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)

In colorectal cancer patients, prognosis is not determined by the primary tumor but by the formation of distant metastases. Molecules that have been implicated in the metastatic process are the proto-oncogene product c-Met and CD44 glycoproteins. Recently, we obtained evidence for functional collaboration between these two molecules: CD44 isoforms decorated with heparan sulfate chains (CD44-HS) can bind the c-Met ligand, the growth and motility factor hepatocyte growth factor/scatter factor (HGF/SF). This interaction strongly promotes signaling through the receptor tyrosine kinase c-Met. In the present study, we explored the expression of CD44-HS, c-Met, and HGF/SF in the normal human colon mucosa, and in colorectal adenomas and carcinomas, as well as their interaction in colorectal cancer cell lines. Compared to the normal colon, CD44v3 isoforms, which contain a site for HS attachment, and c-Met, were both overexpressed on the neoplastic epithelium of colorectal adenomas and on most carcinomas. Likewise, HGF/SF was expressed at increased levels in tumor tissue. On all tested colorectal cancer cell lines CD44v3 and c-Met were co-expressed. As was shown by immunoprecipitation and Western blotting, CD44 on these cells lines was decorated with HS. Interaction with HS moieties on colorectal carcinoma (HT29) cells promoted HGF/SF-induced activation of c-Met and of the Ras-MAP kinase pathway. Interestingly, survival analysis showed that CD44-HS expression predicts unfavorable prognosis in patients with invasive colorectal carcinomas. Taken together, our findings indicate that CD44-HS, c-Met, and HGF/SF are simultaneously overexpressed in colorectal cancer and that HS moieties promote c-Met signaling in colon carcinoma cells. These observations suggest that collaboration between CD44-HS and the c-Met signaling pathway may play an important role in colorectal tumorigenesis.
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PMID:Expression of c-Met and heparan-sulfate proteoglycan forms of CD44 in colorectal cancer. 1107 15

The additivity of DNA synthesis induced by hepatocyte growth factor/scatter factor (HGF/SF) and epidermal growth factor (EGF) was revealed in periportal hepatocytes (PPH), perivenous hepatocytes (PVH), and primary hepatocytes. Furthermore, additivity of the signal transduction pathway of HGF/SF and EGF was investigated (i.e., the activity of mitogen-activated protein kinase (MAPK) induced by HGF/SF and EGF), but it was not seen in PPH, PVH, or primary hepatocytes, although wortomannin, a PI 3-kinase inhibitor, abolished the additivity. The additivity of DNA synthesis induced by HGF/SF and EGF was not related to hepatocyte heterogeneity, but to a difference in the signal transduction pathway, probably another pathway that is different from the classical MAPK (MAPK/ERK1,2) path.
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PMID:Additivity of the proliferative effects of HGF/SF and EGF on hepatocytes. 1109 71

Scatter factor/hepatocyte growth factor (SF/HGF) and its tyrosine kinase receptor c-met are developmentally expressed, neuroprotective, and tumorigenic within the CNS. In the present study SF/HGF is shown to induce the expression of c-met in two human glioblastoma cell lines, U-373 MG and T98G, and the signaling pathways involved in this induction are dissected. SF/HGF activated mitogen-activated protein kinase (MAPK) and inhibition of either Ras or MAPK-kinase completely inhibited SF/HGF-mediated c-met induction. Inhibition of phospholipase-C (PLC) did not affect c-met induction in either cell line. Inhibition of phosphoinositide 3-kinase (PI3-kinase) substantially reduced c-met induction by SF/HGF in T98G cells but had no effect in U-373 MG cells. Protein kinase C (PKC) inhibition reduced c-met induction in T98G cells but not in U-373 MG cells. SF/HGF induced the expression of c-fos and c-jun mRNA and increased the levels of AP-1 transcription factor in both cells lines as determined by AP-1-luciferase reporter expression. Transfection of either cell line with TAM-67, a dominant negative for the jun transactivation domain, completely inhibited AP-1 and c-met induction by SF/HGF. These results support a model of c-met induction by SF/HGF in human glioma cells that uniformly involves Ras, MAPK, and AP-1 and additionally involves PI3-kinase and PKC in some cell lines.
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PMID:Signaling pathways in the induction of c-met receptor expression by its ligand scatter factor/hepatocyte growth factor in human glioblastoma. 1123 34

