The EGF receptor is a tyrosine protein kinase. It has 2
components of different molecular weight; both contain phosphotyrosine and phosphothreonine but only the higher
molecular weight form contains phosphoserine (Carlin and Knowles, 1982 ).
NCBI Summary:
The protein encoded by this gene is a transmembrane glycoprotein that is a member of the protein kinase superfamily. This protein is a receptor for members of the epidermal growth factor family. EGFR is a cell surface protein that binds to epidermal growth factor, thus inducing receptor dimerization and tyrosine autophosphorylation leading to cell proliferation. Mutations in this gene are associated with lung cancer. EGFR is a component of the cytokine storm which contributes to a severe form of Coronavirus Disease 2019 (COVID-19) resulting from infection with severe acute respiratory syndrome coronavirus-2 (SARS-CoV-2). [provided by RefSeq, Jul 2020]
General function
Receptor
Comment
Wang Y, et al reported the cloning of Epidermal Growth Factor (EGF) and EGF Receptor from the Zebrafish Ovary: Evidence for EGF as a Potential Paracrine Factor from the Oocyte to Regulate Activin/Follistatin System in the Follicle Cells.
In the present study, we cloned full-length cDNAs for epidermal growth factor (EGF), EGF receptor (EGFR) and three truncated forms of EGFR (EGFR15, 12 and 8) from the zebrafish ovary. Zebrafish EGF was predominantly expressed in the ovary and testis, while EGFR and its truncated forms were highly expressed in all tissues examined except the liver. In the ovary, the expression of EGF seemed to be more abundant in the follicles of early stages, while EGFR had much higher expression levels at later stages. Interestingly, although EGF was expressed in both the follicle cells and oocytes, its expression level was significantly higher in the oocytes. However, the expression of EGFR was mainly restricted to the follicle cells with little expression in the oocytes. The unique spatial patterns of EGF and EGFR expression within the follicle suggest that EGF may serve as a messenger from the oocyte to signal the follicle cells. EGF strongly stimulated the expression of both activin betaA and betaB, while it suppressed basal and hCG-induced follistatin expression in cultured follicle cells. These results, together with the evidence that EGF was predominantly expressed in the oocytes whereas EGFR was expressed in the follicle cells, strongly suggest that EGF is likely a potential paracrine/justacrine factor from the oocytes to regulate the function of the follicle cells.
Cellular localization
Plasma membrane
Comment
Epidermal growth factor receptor downregulation in cultured bovine cumulus cells: reconstitution of calcium signaling and stimulated membrane permeabilization.
Reproduction. 2005 .
Ovarian function
Follicle development, Initiation of primordial follicle growth, Preantral follicle growth, Antral follicle growth, Cumulus expansion, Follicle atresia, Ovulation, Steroid metabolism, Luteinization, Oogenesis, Oocyte maturation, Early embryo development
Comment
Epidermal growth factor receptor signaling uncouples germ cells from the somatic follicular compartment at ovulation. Abbassi L et al. (2021) Germ cells are physically coupled to somatic support cells of the gonad during differentiation, but this coupling must be disrupted when they are mature, freeing them to participate in fertilization. In mammalian females, coupling occurs via specialized filopodia that project from the ovarian follicular granulosa cells to the oocyte. Here, we show that signaling through the epidermal growth factor receptor (EGFR) in the granulosa, which becomes activated at ovulation, uncouples the germ and somatic cells by triggering a massive and temporally synchronized retraction of the filopodia. Although EGFR signaling triggers meiotic maturation of the oocyte, filopodial retraction is independent of the germ cell state, being regulated solely within the somatic compartment, where it requires ERK-dependent calpain-mediated loss of filopodia-oocyte adhesion followed by Arp2/3-mediated filopodial shortening. By uncovering the mechanism regulating germ-soma uncoupling at ovulation, our results open a path to improving oocyte quality in human and animal reproduction.