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Molecular Endocrinology 21 (10): 2311-2319
Copyright © 2007 by The Endocrine Society

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Steroid Receptor Phosphorylation: A Key Modulator of Multiple Receptor Functions

Nancy L. Weigel and Nicole L. Moore

Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030

Address all correspondence and requests for reprints to: Nancy L. Weigel, Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas 77030. E-mail: nweigel{at}bcm.tmc.edu.


   ABSTRACT
TOP
 ABSTRACT
INTRODUCTION
 RECEPTOR PHOSPHORYLATION SITES
 RECEPTOR PHOSPHORYLATION AND THE...
 SUMMARY
 REFERENCES
 
Steroid receptors are hormone-activated transcription factors, the expression and activities of which are also highly dependent upon posttranslational modifications including phosphorylation. The remarkable number of phosphorylation sites in these receptors and the wide variety of kinases participating in their phosphorylation facilitate integration between cell-signaling pathways and steroid receptor action. Sites have been identified in all of the functional domains although the sites are predominantly in the amino-terminal portions of the receptors. Regulation of function is receptor specific, site specific, and often dependent upon activation of a specific cell-signaling pathway. This complexity explains, in part, the early difficulties in identifying roles for phosphorylation in receptor function. With increased availability of phosphorylation site-specific antibodies and better means to measure receptor activities, numerous roles for site-specific phosphorylation have been identified including sensitivity of response to hormone, DNA binding, expression, stability, subcellular localization, and protein-protein interactions that determine the level of regulation of specific target genes. This review summarizes current knowledge regarding receptor phosphorylation and regulation of function. As functional assays become more sophisticated, it is likely that additional roles for phosphorylation in receptor function will be identified.


   INTRODUCTION
TOP
 ABSTRACT
 INTRODUCTION
RECEPTOR PHOSPHORYLATION SITES
 RECEPTOR PHOSPHORYLATION AND THE...
 SUMMARY
 REFERENCES
 
ALTHOUGH STEROID RECEPTORS are hormone-activated transcription factors, their expression and many of their activities are highly regulated by posttranslational modifications including phosphorylation. The receptors and their associated proteins are phosphorylated on multiple sites by a wide range of kinases. These phosphorylations can regulate functions as diverse as protein stability, nuclear localization, sensitivity to hormone, DNA binding, and protein-protein interactions that determine the specificity and extent of the regulation of target genes. Thus, the cellular levels of active kinases and phosphatases, as well as the milieu of coregulators and other receptor-interacting proteins, will determine the specific response of a receptor to its cognate ligand.

Steroid receptor function is complicated, requiring a series of molecular interactions, to induce regulation of target genes (Fig. 1Go). In the absence of hormone, receptor monomers are bound to chaperone complexes that include heat shock protein 90, p23, and a variety of cochaperones among which are cochaperones containing tetratricopeptide repeats including, in some cases, protein phosphatase 5 (PP5) (for a recent review see Ref. 1). In the case of the glucocorticoid receptor (GR), the bound PP5 limits site-specific GR phosphorylation, which rapidly increases when GR is released from the chaperone complex (2). A recent study suggests similar regulation for androgen receptor (AR). Treatment with okadaic acid, a PP2A and PP5 phosphatase inhibitor, enhances site-specific phosphorylation and under these conditions, agonist does not further increase the phosphorylation of AR (3). Receptor complexes are dynamic, and receptors shuttle between the cytoplasm and the nucleus. The relative distribution between the two compartments in the absence of hormone is receptor specific. In response to hormone, receptors dissociate from chaperone complexes; cytoplasmic receptors (GR and AR) move to the nucleus. Although estrogen receptor {alpha} (ER{alpha}), estrogen receptor ß (ERß), and progesterone receptor (PR) are predominantly nuclear in the absence of hormone, nuclear localization is frequently enhanced by hormone treatment. Net phosphorylation of the receptors also increases in response to hormone. All of the steroid receptors form homodimers; in the best-characterized mechanism of action, the receptors bind to palindromic hormone response elements and recruit a series of coactivator complexes that modify chromatin and facilitate transcription. Receptors also interact with DNA indirectly through protein-protein interactions with other transcription factors or through combinations of DNA half -sites and protein-protein interactions. In addition, receptors repress transcription of other target genes both through direct interactions with the DNA as well as through protein-protein interactions. Receptor interaction with DNA and with coregulator complexes is dynamic, and release of receptors from chromatin appears to be integral to efficient transcription (4). Receptors are often ubiquitinated, leading to proteasome-dependent degradation, but receptors are also exported to the cytoplasm, limiting receptor action. As discussed below, there is evidence for regulation of most of these steps by receptor phosphorylation.


