Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Fibroblast growth factors (FGFs) play important roles in diverse aspects of animal development including mammalian lung epithelial cell proliferation, differentiation, and branching morphogenesis. We developed an in vitro lung epithelial cell culture system to study functions and mechanisms of FGFs in regulating growth and differentiation of primary foetal rat lung epithelial cells. In comparison with other growth factors such as IGF-I, EGF, and HGF, FGFs were the most potent mitogens in stimulating lung epithelial cell proliferation. In the presence of FGF-1, 2, or 7, the primary lung epithelial cells could be propagated for generations and grown for more than two mo in vitro. Among the three FGFs tested, FGF-7 showed the strongest stimulation in cell growth. FGF-2, on the other hand, is the most effective inducer of lung epithelial cell-specific surfactant protein gene expression (SP-A, -B, and -C). FGF-2 upregulated SP-C expression in a dose-dependent manner. More interestingly, the induction of surfactant protein gene expression by FGF-2 appeared to be independent of MAPK pathway, since the SP-C expression was not inhibited but rather augmented by MEK1 inhibitor which inhibited MAPK activation and cell proliferation. Similar effects were observed for the expressions of surfactant protein genes SP-A and SP-B. In contrast to MAPK, FGF-2-induced SP-C expression was partially inhibited by PI 3-kinase inhibitor wortmannin. These data suggest dynamic roles and complex signalling mechanisms of FGFs in regulating lung epithelial cell proliferation and differentiation. While a MAPK-dependent pathway is essential for all three FGFs to stimulate cell proliferation, a MAPK-independent pathway may be responsible for the FGF-2-induced surfactant protein gene expression. PI 3-kinase may play an important role in mediating FGF-2-induced lung epithelial cell differentiation during development.
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PMID:FGF-2 induces surfactant protein gene expression in foetal rat lung epithelial cells through a MAPK-independent pathway. 1035 97

Invasion is an essential cellular response that plays an important role in a number of physiological and pathological processes. Matrix metalloproteinase (MMP) production and cell movement are diverse cellular responses integral to the process of invasion. The complexity of the invasive process suggests the necessity of coordinate activation of more than one signaling pathway in order to activate specific factors responsible for regulating these cellular responses. In this report, we demonstrate that cell movement and MMP-9 production are both directly dependent on the activation of endogenous ERK signaling in hepatocyte growth factor (HGF)-or epidermal growth factor (EGF)-stimulated human epidermal keratinocytes. The kinetic profiles of endogenous MEK and ERK activity suggest that prolonged activation of these signal transducers is an underlying mechanism involved in stimulating cell motility and MMP-9 production. In support of this finding, a transient MEK/ERK signal elicited by keratinocyte growth factor (KGF) or insulin-like growth factor-1 (IGF-1) fails to stimulate these invasion-related responses. Specific inhibition of MEK leads to suppression of ERK activation, marked reduction in steady-state levels of c-Fos, and inhibition of cell movement and MMP-9 production. This occurs despite continued activation of JNK and c-Jun signaling in the presence of MEK-specific inhibition. In contrast, when JNK activity is specifically inhibited in HGF-stimulated cells, AP-1 activity is suppressed but cell motility is not affected. This evidence suggests that while ERK and JNK activity are necessary for AP-1 activation, ERK but not JNK is sufficient in stimulating cell motility.
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PMID:Role of ERK and JNK pathways in regulating cell motility and matrix metalloproteinase 9 production in growth factor-stimulated human epidermal keratinocytes. 1039 97

A novel variant of the fibroblast growth factor receptor type 1 (FGFR-1) was identified in human placental RNA. In this receptor (FGFR-1L) portions of the second and third immunoglobulin-like (Ig-like) domains are deleted. To determine whether FGFR-1L was functional, full-length variant (pSV/FGFR-1L) and wild-type (pSV/FGFR-1) receptors were stably transfected into rat L6 myoblasts cells. Transfected L6 clones expressed respective proteins and bound (125)I-labeled FGF-2 with K(d) values of 99 pm (FGFR-1) and 26 pm (FGFR-1L). FGF-1 and FGF-2 competed efficiently with (125)I-FGF-2 for binding to FGFR-1 and FGFR-1L, whereas FGF-4 was less efficient. FGF-1, FGF-2, and FGF-4 enhanced mitogen-activated protein kinase (MAPK) activity, increased steady-state c-fos mRNA levels, and stimulated proliferation through either receptor, whereas KGF was without effect. FGFR-1 expressing clones exhibited ligand-induced tyrosine phosphorylation of fibroblast growth factor receptor substrate 2 (FRS2), a 90-kDa adaptor protein that links FGFR-1 activation to the MAPK cascade. In contrast, tyrosine phosphorylation of FRS2 was not evident with FGFR-1L. In addition, phospholipase C-gamma was not tyrosine phosphorylated via activated FGFR-1L. These findings indicate that FGFR-1L binds FGF-1 and FGF-2 with high affinity and is capable of mitogenic signaling, but may activate MAPK to occur via non-classical signaling intermediates.
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PMID:A novel type I fibroblast growth factor receptor activates mitogenic signaling in the absence of detectable tyrosine phosphorylation of FRS2. 1074 22