//////////////////Oocyte induction of EGF responsiveness in somatic cells is associated with the acquisition of porcine oocyte developmental competence. Ritter LJ et al. (2015) Oocytes progressively acquire the competence to support embryo development as oogenesis proceeds with ovarian folliculogenesis. The objectives of this study were to investigate oocyte-secreted factor (OSF) participation in the development of somatic cell epidermal growth factor (EGF) responsiveness associated with oocyte developmental competence. A well-established porcine model was employed using oocytes from small (<4mm) versus medium sized (>4mm) antral follicles, representing low versus moderate developmental competence, respectively. Cumulus-oocyte complexes (COCs) were treated in vitro with inducers of oocyte maturation and cumulus cell functions and oocyte developmental competence were assessed. COCs from small follicles responded to FSH but, unlike COCs from larger follicles, were incapable of responding to EGF family growth factors known to mediate oocyte maturation in vivo, exhibiting perturbed cumulus expansion and expression of associated transcripts (HAS2, TNFAIP6). Low and moderate competence COCs expressed equivalent levels of EGF receptor (EGFR) mRNA however the former had less total EGFR protein leading to failed activation of phospho-EGFR and phospho-ERK1/2, despite equivalent total ERK1/2 protein levels. Native OSFs from moderate, but not from low, competence oocytes established EGF responsiveness in low competence COCs. Four candidate recombinant OSFs failed to mimic the actions of native OSFs in regulating cumulus expansion. Treatment with OSFs and EGF enhanced oocyte competence but only of the low competence COCs. These data suggest that developmental acquisition by the oocyte of capacity to regulate EGF responsiveness in the oocyte's somatic cells is a major milestone in the oocyte's developmental program and contributes to coordinated oocyte and somatic cell development.//////////////////
Reactive oxygen species are indispensable in ovulation. Shkolnik K et al. Ovulation is stimulated by the preovulatory surge of the pituitary luteinizing hormone (LH). Because the ovulatory response is commonly identified with inflammation, we explored the involvement of reactive oxygen species (ROS) in this process. Our experiments show that administration of broad-range scavengers of oxidative species into the ovarian bursa of mice, hormonally induced to ovulate, significantly reduced the rate of ovulation. LH-induced cumulus mucification/expansion, a necessary requirement for ovulation, was prevented by antioxidants both in vivo and in an ex vivo system of isolated intact ovarian follicles. Along this line, H(2)O(2) fully mimicked the effect of LH, bringing about an extensive mucification/expansion of the follicle-enclosed cumulus-oocyte complexes. Impaired progesterone production was observed in isolated follicles incubated with LH in the presence of the antioxidant agents. Furthermore, LH-stimulated up-regulation of genes, the expression of which is crucial for ovulation, was substantially attenuated upon ROS ablation. This system was also used for demonstrating the role of ROS in phosphorylation and activation of the EGF receptor as well as its downstream effector, p42/44 MAPK. Together, our results provide evidence that ovarian production of ROS is an essential preovulatory signaling event, most probably transiently triggered by LH.
Transactivation of the Epidermal Growth Factor Receptor Is Involved in the Lutropin Receptor-Mediated Down-Regulation of Ovarian Aromatase Expression in Vivo. Andric N et al. Ovarian follicular development and differentiation is characterized by dramatic changes in aromatase (Cyp19a1) expression. In preovulatory follicles, activation of the FSH receptor increases aromatase expression until the surge of LH decreases it. Here we provide in vivo evidence that down-regulation of Cyp19a1 by the LH surge requires efficient signaling through the epidermal growth factor receptor (EGFR). The human chorionic gonadotropin (hCG)-induced down-regulation of Cyp19a1 expression in the two different mouse models with inactivating mutations of the EGFR (wa2 and velvet) is impaired but not abolished. The hCG-induced phosphorylation of ovarian ERK1/2, expression of C/EBPbeta, and the phosphorylation of Connexin43 (two downstream targets of ERK1/2 action) are also decreased in these two mouse models. In contrast, disruption of EGFR signaling does not have any affect on the hCG-induced phosphorylation of cAMP response element-binding protein or AKT. This study provides the first in vivo evidence linking the LH receptor, the EGFR, and ERK1/2 as sequential components of a pathway that regulates ovarian Cyp19a1 expression.
