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)

Hepatocyte growth factor/scatter factor (HGF/SF) induces scattering and morphogenesis of epithelial cells through the activation of the MET tyrosine kinase receptor. Although the activated MET receptor recruits a number of signaling proteins, little is known of the downstream signaling pathways activated by HGF/SF. In this study, we wished to examine the signaling pathway leading to activation of the ETS1 transcription factor. Using in vitro and in vivo kinase assays, we found that HGF/SF activates the ERK1 MAP kinase, leading to the phosphorylation of the threonine 38 residue of ETS1 within a putative MAP kinase phosphorylation site (PLLT38P). This threonine residue was neither phosphorylated by JNK1, nor by p38 MAP kinases and was required for the induction of transcriptional activity of ETS1 by HGF/SF. Using kinase and transcription assays, we further demonstrated that phosphorylation and activation of ETS1 occurs downstream of a RAS-RAF-MEK-ERK pathway. The functional involvement of this pathway in HGF/SF action was demonstrated using U0126, a pharmacological inhibitor of MEK, which blocked phosphorylation and activation of ETS1, RAS-dependent transcriptional responses, cell scattering and morphogenesis. These data demonstrated that ETS1 is a downstream target of HGF/SF acting through a RAS-RAF-MEK-ERK pathway and provides a signaling pathway leading to the regulation of gene expression by HGF/SF.
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PMID:Hepatocyte growth factor/scatter factor activates the ETS1 transcription factor by a RAS-RAF-MEK-ERK signaling pathway. 1194 14

Hepatocyte growth factor-scatter factor (HGF-SF) is a potent hepatic mitogen yet inhibits hepatocellular carcinoma (HCC) cell growth in vitro. Insulin-like growth factor I (IGF-I) is a pleiotropic growth factor shown to be important in cell growth and differentiation in other tumors. We hypothesized that IGF-I may play a role in regulating HGF-SF activity and HCC progression. Using an in vivo model of HCC, we showed elevated IGF-I messenger RNA (mRNA) expression in normal liver from tumor-burdened animals in the absence of changes in circulating IGF-I levels. Analysis of IGF-I receptor (IGF-IR) and HGF-SF (c-met) receptor expression showed significantly higher expression of both receptors in normal liver compared with an HCC specimen. Using cultured HCC cells from this model, we next showed that treatment with IGF-I led to significant increases in mitogen-activated protein kinase (MAPK) activity. Furthermore, we observed significant time-dependent increases in the expression of the c-fos and c-jun proto-oncogenes after addition of IGF-I (n = 5 per group, P <.05). Despite activation of a MAPK pathway and increased proto-oncogene expression, IGF-I failed to significantly affect cell mitogenesis. In contrast, HGF significantly inhibited cell mitogenesis in HCC lines (68.4% +/- 9.4% vs. control, n = 4, P <.05). Pretreatment of HCC cells with IGF-I (60 minutes) led to significant HGF-SF stimulation of total cell mitogenesis dependent on both IGF-I and HGF-SF dose (194% +/- 8% increase vs. control, n = 4, P <.05). In conclusion, tumor burden is important in altering intrahepatic growth factor synthesis. Signal cooperation between multiple cytokine pathways is an important factor in the progression of HCC.
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PMID:Insulin-like growth factor I is a comitogen for hepatocyte growth factor in a rat model of hepatocellular carcinoma. 1239 18

Hepatocyte growth factor (HGF)/scatter factor (SF) is a unique growth factor, in that it binds both heparan sulphate (HS) and dermatan sulphate (DS). The sequences in HS and DS that specifically interact with and modulate HGF/SF activity have not yet been fully identified. Ascidian DS, which uniquely possesses O-sulphation at C-6 (and not C-4) of its N -acetylgalactosamine unit, was analysed for HGF/SF-binding activity in the biosensor. The kinetic analysis revealed a strong, biologically relevant interaction with an equilibrium dissociation constant ( K (d)) of approx. 1 nM. An Erk activation assay also demonstrated stimulation of the MAP kinase pathway downstream of the Met receptor following addition of both HGF/SF and ascidian DS to the glycosaminoglycan-deficient CHO-745 mutant cell line. Furthermore, the activation of Met and the MAP kinase pathway by HGF/SF and ascidian DS leads to a cellular response in the form of migration.
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PMID:Hepatocyte growth factor/scatter factor and its interaction with heparan sulphate and dermatan sulphate. 1265 36

