31).
And now we come full circle. Curiously, the catalytic subunit of PKA
has recently been shown to be phosphorylated and activated by PDK1
in vitro, suggesting that the functional activity of PKA may
be regulated by this pathway as well (59, 107). However, the cellular
consequences of this PDK1-mediated phosphorylation are less clear. In
embryonic stem cells lacking PDK1, PKA activity was normal whereas the
activity of PKB was abolished and levels of PKC isoforms were markedly
reduced (108, 109). Whether this relation of PDK1 to PKA, PKC, and PKB
is true in all cell types is not yet known and could be cell specific.
There is evidence that PDK1/PKB enhances the phosphorylation of CREB
(78, 110) and that phospho-CREB is essential for cell survival because
cotransfection of dominant-negative CREB decreased survival (46, 111, 112). Furthermore, in some situations phosphorylation of CREB on serine
133 is necessary but not sufficient for full activation of CREB (13, 113). Therefore, it is possible that in some cells both PKA-mediated
phosphorylation of CREB as well as its phosphorylation by other kinases
(PDK1, PKB, or MAPK) is obligatory for full activation. The presence of
cAMP-GEFs as well as PKA would ensure that the cAMP signal goes in two
directions in the cell.
Other evidence that we have come full circle is the identification of
intracellular proteins that can activate G-protein signaling (AGS
proteins). These factors activate G-proteins in manner not requiring
the GPCR (114). Furthermore, the ß
-proteins can activate the
p110
isoform of PI3-K, thereby providing another link between GPCR
and the PI3-K, PDK1 pathway (32, 33, 34, 35). Lastly, there is evidence that
some glycoproteins such as FSH bind to receptors that are related to
growth factor type 1 receptors (115). Therefore, depending on the cell
types and levels of each of these intracellular signaling molecules in
these cells, numerous combinations can occur. It is clear the
PI3-K/PDK1/PKB pathway or the PI3-K/PDK1/Sgk pathway may mediate many
actions previously ascribed to PKA. These observations open exciting
new possibilities for controlling hormone action in endocrine
cells.
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PROSPECTUS
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Cellular signaling systems are becoming more and more complex with
multiple check points and on/off switches (39). Some are ubiquitous and
highly conserved but many are cell specific. This review just touches
the tip of the iceberg. It is hoped, however, that it provides a new
focus on the actions of glycoprotein hormones that activate AC and the
subsequent divergent interactions of cAMP with the PKA pathway and the
PI3-K, PDK1, and PKB pathway, as well as with the PKB-related but
distinct kinase, Sgk (Fig. 3
).
These new divergent pathways for cAMP reveal that this nucleotide
should now be considered as a major coordinate integrator of cell
functions by at least three distinct pathways. By activating
cAMP-dependent protein kinases (PKAs), cAMP controls specific steps in
cell proliferation and differentiation by controlling cell
cycle-dependent protein kinase cascades (63, 116) as well as
transcriptional regulation of specific genes (117, 118). By activating
cAMP-GEFs, cAMP impacts small GTPases and their specific kinases (such
as Rap 1/2 and rafs) leading to the activation of other kinases such as
p38 MAPK (73, 74) and transcription factors such as the AP1 factors.
PKA can also impact this Rap-Raf-MAPK kinase pathway, at least in
certain cell types and stages of differentiation (28, 29, 30, 31). In addition,
the cAMP-GEFs via Ras-related GTPases (or other mechanisms) may
activate PI3-K and PDK1 leading to activation of other pathways that
control proliferation (p70S6K), differentiation (PKB, Sgk-1), and cell
survival (31, 43, 45, 84). In these pathways cAMP may act
synergistically with other GPCR-associated molecules such as the
ß
-subunits that can also stimulate some forms of the PI3-K pathway
(32, 33, 34, 35). These observations may have clinical relevance in
characterizing polycystic ovarian syndrome (PCOS).
New GEFs (119), GTPases, and kinases in these cascades are likely to
emerge. For example, Williams and Alessi and colleagues (108) have
recently shown in PDK1-/- embryonic stem cells the phosphorylation of
PKB on Ser473 may be mediated by a kinase distinct from PDK1. We need
to know more about the function of the endogenous proteins in endocrine
cells. We need to know which GEFs are present in specific cells, which
GTPases they activate, and which kinases are their targets. Is Ras or
another small GTPase activated by FSH or TSH via cAMP-GEF? What Sgk
isoforms are expressed in the ovary and other endocrine tissues and
what are the specific substrates for Sgk isoforms and PKB in these
cells? Since Sgk-1, but not PKB, can reverse the lethal phenotype in
yeast, the critical role of Sgk-1 and of the other Sgk isoforms in
mammalian cells will no doubt emerge. For example, when granulosa cells
cease dividing and become luteal cells, what signaling cascade(s) leads
to the phosphorylation of Sgk-1 and PKB? What controls the movement of
Sgk-1 from the nucleus to the cytoplasm, and is there an associated
switch in activity of substrate specificity for this kinase? These and
many other questions need to be answered before the specific roles of
cAMP and its new targets of action are fully understood.
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ACKNOWLEDGMENTS
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The author wishes to thank Dr. Ignacio Robayna-Gonzalez and
Allison Falender whose studies helped formulate the hypothesis
presented in this review. Thanks are also extended to members of the
laboratory for their critical review of this manuscript: Dr. Darryl
Russell, Dr. S. C. Sharma, Scott Ochsner, Minnie Hsieh, and
Kari Heidel.
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FOOTNOTES
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Address requests for reprints to: Dr. JoAnne S. Richards, Department of Cell Biology, Baylor College of Medicine, One Baylor Plaza, Houston, Texas 77030-3411. E-mail: joanner{at}bcm.tmc.edu
Supported, in part by NIH Grant HD-16272.
Received for publication October 20, 2000.
Revision received November 29, 2000.
Accepted for publication December 4, 2000.
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