Prochazka R, et al have recently shown that epidermal growth factor (EGF) strongly stimulates expansion of porcine oocyte-cumulus complexes (OCCs) isolated from large follicles (>6 mm) and does not promote expansion of OCCs from small (3-4-mm) follicles. In order to elucidate the role of EGF in OCCs expansion, in the present study, we first examined the presence of EGF receptors (EGFRs) in cumulus cells isolated from follicles of different sizes. Surprisingly, immunoblotting showed that cumulus cells obtained from all follicular size categories contained similar amounts of EGFR protein. On the other hand, we found a dramatic difference in the pattern of protein tyrosine phosphorylation in a comparison of cumulus cells isolated from small and large follicles treated by EGF. Furthermore, tyrosine-phosphorylated EGFR was specifically immunoprecipitated with antiphosphotyrosine antibodies from EGF-treated cumulus cells isolated from the large follicles. This result strongly indicates that only OCCs from the large follicles contain mature EGFRs that are capable of becoming activated by EGF. Remarkably, preincubation of cumulus cells from small follicles (3-4 mm) with FSH strongly increased EGF-stimulated tyrosine phosphorylation to levels comparable with OCCs from large follicles. The FSH-dependent activation of EGFRs was beneficial for expansion of OCCs isolated from the small follicles since OCCs treated sequentially by FSH (3 h) and EGF (1 h) underwent expansion significantly better then OCCs cultured in FSH or EGF alone. We conclude that a FSH-dependent pathway has an important role in the maturation of the EGFR in cumulus cells and that activation of EGFR-dependent signaling is sufficient to induce expansion.
Dekel N, Sherizly I 1985 reported that epidermal growth factor induces maturation of rat follicle-enclosed oocytes.
Gonadotropin-induced differentiation of ovarian granulosa cells in culture is inhibited by epidermal growth factor (EGF). The present study was undertaken to test a possible inhibitory effect of EGF on LH-induced maturation of rat follicle-enclosed oocytes. We have found that EGF not only failed to affect LH action but served by itself as an inducer of maturation of follicle-enclosed oocytes. EGF action on the oocytes was dose and time dependent and could be prevented by (Bu)2 cAMP. The response of the oocytes was specific to EGF and could not be elicited by other growth factors such as nerve growth factor and insulin. The response to EGF was not limited to the large antral follicles, as oocytes enclosed by small antral follicles (less than 0.4 mm) were induced to mature by EGF as well. In addition, we have demonstrated that oocytes, induced to mature by EGF, are concomitantly uncoupled from the follicular cells. Based on these results we suggest that EGF may terminate the transfer of a follicular inhibitor to the oocyte. It is also possible, however, that EGF induces oocyte maturation by a mechanism independent of its effect on communication between the cellular components of the follicle.
Maruo T et al reported the expression of epidermal growth factor and its receptor in the
human ovary during follicular growth and regression.
In the preantral follicle stage, immunostaining for EGF and EGF receptor was observed only in
the oocyte. The staining intensity of the oocyte increased as the oocyte reached the preovulatory stage. In the antral follicle stage, immunostaining for EGF and EGF receptor became apparent in the granulosa and
theca interna cell layers, without appreciable staining in the surrounding stromal cells. The
immunostaining for EGF and EGF receptor in the granulosa cells and theca interna cells persisted in
preovulatory follicles and corpus luteum, and intensified in the midluteal phase. The results
obtained support EGF participation in oocyte maturation and in follicular growth and atresia. The intense immunostaining for EGF and EGF receptor observed in the theca interna cells in atretic follicles and the stromal cells surrounding corpus albicans in the cortex region raises the possibility of EGF involvement in transformation of thecal cells into stromal cells. Furthermore, the cell type-specific simultaneous
expression of EGF and EGF receptor in follicular and stromal compartments in the various stages of
follicular development suggests that an autocrine mode of EGF action may exist to regulate follicular
growth and regression in the human ovary.
Tekpetey FR, et al. studied epidermal growth factor (EGF) receptor localization in cultured human granulosa lutein cells and
the stimulation of progesterone production by EGF and transforming growth factor-alpha
(TGF-alpha).