The evolution of multiple myeloma (MM) depends on complex signals from the bone marrow (BM) microenvironment, supporting the proliferation and survival of malignant plasma cells. An interesting candidate signal is hepatocyte growth factor/scatter factor (HGF), since its receptor Met is expressed on MM cells, while HGF is produced by BM stromal cells and by some MM cell lines, enabling para- or autocrine interaction. To explore this hypothesis, we studied the biological effects of HGF stimulation on MM cell lines and on primary MMs. We observed that Met is expressed by the majority of MM cell lines and by approximately half of the primary plasma cell neoplasms tested. Stimulation of MM cells with HGF led to the activation of the RAS/mitogen-activated protein kinase and phosphatidylinositol 3-kinase/protein kinase B (PI3K/PKB) pathways, signaling routes that have been implicated in the regulation of cell proliferation and survival. Indeed, functional studies demonstrated that HGF has strong proliferative and anti-apoptotic effects on both MM cell lines and primary MM cells. Furthermore, by applying specific signal-transduction inhibitors, we demonstrated that MEK is required for HGF-induced proliferation, whereas activation of PI3K is required for both HGF-induced proliferation and for rescue of MM cells from apoptosis. Taken together, our data indicate that HGF is a potent myeloma growth and survival factor and suggest that the HGF/Met pathway is a potential therapeutic target in MM.
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PMID:The hepatocyte growth factor/Met pathway controls proliferation and apoptosis in multiple myeloma. 1268 35

Hepatocyte growth factor/scatter factor (HGF/SF), acting through the receptor tyrosine kinase Met, stimulates cells derived from a variety of different organs to form elongated hollow tubules when grown in three-dimensional gels. In vivo data also indicate a role for HGF/SF and Met in tubule formation during liver and kidney regeneration and mammary gland formation. Activation of Met results in the recruitment of a myriad of signal transducers that regulate dissociation of adherens junctions and the stimulation of cellular motility, survival, proliferation and morphogenesis during tubule formation. Among these many signal transducers, the Gab1 adaptor protein and its effector, the SHP2 tyrosine phosphatase, have been found to be crucial for tubulogenesis and for the sustained stimulation of the ERK/MAP kinase pathway. Here, we discuss the contribution of these and other signaling pathways and the role of HGF/SF and Met in the formation of epithelial cell tubules both in vitro in branching-morphogenesis assays and in vivo during organogenesis.
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PMID:How to make tubes: signaling by the Met receptor tyrosine kinase. 1279 Dec 99

Eph kinases and their ephrin ligands are widely expressed in epithelial cells in vitro and in vivo. Our results show that activation of endogenous EphA kinases in Madin-Darby canine kidney (MDCK) cells negatively regulates hepatocyte growth factor/scatter factor (HGF)-induced branching morphogenesis in collagen gel. Cotreatment with HGF and ephrin-A1 reduced sprouting of cell protrusions, an early step in branching morphogenesis. Moreover, addition of ephrin-A1 after HGF stimulation resulted in collapse and retraction of preexisting cell protrusions. In a newly developed assay that simulates the localized interactions between Ephs and ephrins in vivo, immobilized ephrin-A1 suppressed HGF-induced MDCK cell scattering. Ephrin-A1 inhibited basal ERK1/2 mitogen-activated protein kinase activity; however, the ephrin-A1 effect on cell protrusion was independent of the mitogen-activated protein kinase pathway. Ephrin-A1 suppressed HGF-induced activation of Rac1 and p21-activated kinase, whereas RhoA activation was retained, leading to the preservation of stress fibers. Moreover, dominant-negative RhoA or inhibitor of Rho-associated kinase (Y27632) substantially negated the inhibitory effects of ephrin-A1. These data suggest that interfering with c-Met signaling to Rho GTPases represents a major mechanism by which EphA kinase activation inhibits HGF-induced MDCK branching morphogenesis.
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PMID:EphA kinase activation regulates HGF-induced epithelial branching morphogenesis. 1451 7

Hepatocyte growth factor/scatter factor (HGF/SF), acting through the Met receptor, plays an important role in most human solid tumors, and inappropriate expression of this ligand-receptor pair is often associated with poor prognosis. The molecular basis for the malignant potential of the HGF/SF-Met signal in cancer cells has mostly been attributed to its mitogenic and invasive properties. However, HGF/SF also induces angiogenesis, but the signaling mechanism has not been fully explained, nor has this activity been directly associated with HGF/SF-Met-mediated tumorigenesis. It is known that HGF/SF induces in vitro expression of vascular endothelial growth factor (VEGF), a key agonist of tumor angiogenesis; by contrast, thrombospondin 1 (TSP-1) is a negative regulator of angiogenesis. Here, we show that, in the very same tumor cells, in addition to inducing VEGF expression, HGF/SF dramatically down-regulates TSP-1 expression. We show that TSP-1 shut-off plays an important, extrinsic role in HGF/SF-mediated tumor development, because ectopic expression of TSP-1 markedly inhibits tumor formation through the suppression of angiogenesis. Interestingly, although VEGF-induced expression is sensitive to inhibitors of several pathways, including mitogen-activated protein kinase, phosphoinositide 3-kinase, and signal transducer and activator of transcription 3, TSP-1 shut-off by HGF/SF is prevented solely by inhibiting mitogen-activated protein kinase activation. These studies identify HGF/SF as a key switch for turning on angiogenesis. They suggest that TSP-1 is a useful antagonist to tumor angiogenesis and that it may have therapeutic value when used in conjunction with inhibitors of VEGF.
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PMID:Hepatocyte growth factor/scatter factor mediates angiogenesis through positive VEGF and negative thrombospondin 1 regulation. 1455 67

