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:3.4.11.18 (MAP)
7,412 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Renal nephron segments are heterogeneous, and receptors for endothelin (ET)-1, ET-3, Angiotensin II (AII), epidermal growth factor (EGF), and insulin-like growth factor I distribute differently along the nephron segments. Recently, growth factors and vasoactive substances are reported to stimulate mitogen-activated protein kinase (MAP-K). In this study, we showed that mRNA and proteins of MEK-K, Raf-1-K, MAPK-K, MAP-K (p42 and p44), and S6-K are expressed ubiquitously in intact nephron segment. We demonstrated that four tiers of a cascade composed of the Raf-1-K, MAP-K, MAP-K, and S6-K are stimulated by ET-1 and ET-3 in rat intact glomeruli (Glm) via primarily B-type ET receptors and PKC. The stimulatory effect of EGF and IGF-I to MAP-K activity is inhibited by a tyrosine kinase inhibitor in Glm. IGF-I significantly stimulates MAP-K activity and EGF and All moderately stimulate MAP-K activity in the proximal convoluted tubule (PCT). EGF significantly increased MAP-K cascades and ET-1 and ET-3 slightly increased MAP-K cascades in the medullary thick ascending limb (MTAL). EGF significantly stimulated MAP-K cascades, and ET-1 and ET-3 moderately stimulate MAP-K cascades in the outer medullary collecting duct (OMCD) and the inner medullary collecting duct (IMCD). MAPK-K and S6-K are similarly stimulated by these agonists in each segment. This study shows that MAP-K cascades are expressed in every nephron segment. ET-1, ET-3, All, EGF, and IGF-I stimulate MAP-K cascades heterogeneously along the nephron segment. It was concluded that MAP-K cascades play an important role in the regulation of renal function.
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PMID:Presence and regulation of Raf-1-K (Kinase), MAPK-K, MAP-K, and S6-K in rat nephron segments. 874 82

Simian virus 40 (SV40) binding to growth-arrested cells activated an intracellular signalling pathway that induced the up-regulation of the primary response genes c-myc, c-jun and c-sis within 30 min and of JE within 90 min. The up-regulation of the primary response genes occurred in the presence of cycloheximide and when UV-inactivated SV40 was adsorbed to cells. SV40 binding did not activate Raf or mitogen-activated protein kinase (MAP/ERK1), or mobilize intracellular Ca2+. The SV40-induced up-regulation of c-myc and c-jun was blocked by the tyrosine kinase inhibitor, genistein, and by the protein kinase C (PKC) inhibitor, calphostin C, but not by expression of the MAP kinase-specific phosphatase, MKP-1. These results suggest that the SV40-induced signalling pathway includes the activities of a tyrosine kinase and a Ca(2+)-independent isoform of PKC, but not of Raf or MAP kinase. Finally, SV40 infectious entry into cells was specifically and reversibly blocked by genistein.
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PMID:Extracellular simian virus 40 induces an ERK/MAP kinase-independent signalling pathway that activates primary response genes and promotes virus entry. 881 Oct 17

Although the ability of growth hormone (GH) to stimulate body growth and regulate metabolism has been recognized for many years, only recently has insight been gained into the molecular mechanisms by which binding of GH to its receptor (GHR) elicits its diverse effects. This review provides an overview of what is currently known about the molecular mechanisms of GH action. The model presented is one in which GH binding to two GHRs causes dimerization of GHR, activation of the GHR-associated JAK2 tyrosine kinase, and tyrosyl phosphorylation of both JAK2 and GHR. These events recruit and/or activate a variety of signaling molecules, including MAP kinases, insulin receptor substrates, phosphatidylinositol 3' phosphate kinase, diacylglycerol, protein kinase C, intracellular calcium, and Stat transcription factors. These signaling molecules contribute to the GH-induced changes in enzymatic activity, transport function, and gene expression that ultimately culminate in changes in growth and metabolism.
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PMID:Molecular mechanism of growth hormone action. 881 91