Since autocrine regulation of HGF-Met is implicated in many forms of human cancer, we investigated whether the predisposition to develop ovarian cancer in women with hereditary ovarian cancer syndromes involves changes in the expression of HGF-Met by the tissue of origin of epithelial ovarian cancers, the ovarian surface epithelium (OSE). We compared cultures of normal OSE from women with (FH-OSE) (n=20) and with no (NFH-OSE) (n=48) family histories of ovarian cancer, SV40 Tag immortalized OSE lines (IOSE, n=5) and ovarian cancer cell lines (n=3). Cultures derived from 21/22 women with NFH-OSE and 13/13 women with FH-OSE expressed Met mRNA initially. After two to three passages, Met was downregulated in 37% of NFH-OSE cultures but persisted in 100% of FH-OSE cultures and ovarian cancer lines, like other epithelial differentiation markers that are stabilized in FH-OSE and neoplasia. HGF and Met mRNA were concomitantly expressed by NFH-OSE from only three of 32 women but in FH-OSE from eight of 13 women, and also in five of five IOSE and two of three ovarian cancer lines. Conditioned media from FH-OSE, but not NFH-OSE, contained immunoreactive HGF and induced cohort migration which was inhibited by neutralizing HGF antibody. Several signaling molecules of the PI3K pathway, including Akt2 and p70 S6K, were constitutively activated in FH-OSE from six of six women but in NFH-OSE from only four of eight women. Exogenous HGF was mitogenic in OSE, and that effect was regulated through the MAP kinase (ERK1/ERK2) and FRAP/p70 S6K pathways. The proliferative response to HGF was greater in NFH-OSE than in FH-OSE cultures. The results show that FH-OSE cultures differ from NFH-OSE by increased stability of Met expression and by HGF secretion. Constitutive phosphorylation of kinases and a diminished growth response to HGF suggest the presence of autocrine regulation in FH-OSE. In analogy with other cell types where an autocrine HGF-Met loop has been implicated in tumorigenic transformation, this change in FH-OSE may play a role in the enhanced susceptibility to ovarian carcinogenesis in women with hereditary ovarian cancer syndromes.
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PMID:Coexpression of hepatocyte growth factor-Met: an early step in ovarian carcinogenesis? 1131 76

The urinary collecting duct system of the permanent kidney develops by growth and branching of an initially unbranched epithelial tubule, the ureteric bud. Formation of the ureteric bud as an outgrowth of the wolffian duct is induced by signalling molecules (such as GDNF) that emanate from the adjacent metanephrogenic mesenchyme. Once it has invaded the mesenchyme, growth and branching of the bud is controlled by a variety of molecules, such as the growth factors GDNF, HGF, TGFbeta, activin, BMP-2, BMP-7, and matrix molecules such as heparan sulphate proteoglycans and laminins. These various influences are integrated by signal transduction systems inside ureteric bud cells, with the MAP kinase, protein kinase A and protein kinase C pathways appearing to play major roles. The mechanisms of morphogenetic change that produce branching remain largely obscure, but matrix metalloproteinases are known to be necessary for the process, and there is preliminary evidence for the involvement of the actin/myosin contractile cytoskeleton in creating branch points.
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PMID:Intracellular and extracellular regulation of ureteric bud morphogenesis. 1132 19

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

Hepatocyte growth factor/scatter factor (HGF/SF) promotes the proliferation, differentiation, motility, and invasion of epithelial cells by binding to its cell surface receptor, the Met tyrosine kinase. In the prostate, Met is expressed predominantly by prostate epithelial cells (PrEC), whereas HGF/SF is synthesized by prostate stromal cells (PrSC). Met is also expressed in localized and metastatic prostate cancers. Our results show that PrECs in in vitro culture maintain expression of Met at a level comparable to DU145 cancer cell expression. HGF/SF secreted by PrSC stimulates tyrosine phosphorylation of the Met receptor. In normal PrEC, HGF/SF causes growth inhibition, sustained phosphorylation of mitogen-activated protein kinase, and increased CK18 expression consistent with cell differentiation. In contrast, HGF/SF significantly stimulates the proliferation of DU145 prostate cancer cells. HGF/SF in the conditioned medium of PrSC specifically induces migration of both normal and malignant prostate epithelial cells through MatriGel-coated Transwell filters. HGF/SF depletion reduces cell migration by approximately 50%. The response of PrEC is specific for HGF/SF since the other growth factors tested do not significantly affect growth or migration of PrECs. These results support the in vivo importance of the prostate stroma and specifically of HGF/SF as a unique stromal derived factor in the development and progression of prostate cancer.
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PMID:Normal and malignant prostate epithelial cells differ in their response to hepatocyte growth factor/scatter factor. 1148 16

