Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

---

Query: EC:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The response of granulosa cells to luteinizing hormone (LH) and follicle-stimulating hormone (FSH) is mediated mainly by cAMP/protein kinase A (PKA) signaling. Notably, the activity of the extracellular signal-regulated kinase (ERK) signaling cascade is elevated in response to these stimuli as well. We studied the involvement of the ERK cascade in LH- and FSH-induced steroidogenesis in two granulosa-derived cell lines, rLHR-4 and rFSHR-17, respectively. We found that stimulation of these cells with the appropriate gonadotropin induced ERK activation as well as progesterone production downstream of PKA. Inhibition of ERK activity enhanced gonadotropin-stimulated progesterone production, which was correlated with increased expression of the steroidogenic acute regulatory protein (StAR), a key regulator of progesterone synthesis. Therefore, it is likely that gonadotropin-stimulated progesterone formation is regulated by a pathway that includes PKA and StAR, and this process is down-regulated by ERK, due to attenuation of StAR expression. Our results suggest that activation of PKA signaling by gonadotropins not only induces steroidogenesis but also activates down-regulation machinery involving the ERK cascade. The activation of ERK by gonadotropins as well as by other agents may be a key mechanism for the modulation of gonadotropin-induced steroidogenesis.
...
PMID:The ERK signaling cascade inhibits gonadotropin-stimulated steroidogenesis. 2855 Jan 33

We examined the phosphorylation and acetylation of histone H3 in ovarian granulosa cells stimulated to differentiate by follicle-stimulating hormone (FSH). We found that protein kinase A (PKA) mediates H3 phosphorylation on serine 10, based on inhibition exclusively by PKA inhibitors. FSH-stimulated H3 phosphorylation in granulosa cells is not downstream of mitogen-activated protein kinase/extracellular signal-regulated kinase, ribosomal S6 kinase-2, mitogen- and stress-activated protein kinase-1, p38 MAPK, phosphatidylinositol-3 kinase, or protein kinase C. Transcriptional activation-associated H3 phosphorylation on serine 10 and acetylation of lysine 14 leads to activation of serum glucocorticoid kinase, inhibin alpha, and c-fos genes. We propose that phosphorylation of histone H3 on serine 10 by PKA in coordination with acetylation of H3 on lysine 14 results in reorganization of the promoters of select FSH responsive genes into a more accessible configuration for activation. The unique role of PKA as the physiological histone H3 kinase is consistent with the central role of PKA in initiating granulosa cell differentiation.
...
PMID:Follicle-stimulating hormone stimulates protein kinase A-mediated histone H3 phosphorylation and acetylation leading to select gene activation in ovarian granulosa cells. 1149 42

Primary cultures of Sertoli cells provide an interesting model to study how signalling pathways induced by a single hormone in a single cell type evolve, depending on the developmental stage. In vivo, follicle-stimulating hormone (FSH) induces proliferation of Sertoli cells in neonate and controls the subsequent differentiation of the entire population. Molecular mechanisms underlying Sertoli cell pleiotropic responses to FSH have long been investigated. But to date, only cAMP-dependent kinase (PKA) activation has been reported to account for most FSH biological activities in male. Here, we demonstrate that FSH activates the ERK MAP kinase pathway following dual coupling of the FSH-R both to Gs and to Gi heterotrimeric proteins, in a PKA- and also Src-dependent manner. This activation is required for FSH-induced proliferation of Sertoli cells isolated 5 days after birth. Consistently, we show that the ERK-mediated FSH mitogenic effect triggers upregulation of cyclin D1. In sharp contrast, at 19 days after birth, as cells proceed through their differentiation program, the ERK pathway is dramatically inhibited by FSH treatment. Taken together, these results show that FSH can exert opposite effects on the ERK signalling cascade during the maturation process of Sertoli cells. Thus, signalling modules triggered by the FSH-R evolve dynamically throughout development of FSH natural target cells.
...
PMID:The ERK-dependent signalling is stage-specifically modulated by FSH, during primary Sertoli cell maturation. 1149 92