Chun SY, et al. studied hormonal regulation of apoptosis in early antral follicles. Incubation of follicles with epidermal growth factor (EGF) and
basic fibroblast growth factor maximally suppressed follicle apoptosis by only 32% and 42%,
respectively.
Epidermal growth factor receptor signaling is required for normal ovarian steroidogenesis and oocyte maturation Jamnongjit M,et al .
The midcycle luteinizing hormone (LH) surge triggers several tightly linked ovarian processes, including steroidogenesis, oocyte maturation, and ovulation. We designed studies to determine whether epidermal growth factor receptor (EGFR)-mediated signaling might serve as a common regulator of these activities. Our results showed that EGF promoted steroidogenesis in two different in vitro models of oocyte-granulosa cell complexes. Inhibition of the EGFR kinase prevented EGF-induced steroidogenesis in these in vitro systems and blocked LH-induced steroidogenesis in intact follicles primed with pregnant mare serum gonadotropin. Similarly, inhibition of the EGFR kinase attenuated LH-induced steroidogenesis in MA-10 Leydig cells. Together, these results indicate that EGFR signaling is critical for normal gonadotropin-induced steroidogenesis in both male and female gonads. Interestingly, inhibition of metalloproteinase-mediated cleavage of membrane-bound EGF moieties abrogated LH-induced steroidogenesis in ovarian follicles but not MA-10 cells, suggesting that LH receptor signaling activates the EGFR by different mechanisms in these two models. Finally, steroids promoted oocyte maturation in several ovarian follicle models, doing so by signaling through classical steroid receptors. We present a model whereby steroid production may serve as one of many integrated signals triggered by EGFR signaling to promote oocyte maturation in gonadotropin-stimulated follicles.
Epidermal growth factor activates cytosolic Ca2+ elevations and subsequent membrane permeabilization in mouse cumulus-oocyte complexes. O'Donnell JB et al. The role of epidermal growth factor (EGF) in the maturation of mammalian oocytes is well known but not well characterized. It is known that EGF enhances oocyte maturation in vitro and that EGF stimulation of cumulus-oocyte complexes (COCs) induces pulsatile Ca2+ efflux from the cell complex. By use of quantitative Fura-2 imaging, EGF-stimulated changes in intracellular Ca(2+) in germinal vesicle stage murine COCs are shown to occur in a subpopulation of cumulus cells that interact cooperatively within individual COCs. Oocytes fail to respond to EGF stimulus. In many of the cumulus cells responding with a rise in intracellular Ca(2+), a concomitant permeabilization of the plasma membrane is found. Neither cumulus cells of control COCs nor those that show a rise in intracellular Ca(2+) in response to calcium ionophore treatment display a similar membrane permeabilization, although those cells responding with a prolonged Ca(2+) increase in response to thimerosal or thapsigargin do display plasma membrane permeabilization. Thus, EGF stimulation of mammalian COCs activates release of Ca(2+) from intracellular stores of cumulus cells, the depletion of which activates permeabilization of the plasma membrane. This membrane permeabilization leads to loss of cell contents and presumptive cumulus cell death. This catastrophic EGF-induced plasma membrane permeabilization of individual cumulus cells within a COC leads to pulsatile Ca(2+) efflux as previously seen, and may lead to improved cumulus cell expansion during COC maturation.
Possible mechanism for acceleration of meiotic progression of bovine follicular oocytes by growth factors in vitro. Sakaguchi M et al. The mechanism for the accelerating effects of epidermal growth factor (EGF) and insulin-like growth factor I (IGF-I) on the meiotic cell cycle of bovine oocytes cultured in vitro was investigated. Cumulus-oocyte complexes (COCs) were obtained from small (< or = 3 mm in diameter), medium (4-6 mm in diameter) or large (7-10 mm in diameter) ovarian follicles and cultured with or without a combination of EGF and IGF-I (growth factors). Growth factors significantly increased the frequency of first polar body extrusion of oocytes derived from small follicles at 16 h of culture (PB16 oocytes; with growth factors: 75%; without growth factors: 55%), but did not increase the frequency in oocytes from medium or large follicles. COCs from small follicles were cultured with individual growth factors and sampled for kinase activity. The frequencies of polar body extrusion in EGF only (67%) and EGF + IGF-I (75%) treatment groups were significantly higher than those in the control (no growth factor) group (49%), but not significantly higher than in the IGF-I only group (63%). The H1 kinase activity at 6-8 h of culture in each group increased significantly from the baseline value at 0 h of culture, and the H1 kinase activities in the EGF only, IGF-I only and EGF + IGF-I treatment groups were significantly higher than those in the control group at 8 h of culture. MAP kinase activity was significantly higher than the baseline value and significantly higher than that in the control group at 6 h of culture in the EGF treatment group only. In conclusion, EGF and IGF-I act on COCs from small follicles to accelerate the meiotic cell cycle of the oocytes. This accelerating effect may be related to increased H1 and MAP kinase activities during the early stages of maturation.
