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)

In acute tubular necrosis, there are early transient increases in circulating and local bioactive hepatocyte growth factor (HGF) levels and renal HGF receptor (c-MET) gene expression. It has therefore been suggested that endogenous HGF may play a role in initiating renal repair. To test this hypothesis, changes in the levels, activity, and anatomic distribution of c-MET protein were characterized in relation to the onset and localization of DNA synthesis in kidneys of rats with ischemia-induced acute tubular necrosis. Whole-kidney c-MET protein levels were significantly increased in the injured kidneys 12 h after injury and rose to a maximum after 1 d, exceeding the control values by sevenfold. Eight days after injury, c-MET levels, although decreasing, were still elevated above control values. An increase in the levels of activated c-MET, i.e., tyrosine-phosphorylated c-MET, was also evident as early as 12 h after injury. Histologic analyses demonstrated that the increase in c-MET immunoreactivity was most marked in the most severely damaged nephron segments in the outer medulla. In injured proximal tubules, the receptor was redistributed from an apical location to an intracellular location. DNA synthesis was increased in the injured kidneys, especially in the outer medulla, where the increase in c-MET protein levels was most prominent. The increase in DNA synthesis was first detected 12 h after the initial increase in activated c-MET levels. It is concluded that the early increases in the levels of c-MET protein and activated receptor support the hypothesis that HGF participates in the initiation of renal regeneration. In addition, the persistent elevation of c-Met protein levels suggests that prolonged and even late treatment with HGF may be of therapeutic value
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PMID:Hepatocyte growth factor receptor in acute tubular necrosis. 1118 1

Of the numerous growth factors and cytokines that have been shown to have angiogenic effects, vascular endothelial growth factor (VEGF), also known as vascular permeability factor (VPF), appears to be a key factor in pathological situations which involve neovascularization as well as enhanced vascular permeability. Our aim was to design a low molecular weight synthetic molecule that potently and selectively blocks the VEGF/VEGF receptor system after oral administration, suitable for the chronic therapy of VEGF-dependent pathological neovascularization. PTK787/ZK 222584 is a potent inhibitor of VEGF receptor tyrosine kinases, active in the submicromolar range. It also inhibits other class III kinases, like the PDGFR-beta tyrosine kinase, c-Kit and c-Fms, but at higher concentrations. It is not active against kinases from other receptor families such as EGFR, FGFR-1, c-Met and Tie-2 or intracellular kinases like c-Src, c-Abl, PKC-alpha. PTK787/ZK 222584 inhibits VEGF-induced autophosphorylation of KDR, and endothelial cell proliferation, migration and survival in the nanomolar range in cell based assays. In concentrations up to 1 microM, PTK787/ZK 222584 does not have any cytotoxic or anti-proliferative effect on cells that do not express VEGF receptors. After oral dosing (50 mg/kg) to mice, plasma concentrations of PTK787/ZK 222584 remain above 1 microM for more than 8 h. PTK787/ZK 222584 induces dose-dependent inhibition of VEGF- and PDGF-induced angiogenesis in a growth factor implant model, as well as a tumor cell-driven angiogenesis model after once daily oral dosing (25-100 mg/kg). In the same dose range, it also inhibits the growth of several human carcinomas, grown subcutaneously in nude mice, as well as a murine renal carcinoma and its metastases in syngeneic, orthotopic models. Histological examination of tumors reveals inhibition of microvessel formation in the interior of the tumor. PTK787/ZK 222584 also significantly inhibits ascites formation induced by a human ovarian carcinoma grown in the peritoneum of nude mice as well as pleural effusion induced by a human lung adenocarcinoma in nude mice. PTK787/ZK 222584 is very well tolerated and does not impair wound healing. It also does not have any significant effects on circulating blood cells or bone marrow leukocytes as a single agent, or impair hematopoetic recovery following concomitant cytotoxic anti-cancer agent challenge. These studies indicate that compounds that inhibit the effects of VEGF, such as PTK787/ZK 222584, have the potential to provide a novel, effective and well-tolerated therapy for the treatment of solid tumors. These agents may also provide a new therapeutic approach for the treatment of other diseases where angiogenesis plays an important role.
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PMID:Inhibition of vascular endothelial growth factor (VEGF) as a novel approach for cancer therapy. 1118 30