Figure 1
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  		Fig. 1. Regulation of Steroid Receptor Action: Steroid Receptor-Signaling Mechanisms Influenced by Phosphorylation

In the absence of hormone, steroid receptor (SR) monomers are complexed with chaperone proteins such as heat shock protein (hsp) 90, p23, and tetratricopeptide repeat (TPR) protein. After hormone binding, the receptor undergoes conformational change, dissociates from chaperones, and translocates to the nucleus where it binds to DNA and/or interacts with other proteins including coactivators (CoA) or transcription factors (TF) to regulate transcription. Subcellular localization of SR is a dynamic process, and both nuclear translocation and export are regulated by phosphorylation. Phosphorylation can also affect binding of SR to DNA, interactions with other proteins, and transcription. SR stability is influenced by phosphorylation via regulation of ubiquitination and degradation. Aspects of SR function shown to be regulated by phosphorylation in at least one case are highlighted in red.

 
Steroid receptors share common structures (reviewed in Ref. 5). They are comprised of carboxyl-terminal hormone-binding domains linked through a hinge region to highly conserved DNA-binding domains that contain two Zn++ finger motifs. The hormone-binding domain contains a hormone-dependent coactivator interface [activation function (AF)-2)], which recognizes and binds specific L-X-X-L-L sequence motifs typically found in the interacting coactivators. The amino termini of the receptors are the least conserved and vary in length from less than 200 amino acids to more than 500 amino acids. Recent studies using techniques such as circular dichroism spectroscopy and Fourier transform infrared indicate that these regions contain little intrinsic structure and that binding to DNA or interaction with proteins induces a more ordered structure (6, 7, 8). These regions also contain coactivator-binding regions (AF-1). The relative importance of AF-1 and AF-2 in receptor activity is receptor and context specific. The amino termini of the proteins contain the majority of the receptor phosphorylation sites identified to date. A minimum of four (ER{alpha}) (9) and as many as nine phosphorylation sites (PR) (10) have been identified in this region. Of particular interest with regard to the regulation of receptor structure is the finding that many of the sites reside in Ser-Pro motifs and the receptor coactivator, Pin1 (11), is a peptidyl prolyl isomerase, which recognizes phospho-Ser-Pro motifs. Hence, there is the potential that a phosphorylation not only causes a change in charge, but results in isomerization of the peptide bond, substantially altering receptor structure.


   RECEPTOR PHOSPHORYLATION SITES
TOP
 ABSTRACT
 INTRODUCTION
 RECEPTOR PHOSPHORYLATION SITES
RECEPTOR PHOSPHORYLATION AND THE...
 SUMMARY
 REFERENCES
 
Early studies of receptor phosphorylation used radiolabeling, peptide mapping, and protein sequencing or site-directed mutagenesis to identify candidate sites. More recent studies have also used mass spectrometry to identify phosphorylation sites. Each of these approaches has technical limitations, but they have resulted in the identification of multiple phosphorylation sites in PR, ER{alpha}, GR, AR, and, more recently, in ERß (10, 12, 13, 14, 15, 16, 17, 18, 19). A recent proteomic study of phosphorylation in mouse liver identified Ser299 in the mineralocorticoid receptor as a phosphorylated residue (20). An updated summary of the locations and proposed functions of receptor phosphorylation sites can be found at Phosphosite (http://www.phosphosite.org). Most of the sites identified in receptors isolated from hormone-treated cells are Ser-Pro motifs implicating proline-directed kinases including the cyclin-dependent kinases and MAPKs in regulation of receptor phosphorylation. Although most of the Ser-Pro sites are in the amino terminus, PR, AR, and mouse ER{alpha} all contain a Ser-Pro phosphorylation site in the hinge region (10, 14, 21). The other steroid receptors also contain a corresponding Ser-Pro or Thr-Pro in the hinge region, but phosphorylation of these sites has not been reported.