EGF-like peptides mediate FSH-induced maturation of cumulus cell-enclosed mouse oocytes. Downs SM et al. This study was carried out to examine the participation of epidermal growth factor (EGF)-like peptides in the induction of germinal vesicle breakdown (GVB) in mouse cumulus cell-enclosed oocytes (CEO). The EGF-like peptide, amphiregulin (AR), dose-dependently stimulated meiotic resumption in CEO, but not denuded oocytes (DO) maintained in meiotic arrest with 300 microM dbcAMP. The EGF receptor (EGFR) kinase inhibitor, AG1478, blocked meiotic resumption induced by FSH and AR in CEO, but had no effect in DO. FSH-induced maturation was also suppressed by antisera to both EGFR and EGF. Maturation occurred with slightly faster kinetics in AR-stimulated CEO when compared to FSH-stimulated CEO. When CEO were maintained in meiotic arrest with a low level of dbcAMP, FSH was initially inhibitory to maturation and later stimulatory; the stimulatory phase was prevented by AG1478, indicating mediation by EGF-like peptides. Pulsing CEO with high levels of dbcAMP also stimulated GVB and could be blocked by AG1478. Treatment of arrested CEO with PKC agonists stimulated maturation and this was prevented with AG1478 as well as antibodies to EGFR. FSH-induced maturation of dbcAMP-arrested CEO was blocked by bisindolylmaleimide I (BIM-I), an inhibitor of PKC, implicating PKC in FSH action. EGF-stimulated CEO failed to resume maturation in the presence of glycerrhetinic acid, a gap junction inhibitor, suggesting transfer of positive signal through the cell-cell coupling pathway. These data support the idea that EGF-like peptides provide a common pathway mediating the meiosis-inducing influence of FSH, cAMP pulsing, and PKC activation in mouse CEO by a gap junction-dependent process. Mol. Reprod. Dev. (c) 2007 Wiley-Liss, Inc.
LH Signaling in Preovulatory Follicles Involves Early Activation of the EGFR Pathway. Panigone S et al. LH activates a cascade of signaling events that are propagated throughout the ovarian preovulatory follicle to promote ovulation of a mature egg. Critical to LH-induced ovulation is the induction of EGF-like growth factors and transactivation of EGF receptor (EGFR) signalling. Because the timing of this transactivation has not been well characterized, we investigated the dynamics of LH regulation of the EGF network in cultured follicles. Preovulatory follicles were cultured with or without recombinant LH (rLH) and/or specific inhibitors. EGFR and MAPK phosphorylation were examined by immunoprecipitation and Western blot analyses. By semi-quantitative RT-PCR, increases in amphiregulin and epiregulin mRNAs were detected 30 min after rLH stimulation of follicles, and were maximal after 2 h. LH-induced EGFR phosphorylation also increased after 30 min and reached a maximum at 2 h. EGFR activation precedes oocyte maturation and is cAMP dependent, as forskolin similarly activated EGFR. LH-induced EGFR phosphorylation was sensitive to AG1478, an EGFR kinase inhibitor, and to inhibitors of matrix metalloproteases GM6001 and TAPI-1, suggesting the involvement of EGF-like growth factor shedding. LH- but not amphiregulin-induced oocyte maturation and EGFR phosphorylation were sensitive to protein synthesis inhibition. When granulosa cells were cultured with a combination of neutralizing antibodies against amphiregulin, epiregulin and betacellulin, EGFR phosphorylation and MAPK activation were inhibited. In cultured follicles, LH-induced MAPK activation was partially inhibited by AG1478 and GM6001, indicating that this pathway is regulated in part by the EGF network, but also involves additional pathways. Thus, complex mechanisms are involved in the rapid amplification and propagation of the LH signal within preovulatory follicles and include the early activation of the EGF network.