Scatter factor/hepatocyte growth factor (SF/HGF) is a pleiotropic cytokine that has been implicated in glioma invasion and angiogenesis. The SF/HGF receptor, MET, has been found to be expressed in neoplastic astrocytes as well as in endothelial cells of the tumor vasculature. Both SF/HGF and MET expression have also been described to correlate with the malignancy grade of human gliomas. However, most glioblastoma cell lines lack SF/HGF expression, raising the question of the cellular origin of SF/HGF in vivo. Using in situ hybridization, we analyzed glioblastomas, anaplastic astrocytomas, diffuse astrocytomas, pilocytic astrocytomas, and normal brain for the expression of SF/HGF mRNA. We detected strong SF/HGF expression by the majority of the tumor cells and by vascular endothelial cells in all glioblastoma specimens analyzed. Combined use of in situ hybridization with fluorescence immunohistochemistry confirmed the astrocytic origin of the SF/HGF-expressiong cells. In contrast, CD68-immunoreactive microglia/macrophages, as well as vascular smooth muscle cells reactive to alpha-smooth muscle actin, lacked SF/HGF expression. In anaplastic, diffuse, and pilocytic astrocytomas, SF/HGF expression was confined to a subset of tumor cells, and signals were less intense than in glioblastomas. In addition, we detected SF/HGF mRNA in cortical neurons. SF/HGF expression was not up regulated around necroses or at tumor margins. MET immunoreactivity was observed in GFAP-expressing astrocytic tumor cells and endothelial cells as well as in a subset of microglia/macrophages. We conclude that in vivo, both autocrine and paracrine stimulation of tumor cells and endothelium through the SF/HGF-MET system are likely to contribute to tumor invasion and angiogenesis. Lack of SF/HGF expression by most cultured glioblastoma cells is not representative of the in vivo situation and most likely represents a culture artifact.
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PMID:Expression and localization of scatter factor/hepatocyte growth factor in human astrocytomas. 1129 84

Signal transduction by HGF receptor, the tyrosine kinase encoded by the MET oncogene, switches on a genetic program called 'invasive growth' inducing epithelial cell dissociation, migration, growth, and ultimately leading to differentiation into branched tubular structures. Sustained tyrosine phosphorylation of the downstream adaptor protein Gab1 is required for the HGF response. Here we show that serine/threonine phosphorylation of Gab1 provides a control mechanism for negative regulation. Treatment with okadaic acid, a potent inhibitor of the serine/threonine protein phosphatases PP1 and PP2A, was followed by activation of a number of serine/threonine kinases, hyper-phosphorylation in serine and threonine of Gab1 and severe inhibition of the HGF-induced biological responses. Under these conditions, Gab1 was found to be concomitantly hypo-phosphorylated in tyrosine, and thus endowed with reduced ability to recruit SH2 containing signal transducers such as PI3 kinase. Among the serine-threonine kinases activated by PP1 and PP2A inhibition, we found that PKC-alpha and PKC-beta1 are required for negative regulation of Gab1. These data provide a novel negative mechanism for the HGF receptor signaling pathways and highlight a potentially useful target for inhibitors of invasive growth.
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PMID:Gab1 phosphorylation: a novel mechanism for negative regulation of HGF receptor signaling. 1131 45

Cholangiocarcinoma is a hepatic biliary cancer of high morbidity and mortality, whose molecular pathogenesis is unknown. However, there is increasing evidence to suggest that alterations in selected growth factor pathways, including an overexpression of the growth factor receptor tyrosine kinases c-ErbB-2/c-Neu and c-Met, together with possible aberrant autocrine expression of hepatocyte growth factor/scatter factor, the ligand for c-Met, may be playing important roles associated with the development of cholangiocarcinoma in both the human liver and in the furan rat model of cholangiocarcinogenesis. Cyclo-oxygenase-2, whose regulation has been experimentally related to c-ErbB-2/c-Neu as well as to hepatocyte growth factor/scatter factor, and which has been demonstrated to be overexpressed in other cancers of the gastrointestinal tract, has also been observed in preliminary studies to be upregulated in human biliary cancers and in cholangiocarcinoma induced in the furan rat model. Moreover, new data from our laboratory have demonstrated the cyclo-oxygenase-2 inhibitor NS-398 to produce a significant dose-dependent growth inhibition of rat cholangiocarcinoma cells in vitro, as well as to suppress anchorage-independent growth of these cells in soft agar. Based on the data reviewed, we propose that the selective therapeutic targeting of aberrant growth factor receptor tyrosine kinase signaling and of cyclo-oxygenase-2, alone or in combination, has potential to become a useful new approach for the treatment and/or chemoprevention of cholangiocarcinoma. We further propose that the furan rat model may serve as a powerful preclinical model for testing therapeutic and chemopreventative strategies that selectively target c-ErbB-2/c-Neu, cyclo-oxygenase-2, and/or autocrine hepatocyte growth factor/c-Met, aberrantly expressed in cholangiocarcinogenesis.
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PMID:Biliary cancer growth factor pathways, cyclo-oxygenase-2 and potential therapeutic strategies. 1135 1