The cellular adhesion status and the exposure to soluble growth factors both contribute to mitogen-activated protein (MAP) kinase activation. To date, however, whether mitogens acting through G-protein-coupled receptors (GPCRs) need cell adhesion to activate MAP kinases/extracellular signal-regulated kinases (ERK) 1, 2 has been poorly investigated. We addressed this point in primary cultures of Sertoli cells experimentally maintained in suspension, considering that follicle-stimulating hormone (FSH) activates ERK1, 2 in attached Sertoli cells by acting through a GPCR. We found that FSH actively repressed ERK1, 2, in a cAMP-dependent but cAMP-dependent protein kinase (PKA)-independent manner, and this inhibition required the activity of a tyrosine phosphatase. In comparison, in the absence of anchorage, ERK1, 2 were still activated by epidermal growth factor, in a PKA-dependent manner. Altogether, these data suggest that sensitivity of the MAP kinase response toward cell adhesion may depend, at least in part, on the class of receptor, GPCR or receptor with tyrosine kinase activity, by which it is triggered.
...
PMID:Cellular adhesion of primary Sertoli cells affects responsiveness of the extracellular signal-regulated kinases 1 and 2 to follicle-stimulating hormone but not to epidermal growth factor. 1188 12

In the present study, we analyzed the structural determinants present in the second intracellular loop (IL-2) of the human follicle-stimulating hormone (FSH) receptor (R) involved in G(s) protein-mediated signal transduction. Human embryonic kidney 293 (HEK-293) cells, stably expressing wild-type (Wt) human FSHR (HEK-293((+))), were transiently transfected with plasmids containing cDNAs encoding the entire IL-2 or several IL-2 sequences mutated in R467 (a residue located at the center of the conserved ERW motif in the glycoprotein hormone receptors), T470 (a potential site for phosphorylation by protein kinase-A and -C) or L477 (a residue conserved in all glycoprotein hormone receptors). Expression of the IL-2 Wt in HEK-293((+)) cells reduced the maximum FSH-stimulated cAMP production significantly by approximately 40%; similar results were observed with the R467A and R467K IL-2 mutants. The IL-2(R467H), IL-2(T470A), the triple R467A/T470A/L477A IL-2 mutant and the IL-2 of the oxytocin receptor (G(q/11)-coupled) had no effects on Wt FSHR-mediated intracellular signaling whereas the L477A mutation provoked a higher ( approximately 55%) inhibition of FSH-stimulated cAMP than the free, Wt IL-2. These results suggested a specific role of IL-2 residues in FSHR function. Site directed mutagenesis of the FSHR and the expression of resulting mutants in HEK-293 cells were performed in order to corroborate the effects of these substitutions. Expression of FSHR(R467H), FSHR(R467A) and FSHR(T470A) failed to mediate ligand-provoked G(s) protein activation, whereas the R467K mutant behaved as the Wt receptor. Interestingly, the expression of L477A, L477D and L477P FSHR mutants conferred elevated basal cAMP levels to HEK-293 cells. This study indicates that the IL-2 of the human FSHR possesses amino acid residues that are important for both coupling the receptor to the G(s) protein (R467 and T470) and maintaining the receptor molecule in an inactive conformation (L477). It appears that this particular intracellular domain may act as a conformational switch to produce the activation of G proteins as has been reported for the IL-2 of other G protein-coupled receptors.
...
PMID:Structural determinants in the second intracellular loop of the human follicle-stimulating hormone receptor are involved in G(s) protein activation. 1203 74