Receptors contain many phosphorylation sites, and it has been challenging to identify some of the sites that are phosphorylated under limited circumstances. A number of candidate phosphorylation sites have also been proposed based on in vitro phosphorylation studies. In some cases, phosphorylation site-specific antibodies have been developed and used to verify phosphorylation as well as to study the requirements for site-specific phosphorylation. Table 1Go shows the location of the sites identified in human steroid receptors. The underlined sites have been confirmed using phosphospecific antibodies to sites in AR (22, 23), ER{alpha} (9), GR (2), and PR (24, 25, 26). Several recent studies have led to the identification of sites that are phosphorylated only when specific cell signaling pathways are activated. For example, activation of p38 MAPK is required for phosphorylation of Thr311 in the hormone-binding domain of ER{alpha} (27) whereas activation of protein kinase A induces phosphorylation of Ser305 in ER{alpha} (28). Whether Ser213 is an authentic phosphorylation site in AR was initially controversial. It is a substrate for Akt in vitro but was not detected in a comprehensive analysis of in vivo AR phosphorylation sites. Using a phosphopeptide-specific antibody, Taneja et al. (22) subsequently found that the site was phosphorylated in vivo and that the phosphorylation was blocked by an inhibitor of phosphatidylinositol-3-kinase, the upstream activator of Akt. Moreover, the phosphorylation was detected in some cell types, but not in others.


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  		Table 1. Phosphorylation Sites in Human Steroid Receptors

 
There is also some evidence for tyrosine phosphorylation of some of the receptors. These phosphorylations are often of low stoichiometry and transient and therefore difficult to detect. Phosphorylation site-specific antibodies have confirmed these sites. Tyr537 in the hormone-binding domain of ER{alpha} was the first reported tyrosine phosphorylation site (29). The phosphorylation of this site in ER{alpha} transiently expressed in COS cells has recently been confirmed using a site-specific antibody; however, this site is not phosphorylated in recombinant ER{alpha} purified from Sf9 insect cells (9). Recent studies reveal that Tyr534 in the amino terminus of AR is also phosphorylated (30, 31); the phosphorylation in response to hormone is transient. Src kinase has been implicated in the phosphorylation of both of these receptors.


   RECEPTOR PHOSPHORYLATION AND THE REGULATION OF STEROID RECEPTOR ACTION
TOP
 ABSTRACT
 INTRODUCTION
 RECEPTOR PHOSPHORYLATION SITES
 RECEPTOR PHOSPHORYLATION AND THE...
SUMMARY
 REFERENCES
 
Elucidating the roles for receptor phosphorylation in receptor function is a challenging task, and studies to date have revealed a wide range of roles for receptor phosphorylation. Most of the studies have relied on substituting Ala for Ser to prevent phosphorylation; in some cases Asp or Glu substitutions have been used to mimic the negative charge of a phosphate. Because the size of the Asp or Glu side chain does not mimic the phosphate, changes in structure as a result of the size of the phosphate group are not always reproduced by an acidic residue. One of the first functions identified was sensitivity of transcriptional activation in response to hormone. Mutation of Ser530 in the hinge region of chicken PR increased the concentration of hormone required for 50% maximal transcriptional activation by 5- to 10-fold although hormone binding affinity was unchanged (32). Phosphorylation of Ser305 in the hormone binding domain of ER{alpha} may play a similar role because phosphorylation inhibits the acetylation of Lys303 (33). Substitution of Arg for the acetylation target, Lys303, produces a receptor that is hypersensitive to estrogen (34). Whereas breast cancer cells that express mutant ER{alpha} grow equally well in response to either 10–12 or 10–9 M estradiol, wild-type ER{alpha} expressing cells require 10–9 M estradiol for optimal growth. Recent in vitro studies support a role for phosphorylation in directly regulating the affinity of ER{alpha} for estradiol (35). Phosphorylation of ER{alpha} with either protein kinase A (PKA) or Src increases estradiol binding affinity about 7-fold. PKA phosphorylates both Ser236 and Ser305; whether both or only one of these sites modulates hormone binding affinity is unknown. Similarly, although Src phosphorylates Tyr537, it phosphorylates one or more additional sites in vitro. Thus, additional sites may participate in the modulation of hormone binding of ER{alpha}.

