Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: UNIPROT:P51812 (mitogen-activated protein)
 10,636 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Previous studies have shown that exogenously generated nitric oxide (NO) inhibits smooth muscle cell proliferation. In the present study, we stimulated rabbit vascular smooth muscle cells (RVSMC) with E. coli lipopolysaccharide (LPS), a known inducer of NO synthase transcription, and established a connection between endogenous NO, phosphorylation/dephosphorylation-mediated signaling pathways, and DNA synthesis. Non-confluent RVSMC were cultured with 0, 5, 10, or 100 ng/ml of the endotoxin. NO release was increased by 86.6% (maximum effect) in low-density cell cultures stimulated with 10 ng/ml LPS as compared to non-stimulated controls. Conversely, LPS (5 to 100 ng/ml) did not lead to enhanced NO production in multilayered (high density) RVSMC. DNA synthesis measured by thymidine incorporation showed that LPS was mitogenic only to non-confluent RVSMC; furthermore, the effect was prevented statistically by aminoguanidine (AG), a potent inhibitor of the inducible NO synthase, and oxyhemoglobin, an NO scavenger. Finally, there was a cell density-dependent LPS effect on protein tyrosine phosphatase (PTP) and ERK1/ERK2 mitogen-activated protein (MAP) kinase activities. Short-term transient stimulation of ERK1/ERK2 MAP kinases was maximal at 12 min in non-confluent RVSMC and was prevented by preincubation with AG, whereas PTP activities were inhibited in these cells after 24-h LPS stimulation. Conversely, no significant LPS-mediated changes in kinase or phosphatase activities were observed in high-density cells. LPS-induced NO generation by RVSMC may switch on a cell density-dependent proliferative signaling cascade, which involves the participation of PTP and the ERK1/ERK2 MAP kinases.
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PMID:Effects of lipopolysaccharide on low- and high-density cultured rabbit vascular smooth muscle cells: differential modulation of nitric oxide release, ERK1/ERK2 MAP kinase activity, protein tyrosine phosphatase activity, and DNA synthesis. 1184 21

Low-molecular-weight protein tyrosine phosphatase (LMW-PTP) has been implicated in the regulation of cell growth and actin rearrangement mediated by several receptor tyrosine kinases, including platelet-derived growth factor and epidermal growth factor. Here we identify the Xenopus laevis homolog of LMW-PTP1 (XLPTP1) as an additional positive regulator in the fibroblast growth factor (FGF) signaling pathway during Xenopus development. XLPTP1 has an expression pattern that displays substantial overlap with FGF receptor 1 (FGFR1) during Xenopus development. Using morpholino antisense technology, we show that inhibition of endogenous XLPTP1 expression dramatically restricts anterior and posterior structure development and inhibits mesoderm formation. In ectodermal explants, loss of XLPTP1 expression dramatically blocks the induction of the early mesoderm gene, Xbrachyury (Xbra), by FGF and partially blocks Xbra induction by Activin. Moreover, FGF-induced activation of mitogen-activated protein (MAP) kinase is also inhibited by XLPTP1 morpholino antisense oligonucleotides; however, introduction of RNA encoding XLPTP1 is able to rescue morphological and biochemical effects of antisense inhibition. Inhibition of FGF-induced MAP kinase activity due to loss of XLPTP1 is also rescued by an active Ras, implying that XLPTP1 may act upstream of or parallel to Ras. Finally, XLPTP1 physically associates only with an activated FGFR1, and this interaction requires the presence of SNT1/FRS-2 (FGFR substrate 2). Although LMW-PTP1 has been shown to participate in other receptor systems, the data presented here also reveal XLPTP1 as a new and important component of the FGF signaling pathway.
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PMID:Low-molecular-weight protein tyrosine phosphatase is a positive component of the fibroblast growth factor receptor signaling pathway. 1197 72

CD45 plays a critical regulatory role in receptor signaling through its protein tyrosine phosphatase and Janus kinase (JAK) phosphatase activities. To investigate whether CD45 also plays a regulatory role in Ig class switching in human B cells, we examined the effects of CD45 triggering on Ig class switching to IgE and its relationship with CD45 JAK phosphatase activity. Anti-CD45 triggering of CD45 significantly inhibited interleukin-4 + anti-CD40-induced switch recombination in a switch recombination vector assay in stably transfected Ramos 2G6 human B cells, as well as Ig epsilon germ-line transcription and Smu-Sepsilon switch recombination in primary human B cells. These negative regulatory effects on Ig class switching were concomitant with the ability of CD45 to dephosphorylate the induced phosphorylation of JAK1, JAK3, and signal transducer and activator of transcription 6, but not on stress-activated/mitogen-activated protein kinases. We also showed that phosphorylated JAK1 and JAK3 were directly dephosphorylated by recombinant CD45 in vitro. These results indicate that CD45 is able to function as JAK phosphatase in human B cells and that this activity is directly associated with the negative regulation of the class switch recombination to IgE. CD45 may be an appropriate target drug for modulating IgE in allergic diseases.
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PMID:CD45 controls interleukin-4-mediated IgE class switch recombination in human B cells through its function as a Janus kinase phosphatase. 1199 88