Hepatocyte growth factor/scatter factor (HGF/SF) is a growth factor with pleiotropic effects on different cell types. It acts as a mitogen and motility factor for many epithelial cells. HGF/SF and its receptor Met are present in the developing and adult mammalian brain and control neuritogenesis of sympathetic and sensory neurons. We report that the striatal progenitor ST14A cells express the Met receptor, which is activated after binding with HGF/SF. The interaction between Met and HGF/SF triggers a signaling cascade that leads to increased levels of c-Jun, c-Fos, and Egr-1 proteins, in agreement with data reported on the signaling events evoked by HGF in other cellular types. We also studied the effects of the exposure of ST14A cells to HGF/SF. By time-lapse photography, we observed that a 24-hr treatment with 50 ng/ml HGF/SF induced modification in cell morphology, with a decrease in cell-cell interactions and increase of cell motility. In contrast, no effect on cell proliferation was observed. To investigate which intracellular pathway is primarily involved we used PD98059 and LY294002, two specific inhibitors of mitogen-activated protein kinase/extracellular signal-regulated kinase (MAP-kinase/ERK-kinase) and phosphoinositide 3-OH kinase (PI3-K), respectively. Cell motility in HGF/SF treated cultures was inhibited by LY294002 but not by PD98059, suggesting that PI3-K plays a key role in mediating the HGF/SF-induced dissociation of ST14A cells. Previous evidence of HGF stimulation of motility in nervous system has been obtained on postmitotic neurons, which have already acquired their specificity. Data reported here of a motogenic response of ST14A cell line, which displays properties of neuronal progenitors, seem of interest because they suggest that HGF could play a role in very early steps of neurogenesis.
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PMID:Hepatocyte growth factor stimulates cell motility in cultures of the striatal progenitor cells ST14A. 1463 27

Epidemiological studies have indicated a reduced risk of malignancies with the use of nonsteroidal anti-inflammatory drugs (NSAIDs), although the exact mechanisms are debated. NSAIDs inhibit angiogenesis, which is a key step for tumor growth. Hepatocyte growth factor/scatter factor (HGF/SF), a potent and independent angiogenic factor, has been implicated in tumorigenesis, but limited knowledge exists on the potential targets for inhibiting HGF/SF-induced pathological angiogenesis. The current study was designed to elucidate the possible role of cyclooxygenase (COX) downstream of HGF/SF during angiogenesis and to evaluate the potential for harnessing NSAIDs as a therapeutic strategy. Known NSAIDs were classified as COX-1 or COX-2 selective based on their activity in a platelet aggregation experiment. The inhibitors were administered into a polyether polyurethane scaffold implant in mice at the selected doses, and the total neovascularization after the administration of HGF/SF was quantified using a (133)Xenon clearance technique, vessel counts, and immunohistochemistry. Angiogenesis was also quantized into chemoinvasion, migration, proliferation, and tube formation events in vitro, and the effects of the NSAIDs were evaluated on HGF/SF-induced activity of human umbilical vein endothelial cells (HUVECs). HGF/SF accelerated the angiogenic process in the murine implant, and this activity was inhibited by COX-2-selective meloxicam and NS398. The COX-1 inhibitors ketoprofen and SC560 failed to inhibit the HGF/SF-induced angiogenic events in vitro and in vivo. A COX-2 blockade inhibited the HGF/SF-induced chemoinvasion and migration of human umbilical vein endothelial cells, without affecting the proliferative or tubulogenic responses. Western blots revealed the induction COX-2 expression after HGF/SF treatment, and the pharmacological inhibition of COX-2 executed a temporal inhibition of phosphorylation of the mitogen-activated protein kinases. The current study, for the first time, implicates COX-2 as a downstream signal during HGF/SF-induced angiogenesis, temporally impinging on the mitogen-activated protein kinase signaling. However, the mediation is restricted to only the early events of the angiogenic process, emphasizing the chemopreventive role for NSAIDs. Few therapeutic options currently exist for HGF/SF-induced pathological angiogenesis, and the vast knowledge on COX-2 inhibitors can be harnessed to design a newer therapeutic approach.
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PMID:Cyclooxygenase-2-selective nonsteroidal anti-inflammatory drugs inhibit hepatocyte growth factor/scatter factor-induced angiogenesis. 1467 96

We investigated whether repression of JNK by hepatocyte growth factor/scatter factor (HGF/SF) in MDCK epithelial cells is linked to its ability to protect cells from apoptosis. To this purpose, cells were treated by TNF-alpha, a well-known inducer of JNK and of cell death, and the effects of HGF/SF were investigated under these conditions. We identified repression of JNK as a signaling target of HGF/SF for protection against TNF-alpha-induced cell death. This effect of HGF/SF occurs via the activation of the PI3K and MEK1 pathways.
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PMID:Inhibition of JNK by HGF/SF prevents apoptosis induced by TNF-alpha. 1503 2


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