Regulation of Receptor Stability
Phosphorylation plays a major role in the regulation of receptor stability, although the mechanisms for regulation appear to be receptor specific. This function was first identified in studies of mouse GR. Substitution of Ala for seven or all eight of the identified phosphorylation sites in mouse GR increases the stability of the unliganded receptor as well as reducing or even eliminating the hormone-induced decrease in stability (t1/2 = 10 min for wild type and 20–25 min for mutant) that is characteristic of the wild-type receptor (36). Studies of human GR revealed that binding of a GR-interacting protein, TSG101 (tumor suppressor gene 101), to the hypophosphorylated unliganded GR (produced by substituting Ala for two of the GR phosphorylation sites, Ser203 and Ser211), increases GR protein stability. Overexpression of TSG101 increases expression of the Ala mutant, but not the wild-type GR. Conversely, small interfering RNA for TSG101 decreases expression of the Ala mutant (37).

Regulation of human PR stability has been attributed to the Ser294 phosphorylation site. Substituting Ala for this hormone-dependent phosphorylation site in the amino terminus of PR greatly decreases hormone-dependent degradation (38). Whereas wild-type PR expression is nearly undetectable by 6 h of hormone treatment, substantial amounts of the Ala294 mutant are retained even after 10 h of treatment. Ser294 resides in a PEST sequence, which is often a signal for proteasome-mediated degradation. Proteasome inhibitors stabilize PR, and the Ala294 mutant is less readily ubiquitinated than the wild-type receptor.

Phosphorylation is also implicated in the regulation of ERß stability (19, 39). Ser16 in ERß is a target for two mutually exclusive posttranslational modifications, phosphorylation and O-GlcNAc (N-acetylglucosamine) modification. Substitution of a Glu for the Ser decreases the receptor’s stability relative to wild type, whereas substitution of an Ala increases stability relative to wild-type ERß. Thus, the phosphorylation likely decreases stability of the receptor. In pulse chase studies, only 60% of wild-type ERß is retained after 6 h, whereas 85% of the Ala mutant remains. The competing modification increases stability by preventing phosphorylation. However, whether the O-GlcNAc intrinsically alters stability has not been determined.

Receptor phosphorylation may also regulate ER{alpha} stability. At least two groups have shown that a stably transfected Ala118 mutant is more stable than the wild-type receptor (40, 41). However, a Glu118 mutant is also more stable (41). Both mutants exhibit reduced hormone-induced ubiquitination and are less effective in recruiting the E3 ligases, Mdm2 and E6-AP, to ER-responsive promoters (41). Hence, it is likely that the phosphorylation of Ser118 is important, although these studies do not exclude an intrinsic importance for the serine, itself.

In contrast to the other steroid receptors, hormone treatment enhances the stability of AR. Inhibition of either cyclin-dependent kinase activity (42) or HER-2 activity (43) reduces AR stability, but in neither case has a specific phosphorylation site in AR been associated with the regulation of receptor stability.

Regulation of DNA Binding
Receptor phosphorylation plays a role both in positive and negative binding of ER{alpha} to DNA. Substitution of an Ala for the Ser167 phosphorylation site amino terminal of the DNA-binding domain reduced the affinity of the receptor for an ER DNA response element 10-fold (44). In vitro phosphorylation of the receptor with casein kinase II, one of several kinases that can phosphorylate this site, also increases binding to an ER DNA response element (45) as does phosphorylation by Akt (35). More recently, a role for Ser167 phosphorylation in ER{alpha} binding to natural promoters in cells has been demonstrated. Shah and Rowan (46) transiently transfected ER-negative HeLa cells with wild-type ER{alpha} or Ala167 ER{alpha} and showed that hormone-dependent binding to the pS2 promoter or to c-myc, measured using chromatin immunoprecipitation assays, was much lower for the mutant (< one third) compared with the wild-type receptor. However, mutation of Ser118, another major ER{alpha} phosphorylation site, had no effect on DNA binding. In contrast, phosphorylation of Ser236 or substitution of a negatively charged glutamic acid has been reported to reduce hormone-independent dimerization and DNA binding (47). However, in vitro phosphorylation with PKA does not appear to alter ER{alpha} binding to DNA in the presence of estradiol (35).

Subcellular Localization
There is good evidence that receptor phosphorylation also plays a role in subcellular localization of the steroid receptors, although the roles identified to date are unique to the individual receptors. Epidermal growth factor (EGF) induced phosphorylation of Ser294 in the human PR-B isoform induces nuclear translocation of the small amount of unliganded PR-B that is cytoplasmic (48). Mutation of Ser294 to Ala abrogates the response to EGF. However, Ser294 phosphorylation is not required for hormone-dependent nuclear translocation or for the constitutive nuclear localization of the smaller PR-A isoform.

