Mitogen-activated protein (MAP) kinases, also known as extracellular signal-regulated
kinases (ERKs), are thought to act as an integration point for multiple biochemical
signals because they are activated by a wide variety of extracellular signals, are rapidly
phosphorylated on threonine and tyrosine residues, and are highly conserved in
evolution.
NCBI Summary:
This gene encodes a member of the MAP kinase family. MAP kinases, also known as extracellular signal-regulated kinases (ERKs), act as an integration point for multiple biochemical signals, and are involved in a wide variety of cellular processes such as proliferation, differentiation, transcription regulation and development. The activation of this kinase requires its phosphorylation by upstream kinases. Upon activation, this kinase translocates to the nucleus of the stimulated cells, where it phosphorylates nuclear targets. One study also suggests that this protein acts as a transcriptional repressor independent of its kinase activity. The encoded protein has been identified as a moonlighting protein based on its ability to perform mechanistically distinct functions. Two alternatively spliced transcript variants encoding the same protein, but differing in the UTRs, have been reported for this gene. [provided by RefSeq, Jan 2014]
General function
Intracellular signaling cascade
Comment
Cellular localization
Cytoplasmic, Nuclear
Comment
The MAP kinase ERK2 is widely involved in eukaryotic signal transduction. Upon activation, it translocates to the nucleus of
the stimulated cell, where it phosphorylates nuclear targets.//////////Extracellular signal-regulated protein kinase activation in endometrium with polycystic ovary syndrome and its significance]. [Song XR et al. (2010) to investigate the activation of mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) signaling pathway in the endometrium of women with polycystic ovary syndrome (PCOS) and its effect and significance in the cause of hyperplasia and carcinoma; and investigate the factors which affect the activation of the MAPK/ERK signaling pathway. collected 52 patients diagnosed as PCOS who were taken dilation and curettage of uterus as study, while 32 non-PCOS patients matched as control group. Serum hormonal parameters, fasting blood glucose and insulin were measured in all patients. The PCOS patients were sub-group as insulin resistance group and non-insulin resistance group; all the patients were carried out pathology inspection of endometria, and the PCOS patients were sub-group as endometrial hyperplasia and carcinoma group and normal endometrium group based on the outcome of pathology inspection. Western blot were performed to detect the expressions of ERK1/2 and phosphorylated ERK1/2 (p-ERK1/2), the activation of ERK1/2. (1) the expression of p-ERK1/2 [(61 ± 13)%] in the endometrium in PCOS group was higher than that in the control [(44 ± 10)%, P < 0.01]. (2) The expression of p-ERK1/2 was significantly increased in group of endometrial hyperplasia and carcinoma [(70 ± 11)%] compared to that in group of normal endometrium [(55 ± 10)%, P < 0.01], while there were significant difference between group of insulin resistance [(63 ± 13)%] and group of non-insulin resistance [(55 ± 7)%, P < 0.01]. (3)Fasting insulin level, insulin area under the curve and body mass index were related to the expression of p-ERK1/2 in endometrium with PCOS, the correlation coefficient were 0.447, 0.456 and 0.381, respectively (all P < 0.01). the MAPK/ERK signaling pathway in endometrium with PCOS was overactivation, which was related to the endometrial hyperplasia and carcinoma; while the activation of MAPK/ERK signaling pathway were effected by insulin resistance and hyperinsulinemia.//////////////////
Protein Kinase A: A Master Kinase of Granulosa Cell Differentiation. Puri P et al. (2016) Activation of protein kinase A (PKA) by follicle stimulating hormone (FSH) transduces the signal that drives differentiation of ovarian granulosa cells (GCs). An unresolved question is whether PKA is sufficient to initiate the complex program of GC responses to FSH. We compared signaling pathways and gene expression profiles of GCs stimulated with FSH or expressing PKA-CQR, a constitutively active mutant of PKA. Both FSH and PKA-CQR stimulated the phosphorylation of proteins known to be involved in GC differentiation including CREB, ß-catenin, AKT, p42/44 MAPK, GAB2, GSK-3ß, FOXO1, and YAP. In contrast, FSH stimulated the phosphorylation of p38 MAP kinase but PKA-CQR did not. Microarray analysis revealed that 85% of transcripts that were up-regulated by FSH were increased to a comparable extent by PKA-CQR and of the transcripts that were down-regulated by FSH, 76% were also down-regulated by PKA-CQR. Transcripts regulated similarly by FSH and PKA-CQR are involved in steroidogenesis and differentiation, while transcripts more robustly up-regulated by PKA-CQR are involved in ovulation. Thus, PKA, under the conditions of our experimental approach appears to function as a master upstream kinase that is sufficient to initiate the complex pattern of intracellular signaling pathway and gene expression profiles that accompany GC differentiation.//////////////////
Keel BA et al demonstrate that porcine GCs contain
immunodetectable MAP kinases. EGF, in a concentration- and time-dependent manner, increases tyrosine phosphorylation
and MBP kinase activity (i.e. activation) of ERK2, and to a lesser degree ERK1, suggesting that the activation of MAP
kinase may mediate the mitogenic action of EGF in GCs.
