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)

Middle-ear cholesteatoma is characterized by enhanced proliferation of epithelial cells and granular tissue formation. However, the molecular mechanism underlying these pathological changes is largely unknown. Keratinocyte growth factor (KGF) is a mesenchymal cell-derived paracrine growth factor that specifically stimulates epithelial cell proliferation. In the present study, we investigated the possible involvement of KGF and its receptor, KGFR, in the pathogenesis of cholesteatoma using in situ hybridization and immunohistochemistry, respectively. We examined 56 cholesteatoma specimens, and 8 normal skin areas as control. KGF and KGFR expression was examined by immunohistochemistry using rabbit anti-human KGF and anti-human KGFR polyclonal antisera raised in our laboratories against synthetic peptides corresponding to parts of human KGF and KGFR, respectively. KGF protein and mRNA were detected exclusively in stromal fibroblasts and infiltrating T lymphocytes in 80% of cholesteatoma cases, whereas KGFR protein and mRNA were localized in the epithelium in 72% of cases. Assessment of the proliferative activity of cholesteatoma using the labeling index for Ki-67 showed a significantly higher Ki-67 labeling index (66%) in KGF+/KGFR+ cases than other cases. There was a significant correlation between KGF+/KGFR+ expression and recurrence. Our results indicate the possible involvement of both KGF and KGFR in enhanced epithelial cell proliferative activity and recurrence of cholesteatoma.
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PMID:Possible involvement of keratinocyte growth factor and its receptor in enhanced epithelial-cell proliferation and acquired recurrence of middle-ear cholesteatoma. 1253 93

Keratinocyte growth factor (KGF or FGF-7) stimulates alveolar type II cell proliferation, but little is known about the signaling pathways involved. We investigated the role of the ERK (p42/44 mitogen activated protein [MAP] kinase) and phosphatidylinositol 3-OH kinase (PI3 kinase) pathways on alveolar type II cell proliferation and differentiation. Rat type II cells were cultured on tissue culture plastic and Matrigel in the presence or absence of KGF and specific chemical inhibitors PD98059, LY294002, and rapamycin at various concentrations. Proliferation was measured by thymidine incorporation and DNA quantitation, and differentiation was measured by expression of surfactant protein A and alkaline phosphatase. We demonstrate that KGF activates distal effectors of the PI3 kinase pathway, PKB/Akt, and p70S6 kinase, as well as p42/44 MAP kinase proteins. Inhibition of these pathways with PD98059, LY294002, or rapamycin inhibited type II cell proliferation but had no significant effect on differentiation. KGF did not activate the c-Jun kinase or p38 MAP kinase pathways. We conclude that the p42/44 MAP kinase and PI3 kinase pathways are important in regulating alveolar type II cell proliferation in response to KGF.
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PMID:Keratinocyte growth factor stimulates alveolar type II cell proliferation through the extracellular signal-regulated kinase and phosphatidylinositol 3-OH kinase pathways. 1474 97

Keratinocyte growth factor receptor (KGFR), also known as FGFR2 IIIb, is a splice variant of FGFR-2. KGFR is expressed in many types of epithelial cell and is activated with four known ligands [FGF-1, FGF-3, FGF-7 (also known as KGF) and FGF-10] that are predominantly synthesized by mesenchymal cells. KGFR is highly expressed in the late-proliferative phase of a normal endometrium and in endometrial adenocarcinoma. In the present study, we attempted to determine the expression and localization of KGFR in human cervical cancer cell lines and cervical cancer tissues. The KGFR protein was detected in CaSki and HeLa cells, but not in ME-180 cells of cervical cancer cell lines. In non-cancer cervical tissues, KGFR immunoreactivity was weakly expressed in the surface of squamous epithelial cells and vascular smooth muscle cells. Immunohistochemically, the KGFR protein was detected in squamous cell carcinoma in 36 of 42 (86%) cervical cancer patients. In cervical cancer tissues, KGFR was detected in 17 of 18 (94%) of patients with the keratinizing type and 19 of 24 (79%) of patients with the non-keratinizing type of cervical cancer. Furthermore, KGFR was prominently localized in proliferating reserve cells and squamous metaplastic reserve cells adjacent to cancer cells. In contrast, KGFR was not detected in cervical ductal cells in cancer or non-cancer cervical tissues. These findings may indicate that KGFR mediates the growth and differentiation of reserve cells and squamous cell carcinoma in the cervix.
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PMID:Expression of keratinocyte growth factor receptor (KGFR/FGFR2 IIIb) in human uterine cervical cancer. 1506 36

