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

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Query: EC:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The androgen receptor (AR) is expressed in differentiated secretory prostate epithelial cells in vivo. However, in the human prostate, it is unclear whether androgens directly promote the survival of secretory cells, or whether secretory cells survive through androgen-dependent signals from the prostate stroma. Biochemical and mechanistic studies have been hampered by inadequate cell-culture models. In particular, large-scale differentiation of prostate epithelial cells in culture has been difficult to achieve. Here, we describe the development of a differentiation system that is amenable to functional and biochemical analysis and its application to deciphering the survival pathways in differentiated AR-expressing epithelial cells. Confluent prostate epithelial cell cultures were treated with keratinocyte growth factor (KGF) and dihydrotestosterone. After 2 weeks, a suprabasal cell layer was formed in which cells no longer expressed alpha2, alpha3, alpha6, alphav, beta1 or beta4 integrins or p63, K5, K14, EGFR, FGFR2IIIb or Bcl-2, but instead expressed AR and androgen-induced differentiation markers, including K18, K19, TMPRSS2, Nkx3.1, PMSA, KLK2 and secreted prostate-specific antigen (PSA). Differentiated prostate cell survival depended on E-cadherin and PI3K, but not KGF, androgen, AR or MAPK. Thus survival of differentiated prostate epithelial cells is mediated by cell-cell adhesion, and not through androgen activity or prostate stroma-derived KGF.
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PMID:E-cadherin-mediated survival of androgen-receptor-expressing secretory prostate epithelial cells derived from a stratified in vitro differentiation model. 2004 43

Human puberty is triggered by the reemergence of GnRH pulsatile secretion, with progressive activation of gonadal function. Several mutations have been identified in an increasing number of genes that influence the onset of puberty. Mutations in GNRH1, KISS1R and GNRHR genes cause normosmic IHH, interfering with the normal synthesis, secretion or action of GnRH. More recently, mutations in TAC3 and TACR3 genes, which encode neurokinin B and its receptor, have been implicated in normosmic IHH, although their precise functions in reproduction remain unclear. Mutations in KAL1, FGFR1, FGF8, PROK2 and PROKR2 are related to disruption of the development and migration of GnRH neurons, thereby resulting in Kallmann syndrome, a complex genetic condition characterized by isolated hypogonadotropic hypogonadism (IHH) and olfactory abnormalities. Furthermore, mutations in CHD7 gene, a major gene involved in the etiology of CHARGE syndrome, were also described in some patients with Kallmann syndrome and normosmic IHH. Notably, the evidence of association of some of the genes implicated with GnRH neurons development and migration with both Kallmann syndrome and normosmic IHH, blurring the simplest clinical distinction between ontogenic and purely functional defects in the axis. Digenic or oligogenic inheritance of IHH has also been described, illustrating the extraordinary genetic heterogeneity of IHH. Interestingly, rare gain-of-function mutations of the genes encoding the kisspeptin and its receptor were recently associated with central precocious puberty phenotype, indicating that the premature activation of the reproductive axis may be also caused by genetic mutations. These discoveries have yielded significant insights into the current knowledge of this important life transition.
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PMID:Genetics basis for GnRH-dependent pubertal disorders in humans. 2018 92

The Kallmann syndrome (KS) combines hypogonadotropic hypogonadism (HH) with anosmia. This is a clinically and genetically heterogeneous disease. KAL1, encoding the extracellular glycoprotein anosmin-1, is responsible for the X chromosome-linked recessive form of the disease (KAL1). Mutations in FGFR1 or FGF8, encoding fibroblast growth factor receptor-1 and fibroblast growth factor-8, respectively, underlie an autosomal dominant form with incomplete penetrance (KAL2). Mutations in PROKR2 and PROK2, encoding prokineticin receptor-2 and prokineticin-2, have been found in heterozygous, homozygous, and compound heterozygous states. These two genes are likely to be involved both in autosomal recessive monogenic (KAL3) and digenic/oligogenic KS transmission modes. Mutations in any of the above-mentioned KS genes have been found in less than 30% of the KS patients, which indicates that other genes involved in the disease remain to be discovered. Notably, KS may also be part of pleiotropic developmental diseases including CHARGE syndrome; this disease results in most cases from neomutations in CHD7 that encodes a chromodomain helicase DNA-binding protein.
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PMID:Clinical genetics of Kallmann syndrome. 2036 62