Oliver RH, et al. reported the induction of apoptosis in luteinized granulosa cells by the MAP kinase kinase (MEK) inhibitor PD98059.
Motlik J, et al. reported that co-culture with pig membrana granulosa cells modulates the activity of cdc2 and MAP kinase in maturing cattle oocytes.
The phosphorylation state of ERK 1,2 proteins was determined by Western blotting.
Lee J, et al 2000
investigate the expression and localisation of active phosphorylated MAPKs
(p44ERK1/p42ERK2) during maturation of pig oocytes. In immunoblot analysis
using anti-p44ERK1 antibody which recognised both active and inactive forms of
p44ERK1 and p42ERK2, they confirmed that MAPKs were phosphorylatred
around the time of germinal vesicle breakdown (GVBD) and the active
phosphorylated MAPKs (pMAKs) were maintained until metaphase II.
Cyclic adenosine 3',5'-monophosphate-dependent activation of mitogen-activated protein kinase in cumulus cells is essential for germinal vesicle breakdown of porcine cumulus-enclosed oocytes Liang CG, et al .
MAPK plays an important role during meiotic maturation in mammalian oocytes, whereas the necessity of MAPK during meiotic resumption in porcine oocytes is still controversial. Here, by applying the method of ultracentrifugation to move the opaque lipid droplets to the edge of the oocyte, therefore allowing clear visualization of porcine germinal vesicles, oocytes just before germinal vesicle breakdown (GVBD) and those that had just undergone GVBD were selected for the assay of MAPK activation. Our results showed that phosphorylation of MAPK in oocytes occurred after GVBD in all three different culture models: spontaneous maturation model, inhibition-induction maturation model, and normal maturation model. Moreover, we found that activation of MAPK in cumulus cells but not in oocytes was essential for GVBD in cumulus-enclosed oocytes. Then the cross-talk between cAMP and MAPK in cumulus cells was investigated by using cell-type-specific phosphodiesterase (PDE) isoenzyme inhibitors. Our results showed that PDE3 subtype existed in oocytes, whereas PDE4 subtype existed in cumulus cells. PDE3 inhibitor prevented meiotic resumption of oocytes, whereas PDE4 inhibitor enhanced the ability of FSH or forskolin to activate MAPK in cumulus cells. We propose that increased cAMP resulting from inhibition of PDE3 in oocytes blocks GVBD, whereas increased cAMP resulting from inhibition of PDE4 activates MAPK pathway in cumulus cells, which is essential for GVBD induction.
A delayed, gonadotropin-dependent and growth-factor mediated activation of the ERK1/2 cascade negatively regulates aromatase expression in granulosa cells* Andric N et al. Human CG and hFSH elicit a transient increase in ERK1/2 phosphorylation lasting less than 60 min in immature granulosa cells expressing a low density of gonadotropin receptors. In cells expressing a high density of receptors hCG and hFSH elicit this fast transient increase in ERK1/2 phosphorylation and also a delayed and more sustained increase that is detectable after 6-9 h. Both, the early and delayed increases in ERK1/2 phosphorylation can be blocked with inhibitors of PKA, the epidermal growth factor receptor (EGFR) kinase, metalloproteases and MEK. The delayed effect, but not the early effect, can also be blocked with an inhibitor of protein kinase C (PKC). Since the delayed increase in ERK1/2 phosphorylation correlates with low aromatase expression in response to gonadotropins we tested the effects of the inhibitors mentioned on aromatase expression. These inhibitors had little or no effect on gonadotropin-induced aromatase expression in cells expressing a low density of receptors but they enhanced gonadotropin-induced aromatase expression in cells expressing a high density of receptors. Phorbol esters also induced a prolonged increase in ERK1/2 phosphorylation and when added together with hFSH, blocked the induction of aromatase expression by hFSH in cells expressing a low density of hFSHR. A MEK inhibitor reversed the inhibitory effect of the phorbol ester on aromatase induction. We conclude that the effects of gonadotropins on ERK1/2 phosphorylation are mediated by EGF-like growth factors and that the delayed effect is partially mediated by PKC and acts as a negative regulator of aromatase expression,
