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)

Reactive oxygen species (ROS) have been implicated in vascular smooth muscle cell (VSMC) apoptosis, a hallmark of advanced atherosclerotic lesions. Transient oxidation and inactivation of protein-tyrosine phosphatases play a critical role in cellular response to ROS production. However, the function of leukocyte antigen-related (LAR) protein-tyrosine phosphatase in ROS signaling is not known. To determine the expression of LAR in ROS-induced apoptosis, we investigated hydrogen peroxide-induced cell death and signaling in aortic VSMCs from wild-type and LAR(-/-) mice. Histone-associated DNA fragmentation and caspase-3/7 activity were significantly enhanced, mitochondrial membrane integrity was compromised, and cell viability was significantly decreased following H(2)O(2) treatment in LAR(-/-) VSMCs compared with wild-type cells. Stronger and sustained increase in autophosphorylation and activity of Fyn, an Src family tyrosine kinase, was observed in LAR(-/-) cells compared with wild-type cells following H(2)O(2) treatment. LAR binds to activated Fyn in H(2)O(2)-treated VSMCs, and recombinant LAR dephosphorylates phosphorylated-Fyn in vitro. In addition, LAR deficiency enhanced H(2)O(2)-induced phosphorylation of Janus kinase 2 (JAK2), signal transducer and activator of transcription 3 (STAT3), and p38 mitogen-activated protein kinase (MAPK). PP2, a Fyn-specific inhibitor, blocked JAK2, STAT3, and p38 MAPK activation and significantly attenuated apoptosis induced by H(2)O(2). AG490, a JAK2-specific inhibitor, significantly attenuated H(2)O(2)-induced apoptosis, and blocked H(2)O(2)-induced activation of STAT3, but not p38 MAPK in both wild-type and LAR(-/-) VSMCs. Attenuation of Fyn expression by short hairpin RNA significantly decreased H(2)O(2)-induced downstream signaling and apoptosis in VSMCs. Together, these data indicate that LAR regulates Fyn/JAK2/STAT3 and Fyn/p38 MAPK pathways involved in ROS-induced apoptosis.
 ...
PMID:Leukocyte antigen-related protein tyrosine phosphatase negatively regulates hydrogen peroxide-induced vascular smooth muscle cell apoptosis. 1885 10

TNF-alpha impairs endothelial cell growth and angiogenesis. The anti-angiogenic effects of TNF-alpha have mainly been explained by its modulating vascular endothelial growth factor (VEGF)-specific angiogenic pathway. Hepatocyte growth factor (HGF) also promotes the growth of vascular endothelial cells and the development of new blood vessels through interaction with its specific receptor, c-met. However, it is little known whether TNF-alpha interacts with the HGF system or not. In this study, we examined the effect of TNF-alpha on HGF receptor function. In human umbilical venous endothelial cells (HUVEC), TNF-alpha acutely inhibited the phosphorylation and activation of c-met induced by HGF. The ability of TNF-alpha to inhibit HGF-induced c-met activity was impaired by sodium orthovanadate, suggesting that the inhibitory effect of TNF-alpha was mediated by a protein-tyrosine phosphatase. Treatment of HUVEC with TNF-alpha impairs the ability of HGF to activate MAPK and Akt, and this effect was blocked by SOV. HGF-induced c-met responses specifically associated with endothelial cell proliferation and mitogen-activated protein kinase activation were also inhibited by TNF-alpha, and these were reversed by sodium orthovanadate. HGF-induced SHP-1 (a cytoplasmic protein-tyrosine phosphatase) and pretreatment of HUVEC with TNF-alpha prior to HGF treatment resulted in substantial increase in the amount of SHP-1. These data suggest that TNF-alpha employs a protein-tyrosine phosphatase and may exert its anti-angiogenic function in part by modulating the HGF-specific angiogenic pathway in pathological settings.
 ...
PMID:TNF-alpha employs a protein-tyrosine phosphatase to inhibit activation of hepatocyte growth factor receptor and hepatocyte growth factor-induced endothelial cell proliferation. 1900 56

The Leishmania parasite is a widespread disease threat in tropical areas, causing symptoms ranging from skin lesions to death. Leishmania parasites typically invade macrophages but are also capable of infecting fibroblasts, which may serve as a reservoir for recurrent infection. Invasion by intracellular pathogens often involves exploitation of the host cell cytoskeletal and signaling machinery. Here we have observed a dramatic rearrangement of the actin cytoskeleton and marked modifications in the profile of protein tyrosine phosphorylation in fibroblasts infected with Leishmania major. Correspondingly, exposure to L. major resulted in degradation of the phosphorylated adaptor protein p130Cas and the protein-tyrosine phosphatase-PEST. Cellular and in vitro assays using pharmacological protease inhibitors, recombinant enzyme, and genetically modified strains of L. major identified the parasite protease GP63 as the principal catalyst of proteolysis during infection. A number of additional signaling proteins were screened for degradation during L. major infection as follows: a small subset was cleaved, including cortactin, T-cell protein-tyrosine phosphatase, and caspase-3, but the majority remained unaffected. Protein degradation occurred in cells incubated with Leishmania extracts in the absence of intact parasites, suggesting a mechanism permitting transfer of functional GP63 into the intracellular space. Finally, we evaluated the impact of Leishmania on MAPK signaling; unlike p44/42 and JNK, p38 was inactivated upon infection in a GP63- and protein degradation-dependent manner, which likely involves cleavage of the upstream adaptor TAB1. Our results establish that GP63 plays a central role in a number of hostcell molecular events that likely contribute to the infectivity of Leishmania.
 ...
PMID:The Leishmania surface protease GP63 cleaves multiple intracellular proteins and actively participates in p38 mitogen-activated protein kinase inactivation. 1906 94