Steady-state level of epidermal growth factor (EGF) mRNA and effect of EGF on in vitro culture of caprine preantral follicles. Celestino JJ et al. Our aim was to verify the steady-state level of epidermal growth factor (EGF) mRNA in goat follicles at various developmental stages and to investigate the influence of EGF on the survival, antrum formation and growth of secondary follicles cultured for 6?days. Primordial, primary and secondary goat follicles and small and large antral follicles were obtained to quantify EGF mRNA by real-time reverse transcription with the polymerase chain reaction. The influence of EGF and the presence or absence of follicle-stimulating hormone (FSH) on the development of secondary follicles and on mRNA expression for EGF and FSH receptor (FSH-R) was determined after 6?days of culture. Survival, antrum formation and follicular diameter were evaluated every other day of culture. EGF mRNA levels in secondary follicles were significantly higher than those in primordial follicles, whereas in small and large antral follicles, EGF mRNA levels in cumulus-oocyte complexes (COCs) were significantly higher than in granulosa/theca cells. During culture, EGF in the presence or absence of FSH increased the follicular daily growth rate of secondary follicles when compared with that in enriched alpha minimal essential medium. FSH, EGF or both reduced EGF mRNA levels, whereas EGF reduced FSH-R mRNA levels after follicle culture for 6?days. Thus, EGF mRNA levels are higher in secondary follicles than in earlier stages, with both FSH and EGF promoting the growth of goat secondary follicles. EGF and/or FSH reduce EGF mRNA levels, whereas EGF decreases FSH-R mRNA levels, in cultured secondary follicles.
Expression regulated by
FSH, LH, Growth Factors/ cytokines, GDF9, BMP15
Comment
Mouse Oocytes Enable LH-Induced Maturation of the Cumulus-Oocyte Complex via Promoting EGF Receptor-Dependent Signaling. Su YQ et al. LH triggers the maturation of the cumulus-oocyte complex (COC), which is followed by ovulation. These ovarian follicular responses to LH are mediated by epidermal growth factor (EGF)-like growth factors produced by granulosa cells and require the participation of oocyte-derived paracrine factors. However, it is not clear how oocytes coordinate with the EGF receptor (EGFR) signaling to achieve COC maturation. The aim of the present study was to test the hypothesis that oocytes promote the expression of EGFR by cumulus cells, thus enabling them to respond to the LH-induced EGF-like peptides. Egfr mRNA and protein expression were dramatically reduced in cumulus cells of mutant mice deficient in the production of the oocyte-derived paracrine factors growth differentiation factor 9 (GDF9) and bone morphogenetic protein 15 (BMP15). Moreover, microsurgical removal of oocytes from wild-type COCs dramatically reduced expression of Egfr mRNA and protein, and these levels were restored by either coculture with oocytes or treatment with recombinant GDF9 or GDF9 plus recombinant BMP15. Blocking Sma- and Mad-related protein (SMAD)2/3 phosphorylation in vitro inhibited Egfr expression in wild-type COCs and in GDF9-treated wild-type cumulus cells, and conditional deletion of Smad2 and Smad3 genes in granulosa cells in vivo resulted in the reduction of Egfr mRNA in cumulus cells. These results indicate that oocytes promote expression of Egfr in cumulus cells, and a SMAD2/3-dependent pathway is involved in this process. At least two oocyte-derived growth factors, GDF9 and BMP15, are required for EGFR expression by cumulus cells.
Fujinaga H, et al. reported that
FSH and LH up-regulate epidermal growth factor receptors in rat granulosa cells.
Peng P, et al. reported the hormonal control of epidermal growth factor receptors by gonadotropins during granulosa cell
differentiation.