Congenital hypogonadotropic hypogonadisms (CHH) are a well-known cause of pubertal development failure in women. In a majority of patients, the clinical spectrum results from an insufficient and concomitant secretion of both pituitary gonadotropins LH and FSH that impedes a normal endocrine and exocrine cyclical ovary functioning after the age of pubertal activation of gonadotropic axis. In exceptional but interesting cases, they can result from an elective deficit of one of the gonadotropins follicle-stimulating hormone (FSH) or luteinizing hormone (LH) by genetic anomaly of their specific ss sub-unit. CHH prevalence, estimated from teaching hospital series, is considered to be two to five fold less important in women compared to men bearing the disease. This frequency is probably under-estimated in reason of under-diagnosis of forms with partial pubertal development. Isolated or apparently isolated forms (i.e., Kallmann syndrome with anosmia or hyposmia not spontaneously expressed by the patients) of these diseases are most of the time discovered during adolescence or in adulthood in reason of lacking, incomplete or even apparently complete pubertal development, but with almost constant primary amenorrhea. In a minority of cases and mainly in familial forms, genetic autosomal causes have been found. These cases are related to mutations of genes impinging the functioning of the pituitary-hypothalamic pathways involved in the normal secretion of LH and FSH (mutations of GnRHR, GnRH1, KISS1R/GPR54, TAC3, TACR3), which are always associated to isolated non syndromic CHH without anosmia. Some cases of mutations of FGFR1, and more rarely of its ligand FGF8, or of PROKR2 or its ligand PROK2 have been shown in women suffering from Kallmann syndrome or its hyposmic or normosmic variant. In complex syndromic causes (mutations of CHD7, leptin and leptin receptor anomalies, Prader-Willi syndrome, etc.), diagnosis of the CHH cause is most often suspected or set down before the age of puberty in reason of the associated clinical signs, but some rare cases of paucisymptomatic syndromic causes can initially be revealed during adolescence, like isolated non syndromic CHH or Kallmann syndrome.
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PMID:Congenital hypogonadotropic hypogonadism in females: clinical spectrum, evaluation and genetics. 2036 64

Kallmann syndrome (KS) is a heterogeneous genetic disorder that associates variable gonadotropin-releasing hormone (GnRH) deficiency with anosmia and, sometimes, other non-reproductive clinical features. X-linked recessive, as well as autosomal recessive and dominant modes of transmission have been described. The first KS-related gene to be described (KAL1) was in the X-linked form. The second gene (KAL2) was initially unexpected, as it was known to encode the fibroblast growth receptor 1 (FGFR1). Its consideration as a candidate gene arose as a result of cases with contiguous gene syndrome and, initially, mutations were mostly described in familial cases with autosomal dominant transmission of KS. Since its initial discovery, numerous mutations of FGFR1 have been described in several functional domains of the receptor. Genotype-phenotype correlations have shown that some clinical features associated with KS, such as loss of nasal cartilage, hearing impairment, and anomalies of the limbs seem to be mainly associated with KAL2 mutations. The role of FGFR1 in the normal development of the olfactory bulb explains the association of anosmia with GnRH deficiency in FGFR1-mutated patients. Phenotype analysis indicates that FGFR1 is involved in normal migration of GnRH fetal neurons, but this is clearly not the whole story as a substantial proportion of KAL2-mutated individuals have normosmic GnRH deficiency. Finally, recent additional observations, notably using animal models, but also the description of human mutations in a specific ligand of FGFR1, FGF8, are beginning to shed light on the pathogenesis of GnRH deficiency in general, not just KS.
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PMID:FGFR1 mutations in Kallmann syndrome. 2038 85

