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


    ABSTRACT
 TOP
 ABSTRACT
 INTRODUCTION
 DISCUSSION
 PROSPECTUS
 REFERENCES
 
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.


    INTRODUCTION
 TOP
 ABSTRACT
 INTRODUCTION
 DISCUSSION
 PROSPECTUS
 REFERENCES
 
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. 1AGo). 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. 1AGo).



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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{gamma}-subunits now have functions beyond regulating G{alpha}-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.

 
Despite the appealing linearity and apparent simplicity of this cascade, recent observations have challenged the model (Fig. 1Go, 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{alpha} (ER{alpha}/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{kappa}B (NF{kappa}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{gamma}-subunits have functions beyond the regulation of G{alpha}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{alpha}-subunits, thereby turning off G protein activation. In this light, the GPCRs may be viewed as a type of G{alpha} guanine nucleotide exchange factor (G{alpha}-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.


    DISCUSSION
 TOP
 ABSTRACT
 INTRODUCTION
 DISCUSSION
 PROSPECTUS
 REFERENCES
 
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. 2Go). 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. 2Go).



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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{gamma}-subunits or by the newly described cAMP-regulated guanine nucleotide exchange factors (cAMP-GEFs).

 
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, yes—at least in some cell types (Fig. 2Go). 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 {alpha}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{gamma}-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. 3Go). 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 antagonistic—at 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.

 
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 PKA’s 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 1–2 h followed by a decline at 6 h and then a secondary increase at 24–48 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 (Sgk1–3) (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{gamma}-proteins can activate the p110{gamma} 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.


    PROSPECTUS
 TOP
 ABSTRACT
 INTRODUCTION
 DISCUSSION
 PROSPECTUS
 REFERENCES
 
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. 3Go).

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{gamma}-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.


    ACKNOWLEDGMENTS
 
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.


    FOOTNOTES
 
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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 ABSTRACT
 INTRODUCTION
 DISCUSSION
 PROSPECTUS
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