Murine Sprouty2 (mSpry2) is a conserved ortholog of Drosophila Sprouty, a gene that inhibits several tyrosine kinase receptor pathways, resulting in net reduction of mitogen-activated protein (MAP) kinase activation. However, the precise mechanism mediating mSpry2 function as a negative regulator in tyrosine kinase growth factor pathways that regulate diverse biological functions remains incompletely characterized. Fibroblast growth factor 10 (FGF10) is a key positive regulator of lung branching morphogenesis and induces epithelial expression of mSpry2 adjacent to mesenchymal sites of FGF10. Herein, we demonstrate that FGF10 stimulation of mouse lung epithelial cells (MLE15) overexpressing mSpry2 results in both mSpry2 tyrosine phosphorylation and differential binding of mSpry2 to several key upstream target proteins in the MAP kinase-activating pathway. Thus FGF receptor (FGFR) activation results in increased association of mSpry2 with growth factor receptor-binding protein 2, suc-1-associated nuerotrophic factor target 2, and Raf but decreased binding to protein tyrosine phosphatase 2 and GTPase-activating protein 1, resulting in a net reduction of MAP kinase activation. mSpry2 also spatially translocates to the plasma membrane and intracellular membrane structures in response to FGF10 stimulation. Our data demonstrate novel intracellular mechanisms mediating mSpry2 function as a negative regulator of uncontrolled FGF-induced MAP kinase signaling.
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PMID:mSprouty2 inhibits FGF10-activated MAP kinase by differentially binding to upstream target proteins. 1222 46

The expression and secretion of prostate-specific antigen (PSA) are regulated by androgens in normal prostate secretory epithelial cells. In prostate cancer patients, the serum PSA level is usually elevated and cancer cells are initially responsive to androgens. However, those cancer cells become androgen-independent after androgen ablation therapy. In hormone-refractory cancer patients, even in an androgen-deprived environment, the circulation level of PSA rebounds and is constitutively elevated through a yet unknown mechanism. Tyrosine phosphorylation of ErbB-2 is involved in regulating the androgen-responsive phenotype of prostate cancer cells, and it is at least partly regulated by the cellular form of prostatic acid phosphatase (PAcP), a prostate-unique protein tyrosine phosphatase. We investigated the ErbB-2 signal pathway in androgen-independent PSA secretion. LNCaP C-81 cells, which are androgen-independent LNCaP cells lacking endogenous PAcP expression with a hypertyrosine phosphorylated ErbB-2, secreted a higher level of PSA in conditioned media than did androgen-sensitive LNCaP C-33 parental cells. A restored expression of cellular PAcP in C-81 cells was concurrent with a decrease in tyrophosphorylation of ErbB-2 and reduction of PSA secretion. Moreover, transient transfection of C-33 cells with the wild-type ErbB-2 or a constitutively active mutant of MEK1 cDNA resulted in an increased level of secreted PSA. The elevation of secreted PSA level by the forced expression of ErbB-2 was inhibited by an MEK inhibitor, PD98059. In C-81 cells, the expression of a dominant negative mutant of ErbB-2 reduced the secreted level of PSA. The inhibition of ErbB-2 or mitogen-activated protein (MAP) kinases by specific inhibitors AG879, AG825, or PD98059 led to a decrease in PSA secretion. Taken together, our data clearly indicate that the ErbB-2 signal pathway via MAP kinases (ERK1/2) is involved in regulating the secretion of PSA by androgen-independent human prostate cancer LNCaP C-81 cells in an androgen-depleted environment.
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PMID:ErbB-2 signaling is involved in regulating PSA secretion in androgen-independent human prostate cancer LNCaP C-81 cells. 1256 72