The Hepatocyte Growth Factor receptor transduces proliferating and scattering signals in epithelial and endothelial cells. We have explored potential interactions of the HGF/SF receptor beta-subunit (p145(beta MET)) with F-actin binding partners aiming to identify novel downstream effectors implicated in HGF/SF pluripotent signalling. Cortactin, a p80/85 F-actin binding protein, was found phosphorylated on tyrosine in response to HGF-SF in A431 human epidermoid carcinoma cells, expressing the HGF/SF receptor (c-MET). The HGF/SF receptor was enriched in the detergent-insoluble fraction and was found to co-precipitate with cortactin and to associate in vitro with cortactin. The Grb2 small adapter protein known to associate via its Src homology 2 domain (SH2) with the MET C-terminus, was also associated with cortactin. Transient transfection of A431 cells with dominant-negative Grb2 constructs has revealed that the Grb2-C-SH3 domain possesses a central role in cortactin phosphorylation in response to HGF/SF. Finally, tyrosine phosphorylation of cortactin was found uncoupled of endogenous c-Src kinase activity, thus further supporting the hypothesis that cortactin is a direct target of the MET kinase. We propose that cortactin may constitute a docking site for MET-derived signals within the cytoskeleton.
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PMID:Hepatocyte Growth Factor/scatter factor-induces phosphorylation of cortactin in A431 cells in a Src kinase-independent manner. 1143 36

In a previous immunophenotypic molecular-based analysis it was shown that bcl2 over-expression characterizes the SS gene profile in addition to the non-random translocations. Here we show that the over-expression of an additional potentially antiapoptotic gene, the c-KIT gene, is associated with this tumour. Interestingly, whereas bcl2 over-expression appears to be restricted to the spindle cell tumoral component, c-kit mainly involves the epithelial component of biphasic SS. Twenty-three primary and metastatic samples from 21 patients were analysed by immunophenotyping (23/23), immunoprecipitations and Western blotting (3/23), and RT-PCR (23/23). Ten cases were biphasic and 13 monophasic in sub-type. Twelve, 10 and 1 case carried the SYT-SSX1, SYT-SSX2 and SYT-SSX4 fusion transcript, respectively. Co-presence of both c-Kit and SCF mRNA was observed in almost all cases (20/23), suggesting the occurrence of an autocrine loop. Immunophenotyping, confirmed by biochemical analyses, showed a modulation of c-Kit expression which was faint in the spindle and strong in the epithelial component, respectively. The study was complemented by c-Met/HGF receptor/ligand expression and c-Met protein analysis with results superimposable to those already reported. Since in each tumour, epithelial and spindle cell components harbour the same type of translocation t(X;18) the present findings suggest a shifting of the anti-apoptotic role from BCL2 to c-KIT gene during the transition from the uncommitted spindle to the differentiated epithelial cells.
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PMID:c-KIT and c-KIT ligand (SCF) in synovial sarcoma (SS): an mRNA expression analysis in 23 cases. 1148 73