Hepatocyte growth factor/scatter factor (HGF/SF) is considered to be a mesenchymal-derived factor that acts via a dual system receptor, consisting of the MET receptor and proteoglycans present on adjacent epithelial cells. Surprisingly, HGS/SF stimulated the migration of rat mammary (Rama) 27 fibroblasts, although it failed to stimulate their proliferation. HGF/SF stimulated a transient activation of mitogen-activated protein kinases p44 and p42 (p42/44(MAPK)), with a maximum level of dual phosphorylation of p42/44(MAPK) occurring 10-15 min after the addition of the growth factor, which was followed by a rapid decrease to near basal levels after 20 min. Interestingly, a second phase of p42/44(MAPK) dual phosphorylation was observed at later times (3 h to 10 h). PD098059, a specific inhibitor of MEK-1, prevented the dual phosphorylation of p42/44(MAPK) and also the phosphorylation of p90(RSK) (ribosomal subunit S6 kinase), which mirrored the kinetics of p42/44(MAPK) phosphorylation. Moreover, PD098059 prevented the HGF/SF-induced migration of Rama 27 cells. HGF/SF also induced an early increase in the phosphorylation of protein kinase B/Akt. Akt phosphorylation was elevated 15 min after the addition of HGF/SF and then declined to basal levels by 30 min. Wortmannin, an inhibitor of phosphatidylinositol 3-kinase (PtdIns3K), prevented the increase in Akt phosphorylation and abolished HGF/SF-induced migration of fibroblasts. PD098059 also inhibited the stimulation of Akt phosphorylation by HGF/SF and wortmannin similarly inhibited the stimulation of p42/44(MAPK) dual phosphorylation. These results suggest that HGF/SF-induced motility depends on both the transient dual phosphorylation of p42/44(MAPK) and the activation of PtdIns3K in Rama 27 fibroblasts and that these pathways are mutually dependent.
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PMID:Hepatocyte growth factor/scatter factor stimulates migration of rat mammary fibroblasts through both mitogen-activated protein kinase and phosphatidylinositol 3-kinase/Akt pathways. 1150 2

Hepatocyte growth factor/scatter factor (HGF/SF) acts via a dual receptor system consisting of the MET tyrosine kinase receptor and heparan sulfate or dermatan sulfate proteoglycans. In optical biosensor binding assays, competition by oligosaccharides for binding of HGF/SF to immobilized heparin showed that disaccharides failed to compete, whereas tetrasaccharides inhibited HGF/SF binding (IC(50) 8 microg/ml). The inhibitory potency of the oligosaccharides increased as their length increased by successive disaccharide units, to reach a maximum (IC(50) 1 microg/ml) at degree of polymerization (dp) 10. In binding assays, HGF/SF was found to bind directly to oligosaccharides as small as dp 4, and the binding parameters were similar for oligosaccharides of dp 4-14 (k(a) 2.2-45.3 x 10(6) m(-1) s(-1), k(d) 0.033-0.039 s(-1), and K(d) 9-16 nm). In human keratinocytes, HGF/SF stimulated DNA synthesis, and this was dependent on a sustained phosphorylation of p42/44(MAPK). In chlorate-treated and hence sulfated glycosaminoglycan-deficient HaCaT cells, the stimulation of DNA synthesis by HGF/SF was almost abolished. Heparin-derived oligosaccharides from dp 2 to dp 24 were added together with HGF/SF to chlorate-treated cells to determine the minimum size of oligosaccharides able to restore HGF/SF activity. At restricted concentrations of oligosaccharides (4 ng/ml), HGF/SF required decasaccharides, whereas at higher concentrations (100 ng/ml) even tetrasaccharides were able to partly restore DNA synthesis. The results suggest that HGF/SF binds to a tetrasaccharide and that although this is sufficient to enable the stimulation of DNA synthesis, longer oligosaccharides are more efficient, perhaps by virtue of their ability to bind more easily other molecules.
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PMID:Hepatocyte growth factor/scatter factor binds to small heparin-derived oligosaccharides and stimulates the proliferation of human HaCaT keratinocytes. 1179 24

Acute irreparable UV-induced DNA damage leads to apoptosis of epidermal keratinocytes (KC) and the formation of sunburn cells, whereas less severely damaged cells survive but harbor the potential of tumor formation. Here we report that hepatocyte growth factor/scatter factor (HGF/SF) prevents UVB-induced apoptosis in primary KC cultured in vitro. When we analyzed the signaling pathways initiated by the HGF/SF receptor c-met, we found that the phosphatidylinositol (PI) 3-kinase and its downstream-element AKT and the mitogen-activated protein (MAP) kinase were activated. Inhibition of PI 3-kinase led to a complete abrogation of the anti-apoptotic effect of HGF/SF, whereas blockade of the MAP kinase pathway had no effect. In contrast to the observation with primary KC, HGF/SF could not enhance survival after UVB irradiation of HaCaT and A431 cell lines, despite the fact that in these cells the PI 3-kinase and MAP kinase pathways were also activated by HGF/SF. Cell cycle analysis of KC revealed a G(2)/M arrest after UVB irradiation and a complete loss of proliferating cells. Because HGF/SF in the skin is produced by dermal fibroblasts, our findings suggest that the HGF/SF-mediated rescue of KC from apoptosis represents an important paracrine loop by which UVB-damaged KC can be kept alive to maintain the epidermal barrier function but cannot further proliferate, thereby preventing the induction of epithelial skin tumors.
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PMID:Hepatocyte growth factor/scatter factor inhibits UVB-induced apoptosis of human keratinocytes but not of keratinocyte-derived cell lines via the phosphatidylinositol 3-kinase/AKT pathway. 1182 97


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