The second messenger cyclic adenosine 5'monophosphate (cAMP) has been implicated in controlling meiotic maturation. To date, there have been no direct measurements of cAMP in living mammalian oocytes. Here, we have used the fluorescently labelled cAMP-dependent protein kinase A (PKA), FlCRhR, to monitor cAMP in mouse oocytes. In cumulus-enclosed oocytes, follicle-stimulating hormone (FSH) stimulated an increase in the oocyte [cAMP] that was prevented by using the gap junction inhibitor, carbenoxolone. The FSH-induced increase in oocyte [cAMP] was suppressed in a time-dependent manner by prior exposure to ATP, while epidermal growth factor had no effect on basal or stimulated levels of cAMP. Finally, using confocal microscopy, we show that the regulatory and catalytic subunits of the microinjected PKA are distributed in a punctate manner with a stronger accumulation in the perinuclear region. On an increase in [cAMP], in response to phosphodiesterase inhibition or FSH, the catalytic subunit diffused throughout the cytoplasm and germinal vesicle, while the regulatory subunit remained anchored. These experiments show that increases in cAMP in ovarian somatic cells are communicated via gap junctions to the oocyte, where it can lead to a redistribution of the catalytic subunit of PKA.
...
PMID:Follicle-stimulating hormone induces a gap junction-dependent dynamic change in [cAMP] and protein kinase a in mammalian oocytes. 1205 28

In this report we sought to elucidate the mechanism by which the follicle-stimulating hormone (FSH) receptor signals to promote activation of the p42/p44 extracellular signal-regulated protein kinases (ERKs) in granulosa cells. Results show that the ERK kinase MEK and upstream intermediates Raf-1, Ras, Src, and L-type Ca(2+) channels are already partially activated in vehicle-treated cells and that FSH does not further activate them. This tonic stimulatory pathway appears to be restrained at the level of ERK by a 100-kDa phosphotyrosine phosphatase that associates with ERK in vehicle-treated cells and promotes dephosphorylation of its regulatory Tyr residue, resulting in ERK inactivation. FSH promotes the phosphorylation of this phosphotyrosine phosphatase and its dissociation from ERK, relieving ERK from inhibition and resulting in its activation by the tonic stimulatory pathway and consequent translocation to the nucleus. Consistent with this premise, FSH-stimulated ERK activation is inhibited by the cell-permeable protein kinase A-specific inhibitor peptide Myr-PKI as well as by inhibitors of MEK, Src, a Ca(2+) channel blocker, and chelation of extracellular Ca(2+). These results suggest that FSH stimulates ERK activity in immature granulosa cells by relieving an inhibition imposed by a 100-kDa phosphotyrosine phosphatase.
...
PMID:Follicle-stimulating hormone activates extracellular signal-regulated kinase but not extracellular signal-regulated kinase kinase through a 100-kDa phosphotyrosine phosphatase. 1249 68

Activin A signaling is an important regulator of ovarian granulosa cell function. The cytosolic signal transducer Smad2 is most highly expressed in chicken granulosa cells (cGC) of preovulatory follicles. Moreover, Smad2 shows predominant nuclear localization in freshly isolated cGC, indicating active Smad signaling in vivo. Primary cGC cultured in vitro require activin A to sustain high Smad2 levels, which otherwise drop dramatically in the absence of activin A. This activin A-dependent Smad2 expression is abrogated by protein kinase A (PKA) inhibitors, suggesting a role for PKA in activin signaling. In the absence of activin A, strong PKA activators such as follicle-stimulating hormone (FSH) and 8-bromo-cyclic AMP fail to elicit Smad2 induction. However, FSH and 8-bromo-cyclic AMP boost activin A-dependent Smad2 up-regulation, giving rise to Smad2 levels similar to expression in vivo levels. Interestingly, the effect is specific for Smad2, since expression of the structurally and functionally closely related Smad3 remains entirely unaffected. Hence, activin A induces Smad2, but not Smad3, to high levels requiring PKA activation. Since Smad2 and Smad3 target distinct yet overlapping sets of TGF-beta/activin-responsive genes, the selective Smad2 induction by FSH/activin A could allow FSH to efficiently modulate the transcriptional readout of activin A signaling in avian granulosa cells.
...
PMID:Activin a signaling induces Smad2, but not Smad3, requiring protein kinase a activity in granulosa cells from the avian ovary. 1266 10