Bone morphogenetic proteins (BMPs) have been recognized as crucial molecules in regulating ovarian physiology, with different BMPs having differential actions in FSH-induced estradiol production. To identify the roles of oocyte factors that modulate steroidogenesis controlled by BMPs, we here investigated the effects of FGF-8 in rat granulosa/oocyte co-cultures. FGF-8 potently suppressed FSH-induced estradiol production, but did not affect cAMP-induced estradiol produced by rat granulosa cells. FGF-8 had no effects on progesterone and cAMP production induced by FSH and forskolin. The inhibitory effects of FGF-8 on FSH-induced estradiol production were not altered by BMP-2, -4, -6 or -7. In the presence of FGF-8, BMPs suppressed FSH-induced progesterone by reducing cAMP, suggesting that FGF-8 and BMP independently regulate FSH receptor signaling. Notably, FGF-8-induced ERK and SAPK/JNK phosphorylation in granulosa cells, in which ERK activation was further enhanced by FSH and oocytes. Inhibition of ERK and SAPK/JNK reduced FSH-induced progesterone and cAMP levels, suggesting that the activation of these pathways enhances FSH-induced cAMP signaling. In addition, ERK inhibition upregulated FSH-induced estradiol synthesis, indicating that ERK pathway is also involved in suppressing aromatase activity in granulosa cells. Interestingly, FGF-8 enhanced BMP-induced Smad1/5/8 and Id-1-promoter activities with decreased expression of Smad6/7. Since the SAPK/JNK inhibitor inhibited FGF-8 effects in upregulating Id-1 transcription, SAPK/JNK appears to be involved in the mechanism by which FGF-8 enhances BMP-Smad signaling. Furthermore, in the presence of oocytes, the inhibition of endogenous FGF receptor signaling suppressed FSH- and forskolin-induced progesterone and cAMP, showing that endogenous FGF system is involved in activation of FSH-induced cAMP-PKA signaling via ERK and SAPK/JNK. Thus, the oocyte factor, FGF-8, not only suppresses FSH-induced estradiol production by activating ERK, but also enhances BMP-Smad signaling in granulosa cells. This interaction between FGF-8 and BMPs may play a key role in regulating steroidogenesis through oocyte-granulosa cell communication.
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PMID:Functional relationship between fibroblast growth factor-8 and bone morphogenetic proteins in regulating steroidogenesis by rat granulosa cells. 2043 19

Identification of intracellular signaling pathways necessary for appropriate axon guidance is challenging because many CNS populations used to study these events contain multiple cell types. Here, we resolve this issue by using mouse embryonic stem (ES) cells that were directed to differentiate into a population of motoneurons that exclusively innervate epaxial muscles [medial median motor column (MMCm) motoneurons]. These ES cell-derived MMCm motoneurons, like their endogenous counterparts, express fibroblast growth factor receptor 1 (FGFR1) and selectively extend axons toward the epaxial trophin FGF8. Unlike wild-type MMCm motoneurons, FGFR1(-/-) MMCm motoneurons show guidance defects when transplanted into the neural tube of chick embryos. Furthermore, activation of FGFR1 selectively signals through mitogen-activated protein kinase/extracellular signal-regulated kinase (MAPK/ERK) for appropriate guidance in vitro, whereas overexpression of constitutively active MAPK/ERK in transplanted, or endogenous chick, MMCm cells causes guidance defects in vivo. These results indicate that MAPK/ERK activation downstream of FGFR1 is necessary for MMCm motor axon guidance and that ES cell-derived neurons provide an important tool for dissecting intracellular pathways required for axon guidance.
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PMID:Guidance of postural motoneurons requires MAPK/ERK signaling downstream of fibroblast growth factor receptor 1. 2046 22