Regulation of granulosa cell proliferation and EGF-like ligands during the periovulatory interval in monkeys. Fru KN et al. BACKGROUND This study seeks to clarify cell cycle dynamics of granulosa cells following hCG and elucidate the expression of epidermal growth factor (EGF)-like ligands during luteinization. METHODS Granulosa cells were obtained from rhesus macaques undergoing controlled ovarian stimulation protocols before or after an ovulatory hCG bolus. Cell cycle characteristics were determined by flow cytometry and levels of EGF receptor (EGFR), amphiregulin (AREG), epiregulin (EREG) and betacellulin (BTC) mRNAs were measured by real-time RT-PCR. RESULTS The proportion of cells in S-phase was 7.5% prior to hCG and did not decline until 24 h after hCG (3.1%). EGFR protein and BTC mRNA did not change following hCG, whereas AREG and EREG mRNA increased starting at 3 and 12 h post-hCG, respectively, and remained elevated thereafter. CONCLUSIONS Cell cycle transit of macaque granulosa cells does not change until 24 h after an ovulatory stimulus, whereas the EGF-like ligands EREG and AREG are increased rapidly. This suggests that luteinizing granulosa cells are refractory to mitogenic stimulation by EGFR ligands.
Hill JL et al examined the effects of EGF on Ca2+
mobilization as measured by its efflux from mouse oocytes at three time periods throughout maturation
(0-4 hr, 4-8 hr, and 12 hr). Immature cumulus oocyte complexes (COCs) removed from the ovary for less
than 4 hr exhibit oscillations in Ca2+ efflux that initiated 5-30 min following EGF stimulation. This
response was not observed in COCs matured for 4-8 hr or 12 hr or in unstimulated 0-4 hr COCs.
Denuded oocytes and cumulus cells did not show the same response to EGF (8.2 nM and 16.4 nM).
Immunohistochemistry for detection of the EGF receptor along with EGF internalization studies showed that receptors are present both on cumulus cells and the oocyte but EGF appears to be internalized mainly by the cumulus cells. These data demonstrate that EGF induces oscillations in Ca2+ efflux in COCs 0-4
hr old and this response is mediated by the cumulus cells.
Almahbobi G, et al. reported hyperexpression of epidermal growth factor receptors in granulosa cells from women with
polycystic ovary syndrome.
Moreno-Cuevas J, et al. analyzed epidermal growth factor receptors in rat ovarian tissue.
Khan-Dawood FS, et al. reported epidermal growth factor receptors in human corpora lutea during the menstrual cycle and
pregnancy.
Scurry JP et al reported immunoreactivity of antibodies to epidermal growth factor,
transforming growth factors alpha, and epidermal
growth factor receptor in the premenopausal ovary.
The growth factor
antibodies reacted with theca, but not granulosa cells, whilst the antibody to EGFR reacted with both
types of follicular cells and was weakly reactive in ovarian stroma.
Immunohistochemical localization of epidermal growth factor receptor (EGF-r) and transforming growth factor alpha (TGF-alpha) in developing human ovarian follicles Ozdogan B,et al .
In this study, we aimed to detect the distribution of epidermal growth factor receptor (EGF-r) and transforming growth factor alpha in ovarian follicles at different stages. Indirect immunohistochemical methods and EGF-r polyclonal and TGF-alpha monoclonal antibodies were used; tissues were examined with light microscope. While dense collection of both growth factors were observed in primordial follicles, there was a strong reaction especially for EGF-r in follicles. Strong reactivity for EGF-r and moderate reactivity for TGF-alpha were observed in the nearby connective tissue. In examinations of primary follicles for EGF-r presence only, dye uptake was moderate in oocytes and dense in apical and basal cytoplasm of follicle cells. Reactivity was moderate in the nearby connective tissue. In the corpus luteum, there was weak reaction for both growth factors. But in stromal cells, reaction was strong. In degenerated follicle cells and in stroma of atretic follicles, reaction was positive for both growth factors; but EGF-r reactivity was more obvious. While strong staining was observed for both factors especially in granulosa cells surrounding the oocyte in Graafian follicle, moderate TGF-alpha reactivity was determined in oocyte cytoplasm. In conclusion, it is possible that EGF-r and TGF-alpha have ortocrine and paracrine effects on development and regression of human ovarian follicles.