Towards a new understanding on the regulation of mammalian oocyte meiosis resumption. Sun QY et al. Mammalian oocytes reach prophase of first meiosis around the time of birth, and remain at this stage for months or years, depending on the species. Only after puberty will the fully-grown oocytes begin to resume meiosis which is stimulated by gonadotropin surge. It has long been known that a high level of intra-oocyte cyclic adenosine 3',5'-monophosphate (cAMP) prevents oocyte meiosis resumption as indicated by germinal vesicle breakdown (GVBD). Recently, guanosine triphosphate-binding (G) protein-coupled receptors/G proteins/adenyl cyclase pathway endogenous to the oocyte as well as cAMP diffusion from the somatic compartment through gap junctions have been implicated in maintaining cAMP at levels that prevent oocytes from resuming meiosis. Another second messager molecule, guanosine 3',5'-cyclic monophosphate (cGMP), has also recently been found to play important roles in maintaining oocyte meiosis arrest. cGMP in the follicular somatic cells diffuses into the oocyte and causes an increase in oocyte cAMP, presumably by acting on phosphodiesterase 3 (PDE3). The cGMP level in the somatic compartment of the follicle decreases in response to luteinizing hormone (LH), and this change may be mediated through the epidermal growth factor (EGF)-like factors and specific cGMP-phosphodiesterase subtype activity. It is well known that gonadotropic stimulation of meiotic resumption depends on mitogen-activated protein kinase (MAPK) activation in the somatic compartment of the follicle; recent studies show that LH, through cAMP/protein kinase A (PKA) and protein kinase C (PKC) pathways, induces the synthesis of paracine factors such as EGF-like facors and meiosis activating sterol (MAS) to regulate oocyte GVBD via the MAPK pathway in follicle cells. A recent granulosa cell-specific knockout study has for the first time provided in vivo evidence for the important role of extracellular regulated kinase 1 and 2 (ERK1/2), two main forms of MAPK, and their downstream molecules in granulosa cells in oocyte meiosis resumption. Unresolved questions and future directions on research regarding signaling changes in follicle cells and oocytes as well their communication in response to the gonadotropin surge are addressed in this review.
Sirotkin AV,et al reported the involvement of MAP kinase in the mediation of GH action on ovarian
granulosa cells.
Growth hormone (GH), prostaglandins F (PGF) and prostaglandins E (PGE) are important
regulators of ovarian function. Therefore, interrelationships between GH and these substances and
their intracellular mechanisms might be of physiological significance in the ovary. The aims of this
study on cultured porcine ovarian granulosa cells were to determine the effect of GH on the
secretion of oxytocin (OT), PGF and PGE and whether MAP kinase could be involved in the
mediation of GH action. Experiments were carried out with cultured porcine granulosa cells to
investigate the effects of exogenous pGH (1-100 ng/ml) on the expression of MAP kinase (ERK-1,
-2) and of PGH (1-100 ng/ml) and the MAP kinase blocker PD 98059 (1 microg/ml) on the
secretion of PGF, PGE and OT. The cellular content of ERK-1 and -2 was analyzed by Western
immunoblotting and immunocytochemistry, whilst PGF, PGE and OT accumulation in the medium
was measured by RIA. Addition of GH to culture medium significantly altered the pattern of ovarian
ERK MAP kinase on SDS-PA gels: the 44 and 42 kDa bands were reduced and additional 50 and
48 kDa bands appeared. Moreover, there was an increase in the percentage of cells containing ERK
MAP kinase. GH stimulated the secretion of PGF (at a concentration of 1 ng GH per ml medium)
and OT (100 ng GH per ml), but not PGE. The MAP kinase blocker alone did not affect PGF, PGE
and OT secretion but did prevent the stimulatory effects of GH on PGF and induced stimulatory
action of GH (10 ng/ml) on PGE. GH-stimulated OT secretion was unaffected. These observations
confirm the role of GH in regulating porcine ovarian PGF, PGE and OT secretion and the presence
of ERK MAP kinase in porcine granulosa cells. Furthermore, our studies demonstrate that MAP
kinase-dependent intracellular mechanisms are dependent on GH, and that these mechanisms are
involved in the mediation of GH action on ovarian PGF and PGE but not OT secretion.
Activation of the p38 MAPK pathway by follicle-stimulating hormone regulates steroidogenesis in granulosa cells differentially.
J Endocrinol. 2005 .