In Ishikawa cells, phosphorylation of Thr311 in helix 1 of the hormone-binding domain of ER{alpha} has been implicated in the nuclear localization of the receptor (27). The Ala311 mutant in estradiol-treated cells is largely cytoplasmic despite a normal capacity to bind hormone. In these endometrial cells, estradiol treatment causes activation of p38 MAPK and a transient phosphorylation of Thr311, which is quite strong at 45 min but lost by 4 h of treatment. Although immunoprecipitated activated p38 MAPK complexes phosphorylate Thr311, additional inhibitor studies and the lack of a Thr-Pro sequence suggest that the kinase that phosphorylates ER{alpha} is a p38 MAPK-activated kinase rather than p38 MAPK, itself. The authors suggest that the phosphorylation limits nuclear export. Thr311 is found within a sequence related to other nuclear export sequences. They found that treatment with leptomycin B, a nuclear export inhibitor, enhances nuclear localization in the presence of the kinase inhibitor. Thus, phosphorylation is not required for hormone-dependent import, although the kinetics of uptake was not measured and may have been altered.

In contrast to ER{alpha}, phosphorylation of a hinge site in AR, Ser 650, promotes nuclear export measured in a heterokaryon assay (49). Whereas wild-type AR and an Asp650 phosphorylation site mimic efficiently relocalize from COS cell nuclei to 3T3 cell nuclei when the two cells are fused, the Ala650 mutant exhibits reduced relocalization. Because the wild-type and Ala650 mutant both localize to the nucleus of COS cells upon treatment with hormone, the defect appears to be in export rather than import. Ser650 can be phosphorylated by either p38 MAPK or c-Jun N-terminal kinase (JNK); inhibition of these kinases reduces AR shuttling, but the shuttling of an Asp650 mutant is unaffected by the inhibitors. The export of AR appears to reduce overall AR transcriptional activity because reducing expression of MKK4 or MKK6, upstream activators of these kinases, enhances hormone-dependent induction of prostate specific antigen in LNCaP prostate cancer cells.

The nuclear localization of GR is also affected by phosphorylation. In the absence of hormone, GR is predominantly cytoplasmic. Dexamethasone treatment induces nuclear localization, and wash out of dexamethasone causes a gradual relocalization to the cytoplasm over the course of several hours (50). If JNK is activated by UV irradiation in combination with dexamethasone washout, GR rapidly relocalizes to the cytoplasm. JNK phosphorylates Ser226 in the amino terminus of human GR, and an Ala226 mutant exhibits both reduced basal relocalization as well as reduced JNK-stimulated relocalization. The rapid JNK-induced relocalization is sensitive to leptomycin B, implicating the exportin 1/CRM 1 pathway in nuclear export. However, it appears that the slow relocalization in the absence of JNK activation is insensitive to leptomycin B (51); thus, there may be two pathways involved in GR nuclear export. An earlier study of rat GR showed that treatment with the phosphatase inhibitor, okadaic acid, enhanced GR phosphorylation and prevented reentry into the nucleus in response to hormone (52). Whether the site corresponding to Ser226 in rat GR is involved in this process is unknown.

In summary, receptor phosphorylation plays a role in the subcellular localization of AR, GR, PR, and ER{alpha}. There is some evidence that phosphorylation may also play a role in the localization of the mineralocorticoid receptor as well, but specific sites have not been identified (53). The roles of the individual phosphorylations have not been elucidated. Among the possibilities are altered interactions with nuclear proteins affecting availability for export and altered interactions with proteins that facilitate nuclear export/import. Neither the location of the site nor the effect on receptor localization is conserved from receptor to receptor. An amino-terminal site enhances nuclear localization of PR, but the amino-terminal site in GR increases nuclear export. In each case the role of the site is most pronounced upon specific activation of the kinase that phosphorylates the site. Because the studies are far from comprehensive, it is possible that some of the receptors contain additional sites regulated by other kinases that either enhance or oppose the actions of the regulatory sites described here.