Fibroblast growth factors (FGFs) transmit their signals through four transmembrane receptors that are designated FGFR1-4. Alternative splicing in the extracellular region of FGFR1-3 generates receptor variants with different ligand binding affinities. Thus two types of transmembrane receptors (IIIb and IIIc isoforms) have been identified for FGFR2 and FGFR3, and the existence of analogous variants has been postulated for FGFR1 based on its genomic structure. However, only a single full-length transmembrane FGFR1 variant (FGFR1-IIIc) has been identified so far. Here we describe the cloning of a full-length cDNA encoding FGFR1-IIIb from a mouse skin wound cDNA library. This receptor isoform was expressed at the highest levels in a subset of sebaceous glands of the skin and in neurons of the hippocampus and the cerebellum. FGFR1-IIIb was expressed in L6 rat skeletal muscle myoblasts and used in cross-linking and receptor binding studies. FGF-1 was found to bind the receptor with high affinity, whereas FGF-2, -10, and -7 bound with significantly lower affinities. Despite their apparently similar but low affinities, FGF-10 but not FGF-7 induced the activation of p44/42 mitogen-activated protein kinase in FGFR1-IIIb-expressing L6 myoblasts and stimulated mitogenesis in these cells, demonstrating that this new receptor variant is a functional transmembrane receptor for FGF-10.
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PMID:Fibroblast growth factor (FGF) receptor 1-IIIb is a naturally occurring functional receptor for FGFs that is preferentially expressed in the skin and the brain. 1082 61

Fibroblast growth factor (FGF) -10 is a new member of the FGF family initially reported in Japan. It is mainly synthesized by mesenchymal cells and acts on epithelial cells in a paracrine manner. FGF-10 actions are dependent on their binding to the iiib form of FGF receptor 2 (FGFR2) iiib, also known as keratinocyte growth factor receptor (KGFR). FGF-10 has high amino acid homology to keratinocyte growth factor (KGF) and plays an important role in fetal limb and lung development and skin wound healing. In the present study, the expression of FGF-10 and FGFR2 iiib messenger RNA (mRNA) in two different human uterine cervical cancer cell lines (CaSki and ME-180) were examined. Both CaSki and ME-180 cells expressed FGFR2 iiib mRNA, while only CaSki cells expressed FGF-10 mRNA and protein. Recombinant FGF-10 (1 ng/ml) increased the growth rate of ME-180 cells and also enhanced mitogen-activated protein kinase (MAPK) phosphorylation of the cells. These data indicate that FGF-10 may directly promote the growth of squamous cell cancer in the uterine cervix via the MAPK pathway.
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PMID:[Expression and intracytoplasmic signal transduction pathway of fibroblast growth factor (FGF)-10 in human cervical cancer cell lines]. 1140 72

In this study we have investigated the involvement of PI-3K and its downstream target p70 S6K in the signaling response of corneal epithelial cells after HGF and KGF stimulation. HGF induced three- to five-fold increase in PI-3K activity in 5-10 min, whereas KGF stimulation resulted in two- to three-fold increase in activity in 2-10 min. Both growth factors also caused the phosphorylation of p70 S6K and stimulation of its activity. HGF increased p70 S6K activity by 300% and KGF by about 200%. Protein kinase C (PKC) activator TPA also induced the phosphorylation of p70 S6K. Both the PI-3K inhibitor wortmannin and PKC inhibitor calphostin C blocked the phosphorylation of p70 S6K mediated by the growth factors. However, the mitogen-activated protein kinase (p42/44 MAPK) cascade inhibitor PD98059 had no effect on p70 S6K activation. Furthermore, HGF and KGF increased the rate of corneal epithelial wound healing in an organ culture model, and wortmannin and rapamycin (the p70 S6K inhibitor) blocked corneal epithelial wound healing promoted by the growth factors. These studies suggest that PI-3K and p70 S6K are important signal transducers in the stimulation of corneal epithelial cells by HGF and KGF. PKC is involved in the PI-3K-dependent activation of p70 S6K but not MAPK. Inhibition of wound closure by PI-3K and p70 S6K inhibitors suggests these enzymes play a significant role in corneal wound repair stimulated by HGF and KGF.
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PMID:HGF- and KGF-induced activation of PI-3K/p70 s6 kinase pathway in corneal epithelial cells: its relevance in wound healing. 1144 69