Gonadotropin-stimulated EGFR expression in human ovarian surface epithelial cells: involvement of cyclic AMP-dependent Epac pathway. Choi JH et al. In addition to their critical roles in folliculogenesis and ovarian granulosa cell steroidogenesis, gonadotropins have been implicated as potential risk factors in ovarian epithelial carcinomas, most of which are derived from ovarian surface epithelium (OSE). However, the molecular mechanism underlying the effects of follicle-stimulating hormone (FSH) and luteinizing hormone (LH) in OSE and its neoplastic counterpart is not well understood. We previously demonstrated that gonadotropins promote the growth of OSE cells by regulating the levels of epidermal growth factor receptor (EGFR) via the activation of ERK1/2 and PI3K pathways in immortalized human OSE (IOSE) cells. In this study, we further investigated whether cAMP and its novel binding target, named exchange protein activated by cAMP (Epac), are involved in the gonadotropin-induced EGFR expression in OSE cells. Gonadotropins elevated intracellular cAMP levels in both IOSE and granulosa cells, and this increase was attenuated by SQ22536, an inhibitor of adenylyl cyclase (AC). The activation of the ERK1/2 and Akt pathways as well as the expression of EGFR was stimulated by reagents that elevate intracellular cAMP levels, via. cAMP analogue 8-bromo-cAMP and AC activator forskolin. A similar increase was observed when the cells were treated with a novel cAMP analogue, 8-(4-chlorophenylthio)-2'-O-methyl adenosine-3',5'-cyclic monophosphate (8-CPT-2ME-cAMP), which activates Epac specifically but not PKA. Moreover, the gonadotropin-induced EGFR expression and ERK1/2 and Akt activation were abolished by overexpression of dominant negative Epac. Taken together, these results indicate that the AC/cAMP/Epac signaling pathway may mediate the up-regulation of EGFR by gonadotropins via ERK1/2 and Akt activation.
Follicle stages
Primordial, Primary, Secondary, Antral, Preovulatory, Corpus luteum
Comment
Immunohistochemical study showed that immunoreactivity for the epidermal
growth factor (EGF) receptor was detected in
primordial follicles of adult ovarian tissue. (Qu et al ). EGF receptor staining was
most intense in the oocytes of primordial follicles.
Weak staining for EGF receptor was observed in some surrounding
pregranulosa cells. Immunohistochemical staining for
EGF receptor was also present in the stromal cells of ovarian tissue, but
to a much lesser degree.
Bennett RA et al reported immunohistochemical localization of transforming growth
factor-alpha, epidermal growth factor (EGF), and EGF receptor
in the human fetal ovary.
Phenotypes
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: subfertile Comment: Genetic Dissection of Epidermal Growth Factor Receptor Signaling during Luteinizing Hormone-Induced Oocyte Maturation. Hsieh M et al. Recent evidence that luteinizing hormone (LH) stimulation of ovulatory follicles causes transactivation of the epidermal growth factor receptor (EGFR) has provided insights into the mechanisms of ovulation. However, the complete array of signals that promote oocyte reentry into the meiotic cell cycle in the follicle are still incompletely understood. To elucidate the signaling downstream of EGFR involved in oocyte maturation, we have investigated the LH responses in granulosa cells with targeted ablation of EGFR. Oocyte maturation and ovulation is disrupted when EGFR expression is progressively reduced. In granulosa cells from mice with either global or granulosa cell-specific disruption of EGFR signaling, LH-induced phosphorylation of MAPK3/1, p38MAPK, and connexin-43 is impaired. Although the LH-induced decrease in cGMP is EGFR-dependent in wild type follicles, LH still induces a decrease in cGMP in Egfr(delta/f) Cyp19-Cre follicles. Thus compensatory mechanisms appear activated in the mutant. Spatial propagation of the LH signal in the follicle also is dependent on the EGF network, and likely is important for the control of signaling to the oocyte. Thus, multiple signals and redundant pathways contribute to regulating oocyte reentry into the cell cycle.