Regulation of Transcription and Interactions with Coregulators
Cell-based transcriptional activity assays reflect the net result of modulation of all of the steps involved in the regulation of receptor activity. Initial studies of the role of receptor phosphorylation in the regulation of receptor-dependent transcription relied on transient transfection assays using receptors with alanine substitutions for the phosphorylation sites and reporters with artificial promoters containing hormone response elements. These simplified assays eliminate or minimize many of the potential regulatory steps in modulating receptor action, including autoregulation of promoter elements, interactions with other transcription factors found in natural promoters, and the need to extensively modify the chromatin of target genes integrated into the genome. Despite these limitations, significant reductions in transcriptional activity were detected when an alanine was substituted for Ser211 in chicken PR (20–70% depending upon the reporter and cell type) (54) or when the three amino-terminal Ser-Pro sites in human ER{alpha} (15) were mutated to alanines (45–50% depending upon the promoter). AR activity was reduced about 30% when Ser650 was mutated (18), and some reduction in human PR activity was detected when sites including Ser190 were mutated (≤50% depending upon the promoter used) (55). Whereas mutation of the phosphorylation sites in mouse GR had little effect on the ability of GR to transactivate a mouse mammary tumor virus chloramphenicol acetyltransferase reporter, Ala substitutions for several of the mouse (m) GR phosphorylation sites including Ser212 and Ser220 strongly reduced (~70%) the ability of mGR to induce transcription from a minimal promoter consisting of two glucocorticoid-response elements and a TATA box (36). More pronounced effects of receptor phosphorylation on the regulation of receptor activity are noted when specific cell signaling pathways are activated. For example, phosphorylation or substitution of a negatively charged amino acid for Ser118 in ER{alpha} is required for EGF-induced ligand-independent activation of ER{alpha} (56). Potentiation of ER{alpha} activity by cyclin A/cyclin-dependent kinase 2 activity is lost when alanines are substituted for Ser104 and Ser 106 in ER{alpha} (57). In contrast, substitution of an Ala for either Ser118 or Ser167 blocks Src-dependent potentiation of ER{alpha} activity (46). Potentiation of human PR activity by MEKK1 requires Ser294 (58). Although many of the phosphorylations enhance receptor activity, phosphorylation of Ser246 in rat GR reduces its activity (59). Activation of JNK induces phosphorylation of Ser246 and reduces GR activity about 75%; mutation of this site reduces the inhibitory effects of JNK.

Although studies of the effects of receptor phosphorylation on the regulation of natural promoters are limited, the effects of the loss of phosphorylation are more striking than those observed in transient transfection assays. Mutation of all of the known phosphorylation sites in mGR prevented dexamethasone-induced down-regulation of GR mRNA, and mutation of a few sites had more modest effects (36). Mutation of Ser211 in a constitutively active fragment of human GR markedly reduces its ability to induce apoptosis (40% of wild type) in ICR-27 cells (60), demonstrating a role for phosphorylation in regulating known biological functions of receptors. In breast cancer cells stably expressing wild-type PR-B, progestins induce expression of TGF{alpha} and heparin-binding EGF, whereas in cells expressing an Ala294 mutant PR-B, there was no progestin-dependent induction of these targets (61). These initial studies suggest that receptor phosphorylations likely play important target gene-specific roles in regulating steroid receptor activity.

Recent studies show that phosphorylation regulates both positive and negative interactions with coactivators and corepressors. The Ser-Pro phosphorylation sites in the amino terminus of ER{alpha} modulate interactions with coactivators, with Ser118 playing a particularly important role. Phosphorylation of Ser118 facilitates interaction with the coactivator, (SF)3ap120, a splicing factor; this results in phosphorylation-dependent potentiation of splicing (62). The same site has been implicated in the binding of stromelysin-1 platelet-derived growth factor-responsive element-binding protein, a repressor of ER activity (63). Phosphorylation also enhances the interaction between the receptor interaction domain of amplified in breast cancer 1/steroid receptor coactivator (SRC)-3 and ER{alpha} (35). In vitro phosphorylation of ER{alpha} with p42/p44 MAPK, Akt, or PKA increases affinity for the receptor interaction domain measured using fluorescence resonance energy transfer (35). Phosphorylation of the amino terminus of ERß induced by p42/p44 MAPK activation enhances interaction with the p160 coactivator, facilitating ligand-independent activation of the receptor (64). On the other hand, phosphorylation of Ser255 in ERß by Akt has been implicated in inhibition of the interaction between ERß and cAMP response element-binding protein (CREB)-binding protein (65). Coactivator phosphorylation is also extremely important in regulating physical and functional interactions between coregulators and steroid receptors. Roles for coactivator phosphorylation have been identified for all of the p160 coactivators. For example, amplified in breast cancer 1/SRC-3 is highly phosphorylated, and the individual sites contribute to the ability to coactivate specific transcription factors (66, 67). Interestingly, the peptidyl-prolyl isomerase Pin1 regulates the activity of the phosphorylated SRC-3. Phosphorylation of GR-interacting protein 1/transcriptional intermediary factor 2/SRC-2 by p42/p44 MAPK has been implicated in potentiation of AR activity (68), and phosphorylation of specific sites in SRC-1 aid in hormone-independent activation of AR (69) and chicken PR (70). Inhibition of cyclin-dependent kinase activity by roscovitine blocks the ability of human PR to recruit SRC-1 to a mouse mammary tumor virus promoter, and in vitro studies show that phosphatase treatment of SRC-1 reduces its ability to interact with human PR (71). Thus, coactivator phosphorylation is an important component of the regulation of steroid receptor activity.