FGF7/Keratinocyte growth factor (KGF) regulates the differentiation and development of the prostate epithelium, while over-expression of FGF8 and FGF1 are implicated in carcinogenesis of the prostate. We tested the hypothesis that different members of the FGF family function through different signalling molecules. In prostate DU145 cells, both FGF1 and FGF2 activated ERK1/2 potently and p38 moderately. KGF was however most efficient in inducing p38 activities but had no effect on ERK1/2 function. JNK and STAT activities were not induced by FGFs in prostate cells. In vitro expression of the transcription factors Elk-1 and MEF2A (substrates for ERK1/2 and p38, respectively) for functional quantification, confirmed the pattern of FGF-induced MAPK activations in COS-7 cells. Furthermore, KGF was more efficient than FGF1 and FGF2 in inducing actin stress fibres, and the specific p38 inhibitor SB202190 completely abolished this in a dose-dependent manner. The MEK1/2 inhibitor, U0126, had no effect on FGF-induced stress fibre formation. This study demonstrates the selective activation of MAPK family members by FGFs resulting in activation of transcription factors and stress fibre formation. As multiple FGFs are over-expressed in human prostate cancer, characterization of the distinct signalling pathway by FGFs may reveal new specific targets for therapy.
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PMID:Keratinocyte growth factor activates p38 MAPK to induce stress fibre formation in human prostate DU145 cells. 1153 48

Fibroblast growth factors (FGFs) stimulate angiogenesis, of which signals are transduced via FGF receptor (FGFR) tyrosine kinases. Although FGFR1 is a major receptor in endothelial cells, FGFR2 is frequently detectable in endothelial cells. We have previously demonstrated that the intracellular domain of FGFR1 sufficiently transduced signals leading to proliferation, migration, urokinase secretion, and tube formation. However, little is known about the roles of signaling via FGFR2 alone in endothelial cells. Murine brain capillary endothelial cells, denoted IBE cells, express small amounts of IIIc FGFR2, which is not activated by keratinocyte growth factor (KGF). We then transfected the IIIb FGFR2 in these cells. Three stable cell lines expressing IIIb FGFR2 demonstrated chemotaxis toward KGF, but never proliferated, secreted urokinase, or formed tube-like structure by KGF treatment. Weak but sustained activation of mitogen-activated protein kinase (MAPK) was observed in these cells. Chemotaxis toward KGF was significantly attenuated by treatment with PD98059. This is the first demonstration that signaling solely via FGFR2 in endothelial cells only contributes to motility through MAPK.
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PMID:Signals via FGF receptor 2 regulate migration of endothelial cells. 1173 16

FGF-7 is induced after injury and induces the proliferation of keratinocytes. Like most members of the FGF family, the activity of FGF-7 is strongly influenced by binding to heparin, but this glycosaminoglycan is absent on keratinocyte cell surfaces and minimally present in the wound environment. In this investigation we compared the relative activity of heparan sulfate and chondroitin sulfate B (dermatan sulfate), glycosaminoglycans that are present in wounds. A lymphoid cell line (BaF/KGFR) containing the FGF-7 receptor (FGFR2 IIIb) was treated with FGF-7 and with various glycosaminoglycans. FGF-7 did not support cell proliferation in the absence of glycosaminoglycan or with addition of heparan sulfate or chondroitin sulfate A/C but did stimulate BaF/KGFR division in the presence of dermatan sulfate or highly sulfated low molecular weight fractions of dermatan. Dermatan sulfate also enabled FGF-7-dependent phosphorylation of mitogen-activated protein kinase and promoted binding of radiolabeled FGF-7 to FGFR2 IIIb. In addition, dermatan sulfate and FGF-7 stimulated growth of normal keratinocytes in culture. Thus, dermatan sulfate, the predominant glycosaminoglycan in skin, is the principle cofactor for FGF-7.
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PMID:Dermatan sulfate binds and potentiates activity of keratinocyte growth factor (FGF-7). 1221 37

Fibroblast growth factor receptors (FGFRs) genes have been shown to be translocated in multiple myeloma (MM) and myeloproliferative disorder (MPD), indicating an important role for the FGFRs in hematologic malignancies. Here, we describe a novel splice variant of FGFR2 (FGFR2AT-I) arising from skipping exons 7-10 in human myeloid leukemia HL-60 cells, encoding a FGFR2 in which the Ig-like-III domain is deleted while the remainder of the mature molecule is fused in-frame to the transmembrane and COOH-terminal cytoplasmic kinases. Binding assays demonstrated that the FGFR2AT-I was able to bind FGF1, FGF2, and FGF7, leading to loss of ligand binding specificity. Furthermore, overexpression of FGFR2AT-I resulted in increased AKT and MAPK activation, conferring a survival advantage. Taken together, these findings indicate that the dysregulation of FGFRs' function by aberrant mRNA splicing contributes to tumor progression.
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PMID:A novel splice variant of fibroblast growth factor receptor 2 in human leukemia HL-60 cells. 1248 14


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