Ganglioside GM3 is a membrane component that has been described to modulate cell growth through inhibition of EGF receptor associated tyrosine kinase. In order to determine if the inhibition of cell growth by this ganglioside is specifically mediated through EGF receptor signaling, the effects of GM3 on key enzymes implicated in EGF signaling were determined and compared to another inhibitor of the EGF receptor kinase. Treatment of A1S cells in culture by GM3 or a tyrosine kinase inhibitor, leflunomide, led to the inhibition of MAP kinase and PI3 kinase activities. There was no detectable effect on phosphotyrosine phosphatases. In a cell free system, however, GM3 had no effect on the activity of these signaling intermediates. Leflunomide was able to directly inhibit MAP kinase activity. GM3 and leflunomide were also found to act differently on the expression of the early immediate genes. The expression of c-fos and c-jun was inhibited by both GM3 and leflunomide. The expression of c-myc, however, was only inhibited by leflunomide. These findings suggest that the action of GM3 on cell growth and signaling is specifically mediated by EGF receptor and that this ganglioside does not act directly on the intracellular intermediates of EGF receptor signaling. In addition, soluble small molecule tyrosine kinase inhibitors such as leflunomide can directly affect the activity of MAP kinases and possibly other signaling intermediates. The direct effects of leflunomide on signaling intermediates may explain the differential effects of leflunomide and GM3 on gene expression and cell growth.
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PMID:Ganglioside GM3 inhibition of EGF receptor mediated signal transduction. 884 3

Basic fibroblast growth factor (bFGF) is a potent mitogen for bone. In this study, we utilized the clonal rat osteoblastic cell line, Py1a, to examine signal transduction by bFGF and to determine the role of mitogen activated protein kinases (MAPK) and induction of c-fos mRNA in the mitogenic response to bFGF. Stimulation of [3H]thymidine incorporation (TDR) into DNA by bFGF was determined in the presence of phorbol myristate acetate of (PMA) to down-regulate the protein kinase C (PKC) pathway, genistein, an inhibitor of tyrosine kinase and H-7, a PKC inhibitor, bFGF 10(-8) M and PMA 10(-7) M increased TDR by 242 and 245%, respectively. Treatment with bFGF or PMA for 5 or 30 minutes increased tyrosine phosphorylation of multiple proteins, and immunoblotting with MAPK-specific antibody revealed that two of these bands were the 42 and 44 kD isoforms of MAPK. PMA and bFGF induced c-fos mRNA expression at 30 minutes. Genistein at 10 micrograms/ml blocked the mitogenic effect of bFGF and partially inhibited the mitogenic effect of PMA. Genistein at 100 micrograms/ml also blocked both bFGF- and PMA-induced increases in c-fos mRNA. A 24 h pretreatment with PMA at 10(-7) M inhibited the mitogenic response, tyrosine phosphorylation of MAPK, and induction of c-fos mRNA subsequent to the addition of PMA, but not bFGF. H-7 at 50 microM blocked bFGF-induced mitogenesis and c-fos induction, but did not inhibit bFGF-induced tyrosine phosphorylation of MAPK. In this study, we show that the signaling pathway of bFGF and PMA are similar in that they both induce tyrosine phosphorylation of MAP kinases and activate c-fos. However, the signaling pathways ultimately diverge in that once the PKC pathway is down-regulated by PMA pretreatment or blocked by the PKC inhibitor H-7, tyrosine phosphorylation of MAP kinase, c-fos induction, and the mitogenic effect of PMA is blocked. In contrast, down-regulation of the PKC pathway inhibits c-fos and the mitogenic response to bFGF, but not bFGF's effects on tyrosine phosphorylation of MAP kinase.
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PMID:Signal transduction by basic fibroblast growth factor in rat osteoblastic Py1a cells. 886