   SUMMARY
TOP
 ABSTRACT
 INTRODUCTION
 RECEPTOR PHOSPHORYLATION SITES
 RECEPTOR PHOSPHORYLATION AND THE...
 SUMMARY
REFERENCES
 
Studies to date reveal that receptor phosphorylation is remarkably complex, that receptors are targets for multiple kinases, and that most receptor functions can be regulated by phosphorylation, although the mechanisms of regulation are receptor specific. Many questions remain. Most of the phosphorylation studies have used endogenous or recombinant receptor expressed in cell lines. We know very little about the relative levels of phosphorylation of individual sites in vivo. Is the extent of phosphorylation of individual sites tissue specific and/or dependent upon the physiological status of the cell? Many sites are substrates for multiple kinases; consequently, there is potential for very complex regulatory patterns. Moreover, almost nothing is known about the phosphatases that dephosphorylate the receptors. An important new tool for studying both the regulation and roles of receptor phosphorylation is the site-specific antibody. These antibodies have already resolved questions regarding the authenticity of sites and identified signaling pathways involved in receptor phosphorylation and have led to some unexpected findings. For example, despite the presence of Ser294 in both the PR-B and PR-A isoforms, Ser294 is phosphorylated only in the PR-B isoform (24), suggesting a unique conformation of PR-B and/or the binding of a protein that specifically occludes the site in PR-A. PR activity varies as a function of cell cycle. In cells blocked in G2, transcriptional activity is reduced, and neither hormone-dependent nor p42/p44 MAPK-dependent phosphorylation of Ser162 and Ser294 can be induced despite the presence of activated p42/p44 MAPK (25). Evidence that phosphorylation is tissue specific comes from a study of the phosphorylation of Ser213 in AR using a site-specific antibody. The site is phosphorylated in the differentiated luminal cells in the urogenital sinus, but not in the proliferating Ki67 positive cells (22).

Although roles for some of the sites have been identified, others have not been characterized. Moreover, it is evident that some sites, including Ser118, in ER{alpha} have multiple roles. Global comparisons of gene expression regulated by wild-type and mutant receptors using microarrays followed by detailed mechanistic studies of targets that are differentially regulated should yield a better understanding of the roles of individual sites. Finally, very little is known regarding the biological consequences of the elimination of a phosphorylation. Cell-based models can provide some information, but mouse knock-in studies will be required to address tissue-specific requirements for phosphorylation.


   FOOTNOTES
 
This work was supported in part by National Institutes of Health Grant R01 CA57539.

Disclosure Summary: The authors have nothing to disclose.

First Published Online May 29, 2007

Abbreviations: AF, Activation function; AR, androgen receptor; EGF, epidermal growth factor; ER, estrogen receptor; GR, glucocorticoid receptor; JNK, c-Jun N-terminal kinase; PKA, protein kinase A; PP5, protein phosphatase 5; PR, progesterone receptor; SRC, steroid receptor coactivator.

Received for publication February 21, 2007. Accepted for publication May 24, 2007.


   REFERENCES
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 ABSTRACT
 INTRODUCTION
 RECEPTOR PHOSPHORYLATION SITES
 RECEPTOR PHOSPHORYLATION AND THE...
 SUMMARY
 REFERENCES
 

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NURSA Molecule Pages Link:

Nuclear Receptors:   ERα  |  ERβ  |  GR  |  MR  |  PR  |  AR
Coregulators:   TSG101  |  PIN1  |  SRC-1  |  GRIP1  |  AIB1
Ligands:   17β-Estradiol



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