Glutathione S-transferase pi (GSTpi; EC 2.5.1.18) has been shown recently to be a regulator of mitogen-activated protein kinases (MAPK). We have developed, by chronic exposure of HL60 cells to increasing concentrations of a peptidomimetic GSTpi inhibitor TLK199, a 10-fold resistant cell line (HL60/TLK199). Among the cellular adaptations observed in this cell line was an increase in extracellular signal-regulated kinase (ERK) activity without modification of basal expression levels. Phorbol 12-myristate 13-acetate (PMA) induced monocyte/macrophage cytodifferentiation in both HL60 wild-type (WT) and HL60/TLK199 cells. In contrast, PMA induced a pronounced cell growth inhibition and G(0)/G(1) cell cycle arrest in HL60 WT cells, while this differentiating agent had only a mild effect on cell growth without G(0)/G(1) cell cycle arrest in HL60/TLK199. This effect was associated with a rapid and sustained activation of ERK (up to 6hr) in HL60 WT cells but only a transient induction of these kinases (between 30 and 60min) in HL60/TLK199. Furthermore, treatment of both cell lines with PMA in combination with the protein tyrosine phosphatase inhibitors sodium orthovanadate (OV) or 3,4-dephostatin (DPN) circumvented the resistance to cell growth arrest and potentiated differentiation in HL60/TLK199 but had no effect on HL60 WT cells. The circumvention of the resistance to PMA was associated with a sustained activation of ERK. These data suggest that chronic exposure of HL60 cells to TLK199 alters cellular ERK activation by PMA, which may contribute to the differential response of the WT and resistant cells to PMA.
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PMID:Resistance to phorbol 12-myristate 13-acetate-induced cell growth arrest in an HL60 cell line chronically exposed to a glutathione S-transferase pi inhibitor. 1275 97

1. The Src homology protein tyrosine phosphatase SHP2 is associated with cytoskeletal maintenance, cell division, and cell differentiation, but the role of SHP2 during central nervous system injury requires further definition. We therefore characterized the role of SHP2 during nitric oxide (NO)-induced programmed cell death (PCD). 2. Employing primary hippocampal neurons from mice with a dominant negative SHP2 mutant to render the phosphatase site of the SHP2 protein biologically inactive, but functionally capable of binding substrate, neuronal injury was evaluated by trypan blue, DNA fragmentation, membrane phosphatidyl serine (PS) exposure, mitogen-activated protein (MAP) kinase phosphorylation, and cysteine protease activity. NO was administered through the NO generators SIN-1 (300 microM) or NOC-9 (300 microM). 3. Following NO exposure, neuronal survival decreased from 89 +/- 3% in untreated controls to 37 +/- 2% in wild-type neurons and to 21 +/- 4% in SHP2 mutant neurons. In sister cultures following NO exposure, this increased susceptibility to neuronal injury paralleled enhanced genomic DNA degradation and membrane PS exposure with PCD induction increasing in SHP2 mutant neurons by approximately 42% during specified time periods when compared to wild-type neurons. Interestingly, modulation of the MAP kinase p38 appears to represent an initial level of neuronal protection employed by SHP2. In addition, both the rate and degree of caspase 1- and caspase 3-like activities in SHP2 mutant neurons were significantly increased over a 24-h course when compared to wild-type neurons. Inhibition of caspase 1- and caspase 3-like activities reversed the progression of neuronal PCD, suggesting that inhibition of cysteine protease activity is a downstream mechanism for SHP2 to afford neuronal protection. 4. Our work supports the premise that the tyrosine phosphatase SHP2 plays a dominant role during NO-induced PCD and may offer a potential molecular "checkpoint" against neurodegenerative disease.
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PMID:The tyrosine phosphatase SHP2 modulates MAP kinase p38 and caspase 1 and 3 to foster neuronal survival. 1451 16

We investigated the role of SH2 domain containing protein tyrosine phosphatase (SHP) 2 in Concanavalin A (Con A) -dependent signaling that leads to the augmented secretion and activation of matrix metalloproteinase (MMP) 2. In cells expressing mutant SHP-2 in which 65 amino acids in the SH2-N domain were deleted, we found that production, secretion, and proteolytic activation of MMP-2 in response to Con A treatment was severely impaired. Under Con A stimulation, complex formation of SHP-2 with SOS-1 and Grb-2 together with the activation of Ras signaling was clearly observed in wild-type cells, but not in SHP-2 mutant cells. In wild-type cells, Con A-treatment activated dual signaling pathways, extracellular signal-regulated kinase (Erk) and p38, in a Ras-dependent manner, whereas Con A-dependent activation of these signaling pathways was absent in SHP-2 mutant cells. In addition, pretreatment of wild-type cells with U0126, a potent inhibitor for mitogen-activated protein/ERK kinase 1, or with SB203580, a specific inhibitor for p38, significantly inhibited the Con A-dependent secretion and activation of MMP-2. However, overexpression of active mitogen-activated protein/ERK kinase 1 in SHP-2 mutant cells could not induce clear activation of MMP-2 secretion, although these cells responded well to the Con A treatment in a p38-dependent manner. Finally, reintroduction of wild-type SHP-2 into SHP-2 mutant cells rescued Erk and p38 activation, and also MMP-2 secretion, whereas dominant-negative SHP-2 could block the Con A-dependent activation of Erk and p38. Taken together, our results strongly suggest that SHP-2 plays a critical role as a positive mediator for Con A-dependent activation of MMP-2 secretion via Ras-Erk and Ras-p38 signalings.
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PMID:SH2 domain containing protein tyrosine phosphatase 2 regulates concanavalin A-dependent secretion and activation of matrix metalloproteinase 2 via the extracellular signal-regulated kinase and p38 pathways. 1455 21

