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

Addition of gastrin releasing peptide to serum-starved Swiss 3T3 mouse fibroblasts results in a transient appearance of a myelin basic protein-kinase activity in cytosolic extracts. Increased kinase activity is also observed upon stimulation of cells with bradykinin, epidermal growth factor or 4 beta-phorbol dibutyrate. Chromatographic analysis of the cytosolic extracts show that both gastrin-releasing peptide and 4 beta-phorbol dibutyrate induce the appearance of a kinase activity similar to that induced by epidermal growth factor. The response to gastrin-releasing peptide is abolished by down-regulation of protein kinase C and attenuated by acute inhibition of protein kinase C using staurosporine. The effect of epidermal growth factor was also suppressed under these conditions, albeit to a lesser extent. The results indicate (1) that activation of myelin basic protein kinase(s) may be common to different growth factors, and (2) that protein kinase C may participate in this response, at least in the case of gastrin-releasing peptide.
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PMID:Protein kinase C-dependent activation of a myelin basic protein kinase by gastrin-releasing peptide in Swiss 3T3 fibroblasts. 193 82

We recently reported that gastrin and glycine-extended progastrin processing intermediates (G-Gly) exert growth-promoting effects on AR4-2J cells (derived from rat pancreas) via interaction with distinct receptors. In this study we sought to investigate the mechanisms by which gastrin and G-Gly stimulate cell proliferation. While gastrin increased [Ca2+]i in AR4-2J cells, G-Gly had no effect. Similarly, G-Gly had no effect either on basal and 10(-7) M vasoactive intestinal polypeptide-stimulated cAMP generation, although gastrin is known to inhibit cAMP generation. Gastrin dose dependently stimulated AR4-2J cell mRNA content of both c-fos and c-jun, two genes known to function in regulating cell proliferation, but G-Gly had no effect. Gastrin also induced the expression of luciferase in AR4-2J cells transfected with a construct consisting of a luciferase reporter gene coupled to the serum response element of the c-fos gene promoter. In similar fashion, gastrin stimulated the activity of mitogen-activated protein kinase, an enzyme known to mediate the induction of the c-fos serum response element in response to growth factor stimulation. Although G-Gly had none of these effects of gastrin in AR4-2J cells, it stimulated activity of c-Jun amino-terminal kinase, an enzyme known to phosphorylate and transcriptionally activate c-Jun. These data support the notion that gastrin stimulates cell proliferation by inducing c-fos and c-jun gene expression, while G-Gly acts by post-translationally regulating early gene transcriptional activation. Our studies represent a novel model in which both the precursor and the product of a key processing reaction, peptide alpha-amidation, act cooperatively to stimulate cell proliferation via distinct receptors linked to different signal transduction pathways.
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PMID:Gastrin and glycine-extended progastrin processing intermediates induce different programs of early gene activation. 749 34

The human cholecystokinin (CCK)B/gastrin receptor was stably transfected into Rat1 fibroblasts to examine the signaling pathways mediated by this seven-transmembrane, G protein-linked receptor. We report here that binding of CCK-8 or gastrin to the CCKB/gastrin receptor induced phosphoinositide breakdown and led to a rapid, transient, and concentration-dependent increase in intracellular Ca2+, which was completely blocked by a specific CCKB receptor antagonist. The peptides also stimulated tyrosine phosphorylation of focal adhesion kinase (p125FAK) and paxillin. Both CCK-8 and gastrin induced a dose- and time-dependent activation of MAP kinase and p74raf-1 kinase in the transfected Rat1 cells. These effects could be dissociated from protein kinase C activation and were not dependent on a functional Gi protein. Finally, both CCK-8 and gastrin induced DNA synthesis in Rat1 cells transfected with the human CCKB/gastrin receptor through a pertussis toxin-insensitive pathway. These results indicate that the neuropeptides gastrin and CCK can activate multiple signal transduction pathways and act as sole mitogens by binding to the CCKB/gastrin receptor transfected into Rat1 fibroblasts.
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PMID:The human CCKB/gastrin receptor transfected into rat1 fibroblasts mediates activation of MAP kinase, p74raf-1 kinase, and mitogenesis. 779 6