The addition of platelet-activating factor (PAF) to human neutrophils increases phosphorylation on tyrosine residues and stimulates the activity of p42erk2 mitogen-activated protein kinase (MAP kinase). This action is rapid and transient. In contrast, p42erk2, p44erk1 and the p40hera MAP kinase isoforms are all not tyrosine phosphorylated or activated in human neutrophils stimulated with low concentrations of lipopolysaccharide (LPS) in combination with serum. In spite of this, the PAF-induced tyrosine phosphorylation and activation of the p42erk2 MAP kinase are greatly potentiated in cells pretreated with LPS. More interestingly, although low concentrations of LPS do not affect MAP kinase isoforms in these cells, they cause the phosphorylation of cytosolic phospholipase A2 (cPLA2), as evidenced by a decrease in the electrophoretic mobility of the enzyme. In addition, this stimulus-induced upward shift in the mobility of the enzyme is not inhibited by the tyrosine kinase inhibitor, genistein. Furthermore, LPS increases the release of arachidonic acid in control and PAF-stimulated human neutrophils. These observations clearly show that cPLA2 can be phosphorylated and activated by kinases other than the currently known MAP kinases. It is proposed that there are MAP kinase-dependent and -independent mechanisms for the phosphorylation of cPLA2.
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PMID:Effect of lipopolysaccharide on mitogen-activated protein kinases and cytosolic phospholipase A2. 894 37

GH has long been known as a regulator of body growth and metabolism, yet its mechanism of action at the cellular level has been elusive. We have recently shown that GH promotes the rapid association of GH receptor with the tyrosine kinase JAK2, activates JAK2, and promotes the tyrosyl phosphorylation of both JAK2 and GH receptor. This suggests that the initial signalling event in GH action is the activation of JAK2 which in turn phosphorylates tyrosines within JAK2 and GH receptor. We have identified a number of proteins that appear to bind to these phosphotyrosines in GH receptor/ JAK2 complexes. These proteins in turn become phosphorylated on tyrosines, resulting in their activation. These proteins include: 1) the signal transducers and activators of transcriptions (Stats) 1, 3 and 5 which have been implicated as regulators of transcription of a variety of genes; 2) the insulin receptor substrates (IRS) 1 and 2, which are believed to mediate some of the metabolic effects of GH; and 3) Shc proteins which lie upstream of Ras and the mitogen activator kinases (MAP) designated ERKs 1 and 2, proteins implicated in the regulation of cellular growth and/or differentiation. These various proteins work in concert with each other and with other signalling molecules to elicit the diverse effects of GH. Other hormones and growth factors also activate JAK kinases. Specificity in signalling was investigated by determining whether signalling pathways for particular ligands may be selectively inhibited by hormones or growth factors. Glucocorticoids were found to selectively decrease binding and cellular signalling in response to GH. This decrease appeared to be due to a decrease in the number of GH receptors in the plasma membrane. Using truncated and mutated GHR, two regions of the GH receptor were identified required for the inhibitory effect of glucocorticoids. Interestingly, they appeared to differ from the region required for GH-induced internalization. Hence, a large amount of insight into signalling by GH has been obtained during the 3 years since JAK2 was identified as a signalling molecule for GH and other ligands that bind to members of the cytokine receptor family. This new insight, and the insight that will continue to be gained in the next few years should enable the design of new and better therapeutic uses of GH and the other ligands that bind to JAK kinase-linked receptors.
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PMID:Signalling pathway of GH. 907 44

Fluoride is an acknowledged bone-forming agent that may act through stimulation of osteoblast proliferation. Fluoride's action on osteoblasts and bone is potentiated by aluminum, which can form a complex with fluoride (fluoroaluminate) and activate heterotrimeric G proteins. Here we examined signaling pathways activated by fluoroaluminate in MC3T3-E1 osteoblastic and in NIH3T3 fibroblastic cells. In MC3T3-E1 cells, fluoroaluminate induced a decrease in cAMP levels and an increase in MAP and p70 S6 kinase phosphorylations. These responses were partially or completely prevented by pertussis toxin, an inhibitor of G alpha i proteins. In NIH3T3 cells, fluoroaluminate induced weaker tyrosine and MAP kinase phosphorylations. Fluoroaluminate, but not PDGF, induced a long-lasting tyrosine phosphorylation of a 130 kDa protein only in MC3T3-E1 cells. The expression of G alpha i2, but not of G alpha s and G alpha q/11 proteins was about 10-fold higher in MC3T3-E1 cells. Thus, different signaling in osteoblastic and fibroblastic cells may be due to differential expression of G alpha i proteins and tyrosine kinase substrates and could underlie fluoride's pharmacological action in bone.
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PMID:Fluoroaluminate induces pertussis toxin-sensitive protein phosphorylation: differences in MC3T3-E1 osteoblastic and NIH3T3 fibroblastic cells. 920 19