Neurohormones similar to those of mammals are carried in fish by hypothalamic nerve fibers to regulate directly follicle-stimulating hormone (FSH) and luteinizing hormone (LH). Gonadotropin-releasing hormone (GnRH) stimulates the secretion of FSH and LH and the expression of the glycoprotein hormone alpha (GPalpha), FSHbeta, and LHbeta, as well as their secretion. Its signal transduction leading to LH release is similar to that in mammals although the involvement of cyclic AMP-protein kinase A (cAMP-PKA) cannot be ruled out. Dopamine (DA) acting through DA D2 type receptors may inhibit LH release, but not that of FSH, at sites distal to activation of protein kinase C (PKC) and PKA. GnRH increases the steady-state levels of GPalpha, LHbeta, and FSHbeta mRNAs. Pituitary adenylate cyclase-activating polypeptide (PACAP) 38 and neuropeptide Y (NPY) potentiate GnRH effect on gonadotropic cells, and also act directly on the pituitary cells. Whereas PACAP increases all three subunit mRNAs, NPY has no effect on that of FSHbeta. The effect of these peptides on the expression of the gonadotropin subunit genes is transduced differentially; GnRH regulates GPalpha and LHbeta via PKC-ERK and PKA-ERK cascades, while affecting the FSHbeta transcript through a PKA-dependent but ERK-independent cascade. The signals of both NPY and PACAP are transduced via PKC and PKA, each converging at the ERK level. NPY regulates only GPalpha- and LHbeta-subunit genes whereas PACAP regulates the FSHbeta subunit as well. Like those of the mammalian counterparts, the coho salmon LHbeta gene promoter is driven by a strong proximal tripartite element to which three different transcription factors bind. These include Sf-1 and Pitx-1 as in mammals, but the function of the Egr-1 appears to have been replaced by the estrogen receptor (ER). The GnRH responsive region in tilapia FSHbeta 5' flanking region spans the canonical AP1 and CRE motifs implicating both elements in conferring GnRH responsiveness. Generally, high levels of gonadal steroids are associated with high LHbeta transcript levels whereas those of FSHbeta are reduced when pituitary cells are exposed to high steroid levels. Gonadal or hypophyseal activin also participate in the regulation of FSHbeta and LHbeta mRNA levels. However, gonadal effects are dependent on the gender and stage of maturity of the fish.
...
PMID:Regulation of fish gonadotropins. 1269 92

Id (inhibitor of DNA binding/differentiation) proteins repress differentiation and promote cell division by dimerizing with and inhibiting the action of basic helix-loop-helix transcription factors including those that bind to E-box motifs. Of the four characterized Id proteins, only Id2 is found in the nucleus of Sertoli cells that support the development of spermatozoa in the testis. Differential display analysis of rat primary Sertoli cell mRNA identified Id2 as being inducible by forskolin, a stimulator of cAMP production. Northern blot analysis confirmed that Id2 mRNA expression peaked in Sertoli cells 6-12 h after stimulation with forskolin or follicle-stimulating hormone (FSH), the major physiological stimulator of cAMP in Sertoli cells. Similarly, Id2 promoter activity in Sertoli cells was induced after forskolin or FSH stimulation as well as by overexpression of protein kinase A. Forskolin induction of the Id2 promoter required sequences located between positions -122 and -82. Protein(s) of 40-45 kDa were found to bind two activated transcription factor/cAMP-response element-like sites and a GATA motif within the regulatory region. The induction of the Id2 gene by FSH corresponded with a decrease in protein binding to an E-box consensus motif and decreased E-box-mediated transcription. Together, these findings raise the possibility that FSH-mediated induction of Id2 and resultant inhibition of basic helix-loop-helix transcription factor-regulated genes in Sertoli cells may contribute to the regulation of spermatogenesis.
...
PMID:The Id2 transcriptional repressor is induced by follicle-stimulating hormone and cAMP. 1476 70


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>

---