The roles of gastrin and sodium vanadate in proliferation were examined in cultured IEC-6 cells that are mitotically active and derived originally from jejunal crypts of the rat intestine. Incubation of the cells in the presence of gastrin at a concentration of 250 ng/ml or of sodium vanadate at a concentration of 0.2 mM leads to a 60% increase in cell growth in 24 hr. The stimulated growth in both cases was inhibited by genistein, a tyrosine kinase inhibitor. Incubation in the presence of gastrin and sodium vanadate together produced a small, albeit significant, potentiation of growth of the cells. Gastrin as well as sodium vanadate also promoted the phosphorylation on tyrosine of a similar group of proteins with molecular masses of 42, 45, 52, 60, 78, and 120 kDa. The phosphorylations were rapidly occurring as early as 5 min and lasted for only 15 min. Several proteins were detected in normal IEC-6 cells, including GTPase activating protein, raf1 kinase, phospholipase C gamma-1, and phosphoinositide 3-kinase. The results suggest that gastrin and sodium vanadate induce growth of IEC-6 cells by stimulation of tyrosine kinase and/or inhibition of tyrosine phosphatase. The gastrin and sodium vanadate effects also involve the phosphorylation of a number of proteins, the identities of which are not known at present but may include some of the kinases that are frequently associated with cell growth, such as mitogen-activated protein kinase, raf1 kinase, phosphoinositide 3-kinase, and others.
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PMID:Role of tyrosine kinase and phosphotyrosine phosphatase in growth of the intestinal crypt cell (IEC-6) line. 845 7

Gastrin/CCKB G protein-coupled receptors have been shown to mediate proliferative effects of their endogenous ligands. In the present study, we examined the signal transduction mechanisms linked to the G/CCKB receptor occupancy. We report here that gastrin stimulates MAP kinase activation in a dose- and time-dependent manner, a pathway known to play a key role in cell proliferation. We also characterized the molecular events, upstream of p21-Ras, that may link the MAP kinase pathway to G/CCKB receptors. Gastrin induced a rapid and transient increase in tyrosine phosphorylation of several proteins including the 2 isoforms (46 and 52 kDa) of the adaptor protein Shc. Phosphorylated Shc subsequently associated with a complex that includes Grb2 and the p21-Ras activator, Sos. Our results also indicate that Sos becomes phosphorylated in response to gastrin as shown by a reduction in electrophoretic mobility of the protein. Tyrosine phosphorylation of Shc and subsequent complex formation with Grb2 and Sos appear to be a common mechanism by which tyrosine kinase receptors and the G/CCKB G protein-coupled receptor stimulate the Ras-dependent MAP kinase pathway.
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PMID:Gastrin induces tyrosine phosphorylation of Shc proteins and their association with the Grb2/Sos complex. 854 7

The growth-promoting effects of gastrin on normal and neoplastic gastrointestinal tissues have been shown to be mediated by the gastrin/CCKB receptor, which belongs to the family of G protein-coupled receptors. However, the downstream signaling pathways activated by gastrin are not well characterized. In the present study, we demonstrate that gastrin stimulates tyrosine phosphorylation of insulin receptor substrate 1 (IRS-1), the major cytoplasmic substrate of the insulin receptor. The gastrin-induced phosphorylation of IRS-1 was rapid and transient, occurring within 30 s of treatment and diminishing thereafter. IRS-1 binds several proteins containing Src homology 2 domains through its multiple tyrosine phosphorylation sites. Following gastrin stimulation, we observed a time- and dose-dependent association of IRS-1 with the p85 regulatory subunit of phosphatidylinositol 3-kinase (PI 3-kinase). In addition, activation of PI 3-kinase was detected in anti-IRS-1 immunoprecipitates from gastrin-treated cells, suggesting that tyrosine phosphorylation of IRS-1, which leads to the rapid recruitment of p85, might be one mechanism used by gastrin to activate PI 3-kinase. We have previously reported that tyrosine phosphorylation of Shc and its association with the Grb2-Sos complex may contribute to the activation of the mitogen-activated protein kinase pathway by gastrin. We report here that Grb2 also interacts with tyrosine-phosphorylated IRS-1 in response to gastrin. Taken together, our results suggest that IRS-1 may serve as a converging target in the signaling pathways stimulated by receptors that belong to different families, such as the gastrin/CCKB G protein-coupled receptor and the insulin receptor.
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PMID:Gastrin stimulates tyrosine phosphorylation of insulin receptor substrate 1 and its association with Grb2 and the phosphatidylinositol 3-kinase. 882 90

