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)

Protein tyrosine phosphatases (PTPs) have key roles in a diverse range of cellular processes, and their dysregulation is associated with several human diseases. Many PTPs are recognized as potential drug targets; however, inhibitor development has focused only on a small number of enzymes, most notably PTP1B for type II diabetes and obesity, and MKP1 and CDC25 for cancer. The future challenge of selective-inhibitor development for PTPs will be significantly facilitated by the recent rapid progress in the structural biology of the 'PTPome'. In this article, we focus on the family of mitogen-activated protein kinase (MAPK)-specific tyrosine phosphatases--PTPN5 [also called striatal-enriched phosphatase (STEP)], PTPN7 (also called hematopoietic PTP) and PTPRR (also called PC12 PTP or STEP-like PTP)--and discuss approaches for achieving selectivity for the MAPK-PTPs at the molecular level using recently determined high-resolution X-ray crystal structures. We believe that the development of specific inhibitors would provide a valuable set of experimental pharmacological tools for investigating the physiological role of these phosphatases and exploring their emerging role in human disease.
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PMID:MAPK-specific tyrosine phosphatases: new targets for drug discovery? 1691 85

Human JNK stimulatory phosphatase-1 (JSP-1) is a novel member of dual specificity phosphatases. A C-terminus truncated JSP-1 was expressed in Escherichia coli and was crystallized using the sitting-drop vapor diffusion method. Thin-plate crystals obtained at 278 K belong to a monoclinic space group, C2, with unit-cell parameters a = 84.0 A, b = 49.3 A, c = 47.3 A, and beta = 119.5 degrees , and diffract up to 1.5 A resolution at 100 K. The structure of JSP-1 has a single compact (alpha/beta) domain, which consists of six alpha-helices and five beta-strands, and shows a conserved structural scaffold in regard to both DSPs and PTPs. A cleft formed by a PTP-loop at the active site is very shallow, and is occupied by one sulfonate compound, MES, at the bottom. In the binary complex structure of JSP-1 with MES, the conformations of three important segments in regard to the catalytic mechanism are not similar to those in PTP1B. JSP-1 has no loop corresponding to the Lys120-loop of PTP1B, and tryptophan residue corresponding to the substrate-stacking in PTP1B is substituted by alanine residue in JSP-1.
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PMID:Crystal structure of human dual specificity phosphatase, JNK stimulatory phosphatase-1, at 1.5 A resolution. 1706 12

The protein-tyrosine phosphatase 1B (PTP1B; PTPN1) is an important regulator of mammalian metabolism and also helps control signaling by growth factors, cytokines, and extracellular matrix. Gene knockout studies in mice established PTP1B as a key negative regulator of the insulin and leptin receptors. Experiments using PTP1B(-/-) fibroblast lines, dominant-negative mutants, or small interfering RNAs indicate that PTP1B contributes to dephosphorylation of the epidermal growth factor receptor and platelet-derived growth factor receptors as well. However, PTP1B also may have some positive (signal enhancing) roles downstream of some growth factor receptors and integrins. Previous studies indicated that PTP1B is overexpressed in a significant subset of breast and ovarian cancers, especially in those overexpressing HER2/Neu (HER2(+) tumors). However, experiments using tissue culture cells yield conflicting results on the effects of PTP1B in HER2 signaling, leaving the consequences of PTP1B overexpression for breast carcinogenesis unclear. To determine how PTP1B deficiency affects HER2-evoked breast tumorigenesis, we generated mouse mammary tumor virus (MMTV)-NeuNT transgenic mice lacking one or both alleles of PTP1B. Although heterozygous loss of PTP1B has no effect on tumorigenesis, homozygous PTP1B deficiency dramatically delays or prevents the onset of MMTV-NeuNT-evoked breast tumors. The effects of PTP1B deficiency correlate with defective extracellular signal-regulated kinase activation in preneoplastic mammary glands from compound mutant mice. In contrast, PTP1B deficiency has no effect on MMTV-polyoma middle T tumorigenesis. Our data raise the possibility that PTP1B inhibitors may be chemopreventative for some forms of breast cancer.
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PMID:Protein-tyrosine phosphatase 1B is required for HER2/Neu-induced breast cancer. 1734 13