Ovarian localization
Oocyte, Cumulus, Granulosa, Luteal cells
Comment
Inhibition of extracellular signal-regulated protein kinase-2 phosphorylation by dihydrotestosterone reduces follicle-stimulating hormone-mediated cyclin d2 messenger ribonucleic Acid expression in rat granulosa cells Kayampilly PP, et al .
Granulosa cell mitogenesis is critical for the development of normal ovarian follicles. FSH and other mitogenic stimuli play a crucial role in this process. We have shown that exposing granulosa cells to 5alpha-dihydrotestosterone (DHT) reduces forskolin-stimulated cyclin D2 mRNA expression, which leads to cell cycle arrest resulting in reduced cell proliferation. The present study investigated the signaling molecules upstream of cyclin D2 in FSH-mediated, cAMP-dependent signaling pathway that may be negatively affected by DHT, leading to inhibition of cell cycle progression. Because ERK is an important molecule in mitogenic signaling, the possible effect of DHT on its phosphorylation was examined. Granulosa cells from 3-d estradiol-primed immature rats were treated with DHT (90 ng/ml) for 24 h and subsequently stimulated with forskolin. DHT treatment reduced forskolin stimulation of ERK phosphorylation. Although DHT exposure did not affect cellular cAMP production in response to forskolin, treating the cells with DHT for 24 h significantly reduced protein kinase A activity. DHT also caused a reduction in ERK-2 phosphorylation in response to FSH similar to that seen with forskolin. Furthermore, blocking ERK phosphorylation as well as DHT treatment resulted in a reduction in FSH-stimulated cyclin D2 mRNA expression. From these results, we conclude that DHT treatment reduces the FSH-mediated ERK phosphorylation in granulosa cells, leading to reduced cyclin D2 mRNA expression that culminates in cell cycle arrest.
cAMP-dependent activation of MAPK in cumulus cells is essential for germinal vesicle breakdown of porcine cumulus-enclosed oocytes Liang CG, et al .
Mitogen-activated protein kinase (MAPK) plays important roles during meiotic maturation in mammalian oocytes, while the necessity of MAPK during meiotic resumption in porcine oocytes is still controversial. Here, by applying the method of ultracentrifugation to move the opaque lipid droplets to the edge of the oocyte therefore allowing clear visualization of porcine GVs, oocytes just before GVBD and those that had just undergone GVBD were selected for the assay of MAPK activation. Our results showed that phosphorylation of MAPK in oocytes occurred after GVBD in all three different culture models: spontaneous maturation model, inhibition-induction maturation model and normal maturation model. Moreover, we found that activation of MAPK in cumulus cells but not in oocytes was essential for GVBD in cumulus-enclosed oocytes. Then the crosstalk between cAMP and MAPK in cumulus cells was investigated by using cell-type specific phosphodiesterase (PDE) isoenzyme inhibitors. Our results showed that PDE3 subtype existed in oocytes whereas PDE4 subtype existed in cumulus cells. PDE3 inhibitor prevented meiotic resumption of oocytes, while PDE4 inhibitor enhanced the ability of FSH or forskolin to activate MAPK in cumulus cells. We propose that increased cAMP resulting from inhibition of PDE3 in oocytes blocks GVBD whereas increased cAMP resulting from inhibition of PDE4 activates MAPK pathway in cumulus cells, which is essential for GVBD induction.
Follicle stages
Preovulatory, Corpus luteum
Comment
Phenotypes
PCO (polycystic ovarian syndrome)
Mutations
1 mutations
Species: mouse
Mutation name: None
type: null mutation fertility: infertile - ovarian defect Comment: MAPK3/1 (ERK1/2) in ovarian granulosa cells are essential for female fertility. Fan HY et al. A surge of luteinizing hormone (LH) from the pituitary gland triggers ovulation, oocyte maturation, and luteinization for successful reproduction in mammals. Because the signaling molecules RAS and ERK1/2 (extracellular signal-regulated kinases 1 and 2) are activated by an LH surge in granulosa cells of preovulatory follicles, we disrupted Erk1/2 in mouse granulosa cells and provide in vivo evidence that these kinases are necessary for LH-induced oocyte resumption of meiosis, ovulation, and luteinization. In addition, biochemical analyses and selected disruption of the Cebpb gene in granulosa cells demonstrate that C/EBPbeta (CCAAT/Enhancer-binding protein-beta) is a critical downstream mediator of ERK1/2 activation. Thus, ERK1/2 and C/EBPbeta constitute an in vivo LH-regulated signaling pathway that controls ovulation- and luteinization-related events.