Hypogonadotropic hypogonadism (HH) is defined by the absence of sex steroid synthesis associated with the lack of appropriate gonadotrophin secretion. This leads to a variable degree of impuberism, often diagnosed during childhood or adolescence. Genetics of HH involve many genes. However, molecular defects have been identified in only 30 % of patients. Kallmann syndrome (KS) is defined by the association of HH and anosmia. Six genes are involved in KS (KAL1, FGFR1, FGF8, PROK2, PROKR2 and CHD7). However, genetics of KS is complex, because of the variability of the phenotype for a similar molecular defect. Otherwise, heterozygous anomalies are frequently described. Identification in the same patient of several mutations in some of these genes (digenism) could account for this variability. Autosomal recessive transmission is frequently observed in familial cases of HH without anosmia. Molecular alterations have been identified for several neuropeptides or their corresponding receptors, which are involved in the physiology of the gonadotropic axis : GNRHR, KISS1R/GPR54, neurokinin B (TAC3), TACR3 and GNRH1 (and PROK2, PROKR2 and CHD7). Anomalies of leptin or its receptor are also involved in HH cases. A new negative regulating element has been recently identified in humans : RFRP3, which is ortholog of the avian GnIH (gonadotrophin inhibitory hormone). Recent progress about these neuropeptides leads to a new model of comprehension of the gonadotropic axis physiology, from a linear model to a network model, which regulates the central element of regulation of the gonadotropic axis, represented by the GnRH neurons.
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PMID:[Hypogonadotropic hypogonadism: new aspects in the regulation of hypothalamic-pituitary-gonadal axis]. 2123 29

Cardiac neural crest cells migrate into the pharyngeal arches where they support development of the pharyngeal arch arteries. The pharyngeal endoderm and ectoderm both express high levels of FGF8. We hypothesized that FGF8 is chemotactic for cardiac crest cells. To begin testing this hypothesis, cardiac crest was explanted for migration assays under various conditions. Cardiac neural crest cells migrated more in response to FGF8. Single cell tracing indicated that this was not due to proliferation and subsequent transwell assays showed that the cells migrate toward an FGF8 source. The migratory response was mediated by FGF receptors (FGFR) 1 and 3 and MAPK/ERK intracellular signaling. To test whether FGF8 is chemokinetic and/or chemotactic in vivo, dominant negative FGFR1 was electroporated into the premigratory cardiac neural crest. Cells expressing the dominant negative receptor migrated slower than normal cardiac neural crest cells and were prone to remain in the vicinity of the neural tube and die. Treating with the FGFR1 inhibitor, SU5402 or an FGFR3 function-blocking antibody also slowed neural crest migration. FGF8 over-signaling enhanced neural crest migration. Neural crest cells migrated to an FGF8-soaked bead placed dorsal to the pharynx. Finally, an FGF8 producing plasmid was electroporated into an ectopic site in the ventral pharyngeal endoderm. The FGF8 producing cells attracted a thick layer of mesenchymal cells. DiI labeling of the neural crest as well as quail-to-chick neural crest chimeras showed that neural crest cells migrated to and around the ectopic site of FGF8 expression. These results showing that FGF8 is chemotactic and chemokinetic for cardiac neural crest adds another dimension to understanding the relationship of FGF8 and cardiac neural crest in cardiovascular defects.
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PMID:FGF8 signaling is chemotactic for cardiac neural crest cells. 2141 61

Kallmann syndrome (KS) is a clinically and genetically heterogeneous disorder that occurs in either an inherited or a sporadic manner. KS results from failed embryonic migration of GnRH-1 neurons from the nasal placode to the hypothalamus, due to the abnormal development of olfactory nerves and bulbs. Hypogonadotropic hypogonadism is related to GnRH deficiency, and anosmia is associated with the absence or hypoplasia of olfactory bulbs and tracts. KS patients can also present some non-reproductive or non-olfactory anomalies in addition to the above typical symptoms. For the high complexity of the molecular genetic mechanism of KS, to date, only 6 KS-related genes have been identified. The KAL1 gene is responsible for the X chromosome-linked recessive form of KS, while the fibroblast growth factor receptor 1 (FGFR1/KAL2) and fibroblast growth factor 8 (FGF8/KAL6) genes are related to the autosomal dominant form of the disease. However, the mutations in these 6 genes account for only about 25 - 30% of all KS cases, which suggests that other pathogenic genes involved in KS remain to be discovered. This article presents an overview on the studies of the pathogenic genes, clinical diagnosis and treatment of KS.
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PMID:[Molecular genetics of Kallmann syndrome: an update]. 2154 17


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