We observed a contractile action of ethanol (20-500 mM) and other alcohols (methanol and propanol, but not butanol) in guinea pig gastric longitudinal (LM) and circular (CM) smooth muscle preparations. The potency order for the alcohols in the LM preparation was: ethanol = propanol > methanol; and in the CM preparation, propanol > ethanol > methanol. Like epidermal growth factor-urogastrone (EGF), the contractile actions of ethanol in the LM and CM preparations required extracellular calcium and were blocked by the tyrosine kinase inhibitors, genistein and tyrphostin-47 (AG213). The tyrosine phosphatase inhibitor, pervanadate, potentiated the contractile action of ethanol in the LM preparation. Ethanol-induced contractions in both preparations were not affected by 4-methyl pyrazole, an inhibitor of alcohol dehydrogenase, and were unaffected by tetrodotoxin, atropine, prazosine or yohimbine. In the LM preparation, like EGF, the contractile action of ethanol was blocked by the cyclooxygenase inhibitor, indomethacin, and the diacylglycerol lipase inhibitor, U57,908; in the CM preparation, contractions caused by ethanol and EGF were still observed in the presence of these two inhibitors. Contractions caused by ethanol and EGF in the LM preparation were not affected by the epoxygenase inhibitor, ketoconazole; the lipoxygenase inhibitor, nordihydroguaiaretic acid; or the phospholipase A2 inhibitor, mepacrine. In contrast, in the LM preparation, EGF-induced contractions were attentuated by the EGF receptor-kinase inhibitor, PD153035; the MAP-kinase-kinase (MEK) inhibitor, PD98059; the kinase C inhibitor, GF109203X; and the phosphatidylinositol 3'-kinase inhibitors, Wortmannin and LY294002; whereas ethanol-induced contractions were unaffected by these inhibitors. Both ethanol and EGF caused small increases in the phosphotyrosyl protein content of the gastric tissue. We conclude that ethanol causes its contractile effects in the distinct gastric LM and CM preparations independent of nerve-released agonists and via a tyrosine kinase inhibitor-sensitive signal pathway that is in many respects similar to, but distinct from the one activated by EGF.
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PMID:Contractile action of ethanol in guinea pig gastric smooth muscle: inhibition by tyrosine kinase inhibitors and comparison with the contractile action of epidermal growth factor-urogastrone. 922 91

Receptors on macrophages for the Fc region of IgG (FcgammaR) mediate a number of responses important for host immunity. Signaling events necessary for these responses are likely initiated by the activation of Src-family and Syk-family tyrosine kinases after FcgammaR cross-linking. Macrophages derived from Syk-deficient (Syk-) mice were defective in phagocytosis of particles bound by FcgammaRs, as well as in many FcgammaR-induced signaling events, including tyrosine phosphorylation of a number of cellular substrates and activation of MAP kinases. In contrast, Syk- macrophages exhibited normal responses to another potent macrophage stimulus, lipopolysaccharide. Phagocytosis of latex beads and Escherichia coli bacteria was also not affected. Syk- macrophages exhibited formation of polymerized actin structures opposing particles bound to the cells by FcgammaRs (actin cups), but failed to proceed to internalization. Interestingly, inhibitors of phosphatidylinositol 3-kinase also blocked FcgammaR-mediated phagocytosis at this stage. Thus, PI 3-kinase may participate in a Syk-dependent signaling pathway critical for FcgammaR-mediated phagocytosis. Macrophages derived from mice deficient for the three members of the Src-family of kinases expressed in these cells, Hck, Fgr, and Lyn, exhibited poor Syk activation upon FcgammaR engagement, accompanied by a delay in FcgammaR-mediated phagocytosis. These observations demonstrate that Syk is critical for FcgammaR-mediated phagocytosis, as well as for signal transduction in macrophages. Additionally, our findings provide evidence to support a model of sequential tyrosine kinase activation by FcgammaR's analogous to models of signaling by the B and T cell antigen receptors.
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PMID:A critical role for Syk in signal transduction and phagocytosis mediated by Fcgamma receptors on macrophages. 931 52


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