Keratinocyte growth factor (KGF), a member of the fibroblast growth factor (FGF) family, is a specific mitogen for different types of epithelial cells and a potent survival factor for these cells under stress conditions. KGF expression increases strongly after injury to various tissues, including the skin and the intestine, and signaling via the KGF receptor was shown to be crucial for repair of skin wounds and for liver regeneration. Here we demonstrate an increased expression of KGF in chronic liver disease associated with fibrosis. The extent of KGF overexpression correlated strongly with the stage of fibrosis. As the cellular source of KGF we identified activated hepatic stellate cells (HSCs)/myofibroblasts. In contrast to the ligand, the KGF receptor, FGFR2-IIIb, was exclusively expressed by hepatocytes, but not by activated HSCs or other parenchymal or nonparenchymal liver cells. Based on the known effects of KGF on hepatocytes in vitro, our findings suggest that HSC/myofibroblast-derived KGF may enhance liver regeneration and/or hepatocyte survival in patients with chronic liver disease.
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PMID:Activated hepatic stellate cells express keratinocyte growth factor in chronic liver disease. 1546 89

Keratinocyte growth factor receptor (KGFR) is a receptor tyrosine kinase expressed on epithelial cells which belongs to the family of fibroblast growth factor receptors (FGFRs). Following ligand binding, KGFR is rapidly autophosphorylated on specific tyrosine residues in the intracellular domain, recruits substrate proteins, and is rapidly internalized by clathrin-mediated endocytosis. The role of different autophosphorylation sites in FGFRs, and in particular the role of the tyrosine 766 in FGFR1, first identified as PLCgamma binding site, has been extensively studied. We analyzed here the possible role of the tyrosine 769 in KGFR, corresponding to tyrosine 766 in FGFR1, in the regulation of KGFR signal transduction and MAPK activation as well as in the control of the endocytic process of KGFR. A mutant KGFR in which tyrosine 769 was substituted by phenylalanine was generated and transfected in NIH3T3 and HeLa cells. Our results indicate that tyrosine 769 is required for the binding to KGFR and tyrosine phosphorylation of PLCgamma as well as for the full activation of MAPKs and for cell proliferation through the regulation of FRS2 tyrosine phosphorylation, suggesting that this residue represents a key regulator of KGFR signal transduction. Our data also show that tyrosine 769 is not involved in the regulation of the endocytic process of KGFR.
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PMID:Tyrosine 769 of the keratinocyte growth factor receptor is required for receptor signaling but not endocytosis. 1562 45

Lipid synthesis is required for cell growth and is subject to pharmacologic regulation. Keratinocyte growth factor (KGF) stimulates proliferation and lipogenesis in H292 cells, a pulmonary epithelial cancer cell line, but the signaling pathways are not known. KGF stimulated the expression of the transcription factors sterol-regulatory element binding protein-1 (SREBP-1), CCAAT/enhancer binding protein alpha (C/EBPalpha), and C/EBPdelta and two key enzymes involved in lipogenesis, FAS and stearoyl coenzyme A desaturase-1 (SCD-1). We found that KGF induced rapid activation of Akt, p70 S6K, JNK, and extracellular signal-regulated (ERK). Induction of SREBP-1, SCD-1, and FAS by KGF was inhibited by the JNK inhibitor SP600125 and the phosphatidylinositol 3-kinase (PI3K) inhibitor LY294002 but not by the ERK inhibitor PD98059. Using FAS and SCD-1-luciferase promoter constructs, we observed that KGF stimulated the transcription of these promoters and that exogenous cholesterol inhibited the induction. Mutation of the SREBP-1 binding site in the SCD-1 promoter abolished the effect of KGF on SCD-1 transcription. In addition, overexpression of active SREBP-1 directly stimulated SCD-1 and FAS. Conversely, adenovirus-mediated overexpression of a dominant negative form of SREBP-1 inhibited the KGF effect on FAS and SCD-1 expression. In summary, we conclude that KGF requires both PI3K and JNK signaling pathways to induce SREBP-1, which in turn induces SCD-1 and FAS expression in H292 cells.
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PMID:KGF induces lipogenic genes through a PI3K and JNK/SREBP-1 pathway in H292 cells. 1616 44

Prostate epithelial stem cells are self-renewing cells capable of differentiation into prostate epithelium, and are thought to contribute towards both benign and malignant conditions in the human prostate. We have previously demonstrated that prostate epithelial basal cells express high levels of integrin alpha2beta1 and this population can be subdivided into stem (alpha2beta1(hi) CD133+) and transient-amplifying population (TAP) cells (alpha2beta1(hi) CD133-). However, the molecular mechanism(s) controlling the commitment and regulation of these cells towards differentiated epithelium remains unclear. Here, we demonstrate that beta1 integrin function is required for the maintenance of basal prostatic epithelial cells and suppression of its function by either methylcellulose or, more specifically, beta1-blocking antibody (80 microg/ml) induces differentiation, with associated expression of the differentiation-specific markers prostate acid phosphatase (PAP) and cytokeratin 18 (CK18). Keratinocyte growth factor (KGF), a stromal-derived growth factor, has previously been implicated in prostate organogenesis using in vitro tissue recombination experiments. We show that treatment with KGF (10 ng/ml) potently induces epithelial differentiation with concomitant suppression of alpha2beta1 integrin expression as well as the induction of androgen receptor expression. Specifically, p38-MAPK appears to be involved and the presence of SB202190, a p38 inhibitor, significantly blocks KGF-induced differentiation. Furthermore, the expression of the high-affinity receptor tyrosine kinase to KGF (FGFR2) is predominantly detectable in alpha2beta1(hi) CD133- TAP cells when compared with stem cells (alpha2beta1(hi) CD133+), which would therefore be relatively unresponsive to the differentiating effect of KGF. Taken together, using a human primary culture model, we have demonstrated key roles for interactions between KGF and integrin-mediated function in the regulation of prostate epithelial differentiation.
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PMID:KGF suppresses alpha2beta1 integrin function and promotes differentiation of the transient amplifying population in human prostatic epithelium. 1655 39