Pituitary adenylate-cyclase-activating polypeptide (PACAP) has been shown to possess mitogenic activity in various tumor cells. The present study was designed to investigate signal transduction mechanisms and expression of the proto-oncogenes c-fos and c-jun linked to the mitogenic effect of PACAP in the pancreatic carcinoma cell line AR4-2J. PACAP-(1-27)-peptide and PACAP-(1-38)-peptide, but not the structurally related vasoactive intestinal polypeptide (VIP), potently stimulated [3H]thymidine incorporation and cell number at doses of 0.1-10 nM. Both molecular forms of PACAP strongly increased formation of cAMP and inositol trisphosphate, elevated cytosolic Ca2+ levels and induced mitogen-activated protein (MAP) kinase activity. Quantitative reverse-transcription PCR revealed that PACAP-(1-27)-peptide and PACAP-(1-38)-peptide elevated c-fos mRNA levels 50-100-fold, whereas c-jun mRNA levels increased only moderately (2-3-fold). The effect of PACAP on c-fos and c-jun expression in AR4-2J cells was rapid (20 min), transient (1-2 h), dose-dependent IC50, 0.5 nM) and was abolished by the specific PACAP receptor antagonist PACAP-(6-38)-peptide or inhibitors of protein kinase C or tyrosine kinases. Compared with PACAP, epidermal growth factor and gastrin equipotently stimulated c-fos transcription whereas VIP, secretin, forskolin or phorbolester showed only marginal effects. Both PACAP (1-27)-peptide and PACAP-(1-38)-peptide strongly increased the DNA binding activity of the c-fos/ c-jun heterodimer transcription factor AP-1 at 10 nM and also stimulated AP-1 transcriptional activity up to 20-fold in AR4-2J cells. These findings indicate that the mitogenic effect of PACAP mediated via activation of the GTP-binding protein coupled PACAP/VIP-1 (PV1) receptor is linked to the MAP kinase cascade, increased expression of the proto-oncogenes c-fos and c-jun and activation of the heterodimeric transcription factor AP-1.
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PMID:Pituitary adenylate-cyclase-activating polypeptide stimulates proto-oncogene expression and activates the AP-1 (c-Fos/c-Jun) transcription factor in AR4-2J pancreatic carcinoma cells. 902 70

The proliferative effects of gastrin on normal and neoplastic gastro-intestinal tissues have been shown to be mediated by the gastrin/CCKB (G/CCKB) G-protein-coupled receptors. We have recently reported that gastrin stimulates the tyrosine phosphorylation of Shc proteins and their subsequent association with the Grb2/Sos complex, leading to mitogen-activated protein kinase (MAPK) activation, a pathway known to play an important role in cell proliferation. We undertook the present study to characterize the signalling pathways used by this receptor to mediate the activation of the Shc/Grb2 complex. Since G/CCKB receptor occupancy leads to the activation of the phospholipase C (PLC)/protein kinase C (PKC) pathway, we examined whether PKC stimulation and Ca2+ mobilization contribute to the phosphorylation of Shc proteins and their association with Grb2 in response to gastrin. Our results indicate that Shc proteins are tyrosine phosphorylated and associate with Grb2 in response to phorbol esters, suggesting that activation of PKC is a potential signalling pathway leading to activation of the Shc/Grb2 complex. Inhibition of PKC by GF109203X completely blocked the effect of PMA on Shc tyrosine phosphorylation and its subsequent association with Grb2, but had a partial inhibitory effect on the response to gastrin. Depletion of the intracellular Ca2+ pools by treatment with thapsigargin blocked the increase in intracellular free calcium concentration induced by gastrin and diminished the ability of the peptide to stimulate Shc phosphorylation and recruitment of Grb2. In addition, removal of extracellular Ca2+ partially inhibited the effect of gastrin on Shc phosphorylation as well as its association with Grb2, indicating that the effects of gastrin are also mediated by Ca2+-dependent mechanisms. Furthermore, we show that blockage of the two major early signals generated by activation of PLC, which induced the activation of the Shc/Grb2 complex, also blocked gastrin-induced MAPK activation.
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PMID:Ca2+ and protein kinase C-dependent mechanisms involved in gastrin-induced Shc/Grb2 complex formation and P44-mitogen-activated protein kinase activation. 923 Jan 17