Mitogen-activated protein kinase phosphatase 1 (MKP-1) is a tyrosine phosphatase superfamily member that dephosphorylates and inactivates cardinal mitogen-activated protein kinase (MAPK) substrates, such as p38, c-Jun NH(2)-terminal kinase, and extracellular signal-regulated kinase. Although these MAPK substrates regulate many essential cellular processes associated with human diseases, few pharmacological inhibitors have been described. The lack of readily available selective MKP-1 inhibitors has severely limited interrogation of its biological role and was one rationale for using a recently described tricyclic pyrrole-2-carboxamide library in our screening efforts. In this report we demonstrate the pharmacological richness of the pyrrole carboxamide library by the finding that 10 of 172 members inhibited human MKP-1. Two of the pyrrole carboxamides, PSI2106 and MDF2085, were especially notable in vitro inhibitors of recombinant human MKP-1 enzyme activity with IC(50) values of 8.0 +/- 0.9 and 8.3 +/- 0.8 microM, respectively. Both showed some selectivity for MKP-1 over the closely related phosphatases MKP-3, Cdc25B, VHR, and PTP1B. Computational examination of the surface properties near the catalytic site revealed that the phosphatases studied differ significantly in their electrostatic potential at the substrate binding site. The compounds inhibited MKP-1 reversibly but displayed mixed kinetics. Phosphatase inhibition was retained in the presence of physiologically relevant concentrations of glutathione. Molecular docking studies suggested that PSI2106 may interact with His(229) and Phe(299) on MKP-1. These results reveal the power of using a small focused library for identifying pharmacological probes.
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PMID:Structurally unique inhibitors of human mitogen-activated protein kinase phosphatase-1 identified in a pyrrole carboxamide library. 1753 6

Insulin resistance is an important contributor to the pathogenesis of type 2 diabetes, and obesity is a risk factor for its development, in part because adipose tissue secretes proteins, called adipokines, that may influence insulin sensitivity. Among these molecules, tumor necrosis factor (TNF)-alpha has been proposed as a link between obesity and insulin resistance because TNF-alpha is overexpressed in adipose tissues of obese animals and humans, and obese mice lacking either TNF-alpha or its receptor show protection against developing insulin resistance. Direct exposure to TNF-alpha induces a state of insulin resistance in terms of glucose uptake in myocytes and brown adipocytes because of the activation of proinflammatory pathways that impair insulin signaling at the level of the insulin receptor substrate (IRS) proteins. In this regard, the Ser(307) residue in IRS-1 has been identified as a site for the inhibitory effects of TNF-alpha in myotubes, with p38 mitogen-activated protein kinase and inhibitor kB kinase being involved in the phosphorylation of this residue. Conversely, Ser phosphorylation of IRS-2 mediated by TNF-alpha activation of mitogen-activated protein kinase was the mechanism found in brown adipocytes. Protein-Tyr phosphatase (PTP)1B acts as a physiological, negative regulator of insulin signaling by dephosphorylating the phosphotyrosine residues of the insulin receptor and IRS-1, and PTP1B expression is increased in muscle and white adipose tissue of obese and diabetic humans and rodents. Moreover, up-regulation of PTP1B expression was recently found in cells treated with TNF-alpha Accordingly, myocytes and primary brown adipocytes deficient in PTP1B are protected against insulin resistance induced by this cytokine. Furthermore, down-regulation of PTP1B activity is possible by the use of pharmacological agonists of nuclear receptors that restore insulin sensitivity in the presence of TNF-alpha. In conclusion, the lack of PTP1B in muscle and brown adipocytes increases insulin sensitivity and glucose uptake and could confer protection against insulin resistance induced by adipokines.
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PMID:Insulin resistance induced by tumor necrosis factor-alpha in myocytes and brown adipocytes. 1794 Jan 60