Keratinocyte growth factor receptor (KGFR = FGFR2-IIIb) is a tyrosine kinase receptor expressed by keratinocytes, which mediates the effects of fibroblast growth factors (FGF). There are contradictory data in the literature regarding the role of FGFR2-IIIb during the proliferation/differentiation programme of keratinocytes. In this study, we aimed to investigate whether overexpression of FGFR2-IIIb may have a role in the regulation of keratinocyte proliferation. We analysed the expression of FGFR2-IIIb in an in vitro HaCaT model system representing different stages of proliferation and differentiation of keratinocytes. Real-time RT-PCR and Western blot analyses demonstrated a correlation between FGFR2-IIIb mRNA and protein expression and the proportion of cells in S/G2/M phase in synchronized HaCaT keratinocytes and thus with proliferation activity (r = 0.96). After treatment with the antipsoriatic drug, dithranol, FGFR2-IIIb is downregulated dose dependently both at mRNA and protein levels. Moreover, when the rate of proliferation is decreased by the lack of cell attachment to the culturing surface, FGFR2-IIIb mRNA (P = 0.0315) and protein expressions were also reduced (P = 0.0242), while a differentiation marker, keratin 10, mRNA (P = 0.0003) and protein levels (P = 0.001) were increased (r = -0.92). Based on our results we conclude that FGFR2-IIIb expression in HaCaT keratinocytes corresponds with the proliferative activation of the cells and is not related to the differentiation programme.
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PMID:The expression of keratinocyte growth factor receptor (FGFR2-IIIb) correlates with the high proliferative rate of HaCaT keratinocytes. 1684 98

Keratinocyte growth factor (KGF)/fibroblast growth factor-7 (FGF-7) is a paracrine- and epithelium-specific growth factor produced by cells of mesenchymal origin. It acts exclusively through FGF-7 receptor (FGFR2/IIIb), which is expressed predominantly by epithelial cells, but not by fibroblasts, suggesting that it might function as a paracrine mediator of mesenchymal-epithelial interactions. KGF/FGF-7 plays an essential role in the growth of epithelial cells and is frequently overexpressed in cancers of epithelial origin such as pancreatic cancer, switching paracrine stimulation of KGF/FGF-7 to an autocrine loop. Less is known, however, about the signaling pathways by which KGF/FGF-7 regulates the response of epithelial cells. To delineate the signaling pathways activated by KGF/FGF-7 and examine cellular response to KGF/FGF-7 stimulation, we performed functional analysis of KGF/FGF-7 action. In this report, we show that KGF/FGF-7 activated nuclear factor kappaB (NF-kappaB), which in turn induced expression of VEGF, MMP-9, and urokinase-type plasminogen activator and increased migration and invasion of KGF/FGF-7-stimulated human pancreatic ductal epithelial cells. Expression of phosphorylation-defective IkappaBalpha (IkappaBalphaS32A,S36A), which blocked NF-kappaB activation, inhibited KGF/FGF-7-induced gene expression and cell migration and invasion. Our results demonstrate for the first time that KGF/FGF-7 induces NF-kappaB activation and that NF-kappaB plays an essential role in regulation of KGF/FGF-7-inducible gene expression and KGF/FGF-7-initiated cellular responses. Thus, these findings identify one signaling pathway for KGF/FGF-7-regulated cell migration and invasion and suggest that paracrine sources of KGF/FGF-7 are one of the malignancy-contributing factors from tumor stroma.
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PMID:Keratinocyte growth factor/fibroblast growth factor-7-regulated cell migration and invasion through activation of NF-kappaB transcription factors. 1720 Jan 10

Regulation of proliferation and differentiation in keratinocyte is a complex and dynamic process that involves activation of multiple signaling pathways triggered by different growth factors. Keratinocyte growth factor (KGF) is not only a potent mitogen, but differently from other growth factors, is a potent inducer of differentiation. The MAP kinase and AKT pathways are involved in proliferation and differentiation of many cell types including keratinocytes. We investigated here the role of KGF in modulating AKT and MAPK activity during differentiation of human keratinocytes. Our results show that the mechanisms of action of KGF are dose-dependent and that a sustained activation of the MAPK signaling cascade causes a negative regulation of AKT. We also demostrated increasing expression of KGFR substrates, such as PAK4 during keratinocyte differentiation parallel to the receptor upregulation.
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PMID:AKT and MAPK signaling in KGF-treated and UVB-exposed human epidermal cells. 1745 90


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