Regenerating liver was evaluated for the spatiotemporal expression of angiogenic growth factor receptors on endothelial cell (EC) membranes during revascularization resulting from 70% partial hepatectomy (PHx). Fractions enriched in EC membranes were examined by Western blot for angiogenic growth factor receptor expression from 1 to 14 days after PHx. Increases in vascular endothelial growth factor (VEGF) receptors Flt-1 and Flk-1/KDR, angiopoietin receptors Tie-1, Tie-2, and platelet-derived growth factor receptor beta (PDGF-Rbeta), modest increases in epidermal growth factor receptor (EGF-R), and no increase in hepatocyte growth factor receptor (c-Met) or fibroblast growth factor receptors (FGF-R) were observed in isolated membranes during EC proliferation. All receptors were tyrosine phosphorylated, and therefore activated, during peak expression. Immunofluorescence staining of regenerating liver identified populations with increased receptor expression, indicating cells receptive to ligand signaling. EGF-R was upregulated evenly throughout the sinusoidal membrane, whereas c-Met was observed on hepatocyte canaliculae, bile duct epithelium, and large vessel EC. Tie-2 and PDGF-Rbeta were increased on sinusoidal and large vessel EC, whereas Tie-1 was expressed in EC surrounding avascular hepatic islands. Flk-1/KDR was increased on large vessels with slight increases on sinusoidal EC, whereas Flt-1 was increased in arterioles, sinusoidal EC as well as in hepatocytes. Although Flt-1 was phosphorylated on isolated hepatocytes, vascular endothelial growth factor(165) (VEGF(165)) did not induce a proliferative or motogenic response. Proliferation assays on isolated EC indicated responsiveness to VEGF(165), but synergism among several growth factors including PDGF-BB was also observed. The data identify novel autocrine and paracrine interactions and indicate that each growth factor acts on a specific set of EC at specific times during revascularization of regenerating liver.
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PMID:Spatiotemporal expression of angiogenesis growth factor receptors during the revascularization of regenerating rat liver. 1173 3

We have examined the ability of epidermal growth factor (EGF)-stimulated ERK activation to regulate Grb2-associated binder-1 (Gab1)/phosphatidylinositol 3-kinase (PI3K) interactions. Inhibiting ERK activation with the MEK inhibitor U0126 increased the EGF-stimulated association of Gab1 with either full-length glutathione S-transferase-p85 or the p85 C-terminal Src homology 2 (SH2) domain, a result reproduced by co-immunoprecipitation of the native proteins from intact cells. This increased association of Gab1 and the PI3K correlates with an increase in PI3K activity and greater phosphorylation of Akt. This result is in direct contrast to what we have previously reported following HGF stimulation where MEK inhibition decreased the HGF-stimulated association of Gab1 and p85. In support of this divergent effect of ERK on Gab1/PI3K association following HGF and EGF stimulation, U0126 decreased the HGF-stimulated association of p85 and the Gab1 c-Met binding domain but did not alter the EGF-stimulated association of p85 and the c-Met binding domain. An examination of the mechanism of this effect revealed that the treatment of cells with EGF + U0126 increased the tyrosine phosphorylation of Gab1 as well as its association with another SH2-containing protein, SHP2. Furthermore, overexpression of a catalytically inactive form of SHP2 or pretreatment with pervanadate markedly increased EGF-stimulated Gab1 tyrosine phosphorylation. These experiments demonstrate that EGF and HGF-mediated ERK activation result in divergent effects on Gab1/PI3K signaling. HGF-stimulated ERK activation increases the Gab1/PI3K association, whereas EGF-stimulated ERK activation results in a decrease in the tyrosine phosphorylation of Gab1 and a decreased association with the PI3K. SHP2 is shown to associate with and dephosphorylate Gab1, suggesting that EGF-stimulated ERK might act through the regulation of SHP2.
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PMID:ERK negatively regulates the epidermal growth factor-mediated interaction of Gab1 and the phosphatidylinositol 3-kinase. 1189 55

Hepatocyte growth factor (HGF), also known as a scatter factor, regulates a variety of biological activities including cell proliferation, survival, migration, and angiogenesis. Importantly, HGF and its receptor c-Met have been found to be associated with metastasis of human head and neck squamous cell carcinoma (HNSCC). Because anoikis resistance plays an important role in tumor progression and metastasis, here we examined whether HGF suppressed suspension-induced apoptosis (anoikis) in HNSCC cells, and if so, we assessed downstream signaling pathways mediated by HGF. We found that HNSCC cells underwent anoikis upon loss of matrix contact, whereas HGF provided protection against it. HGF-induced anoikis resistance was found to be dependent on both ERK and Akt signaling pathways. The inhibition of either ERK or Akt activation abolished HGF-mediated survival. Furthermore, we found that HGF did not activate NFkappaB transcription in HNSCC cells and that HGF-mediated anoikis resistance was independent of NFkappaB. Taken together, our results suggest that anoikis resistance induced by HGF may also play an important role in the progression and metastasis of HNSCC.
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PMID:Hepatocyte growth factor inhibits anoikis in head and neck squamous cell carcinoma cells by activation of ERK and Akt signaling independent of NFkappa B. 1199 87


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