Sprouty (Spry) proteins modulate signal transduction pathways elicited by receptor tyrosine kinases (RTK). Depending on cell type and the particular RTK, Spry proteins exert dual functions: They can either repress RTK-mediated signaling pathways, mainly by interfering with the Ras/Raf/mitogen-activated protein kinase pathway or sustaining RTK signal transduction, for example by sequestering the E3 ubiquitin-ligase c-Cbl and thus preventing ubiquitylation, internalization, and degradation of RTKs. Here, by the inducible expression of murine Spry4 in pancreatic beta cells, we have assessed the functional role of Spry proteins in the development of pancreatic islets of Langerhans in normal mice and in the Rip1Tag2 transgenic mouse model of beta-cell carcinogenesis. beta cell-specific expression of mSpry4 provokes a significant reduction in islet size, an increased number of alpha cells per islet area, and impaired islet cell type segregation. Functional analysis of islet cell differentiation in cultured PANC-1 cells shows that mSpry4 represses adhesion and migration of differentiating pancreatic endocrine cells, most likely by affecting the subcellular localization of the protein tyrosine phosphatase PTP1B. In contrast, transgenic expression of mSpry4 during beta-cell carcinogenesis does not significantly affect tumor outgrowth and progression to tumor malignancy. Rather, tumor cells seem to escape mSpry4 transgene expression.
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PMID:Modulation of endocrine pancreas development but not beta-cell carcinogenesis by Sprouty4. 1833 53

Mesangioproliferative glomerulonephritis is associated with overactive PDGF receptor signal transduction. We show that the phytoalexin resveratrol dose dependently inhibits PDGF-induced DNA synthesis in mesangial cells with an IC(50) of 10 microM without inducing apoptosis. Remarkably, the increased SIRT1 deacetylase activity induced by resveratrol was not necessary for this inhibitory effect. Resveratrol significantly blocked PDGF-stimulated c-Src and Akt kinase activation, resulting in reduced cyclin D1 expression and attenuated pRb phosphorylation and cyclin-dependent kinase-2 (CDK2) activity. Furthermore, resveratrol inhibited PDGFR phosphorylation at the PI 3 kinase and Grb-2 binding sites tyrosine-751 and tyrosine-716, respectively. This deficiency in PDGFR phosphorylation resulted in significant inhibition of PI 3 kinase and Erk1/2 MAPK activity. Interestingly, resveratrol increased the activity of protein tyrosine phosphatase PTP1B, which dephosphorylates PDGF-stimulated phosphorylation at tyrosine-751 and tyrosine-716 on PDGFR with concomitant reduction in Akt and Erk1/2 kinase activity. PTP1B significantly inhibited PDGF-induced DNA synthesis without inducing apoptosis. These results for the first time provide evidence that the stilbene resveratrol targets PTP1B to inhibit PDGFR mitogenic signaling.
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PMID:Resveratrol inhibits PDGF receptor mitogenic signaling in mesangial cells: role of PTP1B. 1856 37