The HePTP (haematopoietic protein tyrosine phosphatase) is a negative regulator of the ERK2 (extracellular signal-regulated protein kinase 2) and p38 MAP kinases (mitogen-activated protein kinases) in T-cells. This inhibitory function requires a physical association of HePTP through an N-terminal KIM (kinase-interaction motif) with ERK and p38. We previously reported that PKA (cAMP-dependent protein kinase) phosphorylates Ser-23 within the KIM of HePTP, resulting in dissociation of HePTP from ERK2. Here we follow the phosphorylation of this site in intact T-cells. We find that HePTP is phosphorylated at Ser-23 in resting T-cells and that this phosphorylation increases upon treatment of the cells with agents that elevate intracellular cAMP, such as prostaglandin E2. HePTP phosphorylation occurred at discrete regions at the cell surface. Phosphorylation was reduced by inhibitors of PKA and increased by inhibitors of protein phosphatases PP1 and PP2A, but not by inhibitors of calcineurin. In vitro, PP1 efficiently dephosphorylated HePTP at Ser-23, while PP2A was much less efficient. Activation of PP1 by treatment of the cells with ceramide suppressed Ser-23 phosphorylation, as did transfection of the catalytic subunit of PP1. Phosphorylation at Ser-23 is also increased in a transient manner upon T-cell antigen receptor ligation. In contrast, treatment of cells with phorbol ester had no effect on HePTP phosphorylation at Ser-23. We conclude from these results that HePTP is under continuous control by PKA and a serine-specific phosphatase, probably PP1, in T-cells and that this basal phosphorylation at Ser-23 can rapidly change in response to external stimuli. This, in turn, will affect the ability of HePTP to inhibit the ERK and p38 MAP kinases.
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PMID:Haematopoietic protein tyrosine phosphatase (HePTP) phosphorylation by cAMP-dependent protein kinase in T-cells: dynamics and subcellular location. 1461 83

We used the patch-clamp technique to study the effect of insulin-like growth factor I (IGF-I) on the apical 70-pS K channel in the isolated thick ascending limb (TAL) of the rat kidney. The isolated TAL was cut open to gain access to the apical membrane. Addition of 25 nM IGF-I stimulates the apical 70-pS K channel and increases channel activity, defined by the product of channel open probability and channel number, from 0.31 to 1.21. The stimulatory effect of IGF-I is not mediated by nitric oxide- or protein tyrosine phosphatase-dependent mechanisms, because inhibition of nitric oxide synthase or blocking protein tyrosine phosphatase did not abolish the stimulatory effect of IGF-I on the 70-pS K channel. In contrast, inhibition of mitogen-activated protein (MAP) kinase with PD-98059 or U0126 abolished the stimulatory effect of IGF-I. This suggests that MAP kinase is responsible for mediating the effect of IGF-I on the apical K channels. Moreover, the effect of IGF-I on the apical 70-pS K channel is biphasic because high concentrations (>200 nM) inhibit apical 70-pS K channels. Application of 400 nM IGF-I decreased channel activity from 1.45 to 0.2. The inhibitory effect of IGF-I is not blocked by calphostin C (an inhibitor of PKC), but inhibition of protein tyrosine kinase with herbimycin A abolished the IGF-induced inhibition. We conclude that IGF-I has a dual effect on the apical 70-pS K channel in the TAL: low concentrations of IGF-I stimulate, whereas high concentrations inhibit the channel activity. The stimulatory effect of IGF-I is mediated by a MAP kinase-dependent pathway, whereas the inhibitory effect is the result of stimulation of protein tyrosine kinase.
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PMID:Dual effect of insulin-like growth factor on the apical 70-pS K channel in the thick ascending limb of rat kidney. 1515 16


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