The gastrin/CCKB (G/CCKB) G protein-coupled receptor has been shown to mediate the proliferative effects of gastrin on normal and neoplastic gastro-intestinal tissues. In the present study, we examined the signal transduction mechanisms coupled to this receptor. We report here that phosphorylation and activity of the p70S6K, whose major substrate is the ribosomal S6 protein, are enhanced in response to gastrin. These effects were completely reversed by a commonly used PI-3-kinase inhibitor, wortmannin, suggesting that p70S6K may be a downstream target of PI-3-kinase in a signaling cascade induced by gastrin. In addition, blocking PI-3-kinase activity by wortmannin partially decreased gastrin-induced MAPK activation (42% +/- 3) as well as the tyrosine phosphorylation of She (50% +/- 6), an upstream regulator of the Ras-dependent MAPK pathway. These results indicate that at least two signaling pathways lead to MAPK activation by gastrin, only one of which is sensitive to PI-3-kinase inhibitors.
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PMID:Wortmannin-sensitive activation of p70S6-kinase and MAP-kinase by the G protein-coupled receptor, G/CCKB. 929 79

Gastrin stimulates transcription of the human histidine decarboxylase (HDC) gene through binding to the G-protein-coupled cholecystokinin-B/gastrin receptor. We have explored the possibility that mitogen-activated protein kinase cascades play a role in mediating the effects of gastrin on transcription in a gastric cancer (AGS-B) cell line. Gastrin and phorbol 12-myristate 13-acetate (PMA) treatment of AGS-B cells was found to increase the phosphorylation of tyrosine residues of extracellular signal-regulated kinases (ERKs) 1 and 2 and increase ERK activity as determined by the in vitro phosphorylation of myelin basic protein. Reporter gene assays also demonstrated that gastrin and PMA stimulated Elk-1- and c-Myc-dependent transactivation, consistent with gastrin- and PMA-induced activation of ERKs. Overexpression of wild type ERK-1 and ERK-2 or activation of endogenous ERKs using activated MEK-1 (mitogen-activated protein kinase kinase or ERK kinase) overexpression stimulated HDC promoter activity in a dose-dependent fashion. Interruption of the ERK-related pathway using expression vectors for kinase-deficient ERKs or an ERK-specific phosphatase (PAC-1) blocked gastrin- and PMA-stimulated HDC promoter activity. In contrast, inhibition of the Jun kinase pathway using an interfering dominant negative SEK-1 (stress-activated protein kinase/ERK-1) mutant did not inhibit HDC promoter activity. Furthermore, whereas gastrin stimulated phosphorylation of Shc proteins and association with Grb2, activation of the HDC promoter was not influenced by expression of dominant negative Ras (N15 or N17) proteins. However, gastrin stimulated Raf-1 kinase activity, and activation of the HDC promoter was blocked by coexpression of a dominant negative Raf-1 construct. Overall, these data demonstrate that gastrin regulates HDC transcription in a Rafdependent, Ras-independent fashion predominantly through activation of the ERK-related pathway.
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PMID:Gastrin and phorbol 12-myristate 13-acetate regulate the human histidine decarboxylase promoter through Raf-dependent activation of extracellular signal-regulated kinase-related signaling pathways in gastric cancer cells. 934 Nov 40


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