Adipose tissue secretes proteins which may influence insulin sensitivity. Among them, tumour necrosis factor (TNF)-alpha has been proposed as a link between obesity and insulin resistance because TNF-alpha is overexpressed in adipose tissue from obese animals and humans, and obese mice lacking either TNF-alpha or its receptor show protection against developing insulin resistance. The activation of proinflammatory pathways after exposure to TNF-alpha induces a state of insulin resistance in terms of glucose uptake in myocytes and adipocytes that impair insulin signalling at the level of the insulin receptor substrate (IRS) proteins. The mechanism found in brown adipocytes involves Ser phosphorylation of IRS-2 mediated by TNF-alpha activation of MAPKs. The Ser307 residue in IRS-1 has been identified as a site for the inhibitory effects of TNF-alpha in myotubes, with p38 mitogen-activated protein kinase (MAPK) and inhibitor kB kinase being involved in the phosphorylation of this residue. Moreover, up-regulation of protein-tyrosine phosphatase (PTP)1B expression was recently found in cells and animals treated with TNF-alpha. PTP1B acts as a physiological negative regulator of insulin signalling by dephosphorylating the phosphotyrosine residues of the insulin receptor and IRS-1, and PTP1B expression is increased in peripheral tissues from obese and diabetic humans and rodents. Accordingly, down-regulation of PTP1B activity by treatment with pharmacological agonists of nuclear receptors restores insulin sensitivity in the presence of TNF-alpha. Furthermore, mice and cells deficient in PTP1B are protected against insulin resistance induced by this cytokine. In conclusion, the absence or inhibition of PTP1B in insulin-target tissues could confer protection against insulin resistance induced by cytokines.
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PMID:Insulin resistance associated to obesity: the link TNF-alpha. 1862 84

Neurotrophins, such as the nerve growth factor (NGF), play an essential role in the growth, development, survival and functional maintenance of neurons in the central and peripheral systems. They also prevent neuronal cell death under various stressful conditions, such as ischemia and neurodegenerative disorders. NGF induces cell differentiation and neurite outgrowth by binding with and activating the NGF receptor tyrosine kinase followed by activation of a variety of signaling cascades. We have investigated the NGF-dependent neuritogenesis enhancer potential of a food-derived small molecule contained in Brassica vegetables and identified the protein tyrosine phosphatase (PTP) 1B as a key regulator of the NGF receptor-initiated signal transduction. Based on an extensive screening of Brassica vegetable extracts for the neuritogenic-promoting activity in the rat pheochromocytoma cell line PC12, we found the Japanese horseradish, wasabi (Wasabia japonica, syn. Eutrema wasabi), as the richest source and identified 6-methylsulfinylhexyl isothiocyanate (6-HITC), an analogue of sulforaphane isolated from broccoli, as one of the major neuritogenic enhancers in the wasabi. 6-HITC strongly enhanced the neurite outgrowth and neurofilament expression elicited by a low-concentration of NGF that alone was insufficient to induce neuronal differentiation. 6-HITC also facilitated the sustained-phosphorylation of the extracellular signal-regulated kinase and the autophosphorylation of the NGF receptor TrkA. It was found that PTP1B act as a phosphatase capable of dephosphorylating Tyr-490 of TrkA and was inactivated by 6-HITC in a redox-dependent manner. The identification of PTP1B as a regulator of NGF signaling may provide new clues about the chemoprotective potential of food components, such as isothiocyanates.
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PMID:A food-derived synergist of NGF signaling: identification of protein tyrosine phosphatase 1B as a key regulator of NGF receptor-initiated signal transduction. 1879 6

Hyperglycemia stimulates a plethora of intracellular signaling pathways within the cells of the vascular wall resulting in dysfunction-associated pathologies. Most of the studies reported so far explored the effect of rather short-time exposure of smooth muscle cells to high glucose concentrations. To mimic situation in Type 2 diabetes in which vascular wall is constantly exposed to circulating hyperglycemia, we report here the long-term (7days) effect of high glucose concentration on human media artery smooth muscle cells. This consists in up-regulation of PTP1B protein expression, down-regulation of basal Akt phosphorylation, and elevation of basal ERK1/2 activation. Acute stimulation of cells in high glucose with insulin down-regulated PTP1B expression, slightly decreased ERK1/2 activity, and activated Akt, whereas oxidative stress up-regulated Akt and ERK1/2 phosphorylation. In conclusion, long-term high glucose and acute oxidative stress and insulin stimulation imbalance the expression of activated kinases Akt and ERK1/2 and of dephosphorylating PTP1B in the insulin signaling pathway.
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PMID:Long-term high glucose concentration influences Akt, ERK1/2, and PTP1B protein expression in human aortic smooth muscle cells. 1964 19


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