Emerging evidence indicates that aldosterone causes oxidative stress by stimulating proinflammatory/oxidative mediators, including nuclear factor-kappaB, activating protein (AP-1), and c-Jun N-terminal kinase. Thus, in insulin-resistant type 2 diabetes (T2D), oxidative stress generated by hyperglycemia and aldosterone would potentiate the oxidative destruction of tissue and important regulators of glucose metabolism like adiponectin and insulin. Although heme oxygenase (HO)-1 is cytoprotective, its effects on T2D have not been fully characterized. Here we report an enduring antidiabetic effect of the HO inducer, hemin, on Zucker diabetic-fatty rat (ZDF), a model of insulin-resistant T2D. Chronically applied hemin to ZDF reduced and maintained significantly low fasting and postprandial hyperglycemia for 4 months after therapy. The antidiabetic effect was accompanied by enhanced HO activity, catalase, cyclic GMP, bilirubin, ferritin, total antioxidant capacity, and insulin. In contrast, reduced aldosterone alongside markers/mediators of oxidative stress, including 8-isoprostane, c-Jun N-terminal kinase, nuclear factor-kappaB, AP-1, and AP-2 were observed. Interestingly, in hemin-treated ZDF, inhibitory proteins of insulin-signaling, such as glycogen synthase kinase-3 and protein-tyrosine phosphatase-1B were reduced, whereas agents that promote insulin signaling including adiponectin, cAMP, AMP-activated protein kinase, aldolase-B, and glucose transporter-4 (GLUT4), were robustly increased. Correspondingly, hemin improved ip glucose tolerance, reduced insulin intolerance, and lowered insulin resistance (homeostasis model assessment of insulin resistance), and the inability of insulin to enhance GLUT4 was overturned. These results suggest that the suppression of hyperglycemia and aldosterone-induced oxidative stress alongside the potentiation of insulin-sensitizing pathways may account for the 4-month enduring antidiabetic effect. The synergistic interaction between the HO system, aldolase-B, adiponectin, AMP-activated protein kinase, and GLUT4 may be explored for novel strategies against postprandial/fasting hyperglycemia and insulin-resistant T2D.
 ...
PMID:The heme oxygenase system abates hyperglycemia in Zucker diabetic fatty rats by potentiating insulin-sensitizing pathways. 1910 28

Previously we have shown that tyrosine 718 of ASK1 when phosphorylated is critical for SOCS1 binding and SOCS1-mediated degradation of ASK1. However, the kinase and phosphatase responsible for phosphorylation and dephosphorylation of ASK1 at Tyr-718 are unknown. In this study, we identified JAK2 and SHP2 as a Tyr-718-specific kinase and phosphatase, respectively. Interferon-gamma (IFN-gamma) induced degradation of ASK1 in normal but not in SOCS1-KO endothelial cells (EC). IFN-gamma-induced tyrosine phosphorylation of ASK1 at Tyr-718 was blocked by a JAK2-specific inhibitor. IFN-gamma enhanced the association between JAK2 and ASK1, and the ASK1-JAK2 complex was labile and was stabilized by the proteasomal inhibitor MG132. Furthermore, JAK2, but not JAK1, directly bound to and phosphorylated ASK1 at Tyr-718, leading to an enhanced association of ASK1 with SOCS1 and subsequent ASK1 degradation. Next, we showed that overexpression of the SH2-containing protein-tyrosine phosphatase-2 (SHP2) augmented, whereas a phosphatase-inactive mutant of SHP2 inhibited, TNF-induced ASK1 dephosphorylation. SHP2 associated with ASK1 in response to tumor necrosis factor in EC. An SHP-2 substrate-trapping mutant formed a complex with tyrosine-phosphorylated ASK1, suggesting that ASK1 is a direct SHP2 substrate. Moreover, SHP2 wild type, but not a catalytically inactive mutant, dissociated SOCS1 from ASK1. IFN-gamma-induced ASK1 Tyr(P)-718 was enhanced in mouse EC deficient in SHP2 (SHP2-KO). In contrast, tumor necrosis factor-induced dephosphorylation of ASK1 at Tyr(P)-718 and activation of ASK1-JNK signaling, as well as EC apoptosis, are significantly reduced in SHP2-KO EC. Our data suggest that JAK2-SOCS1 and SHP2 reciprocally regulate ASK1 phosphorylation and stability in response to cytokines.
 ...
PMID:JAK2 and SHP2 reciprocally regulate tyrosine phosphorylation and stability of proapoptotic protein ASK1. 1928 4

Density-enhanced phosphatase-1 (DEP-1) is a trans-membrane receptor protein-tyrosine phosphatase that plays a recognized prominent role as a tumor suppressor. However, the mechanistic details underlying its function are poorly understood because its primary physiological substrate(s) have not been firmly established. To shed light on the mechanisms underlying the anti-proliferative role of this phosphatase, we set out to identify new DEP-1 substrates by a novel approach based on screening of high density peptide arrays. The results of the array experiment were combined with a bioinformatics filter to identify eight potential DEP-1 targets among the proteins annotated in the MAPK pathway. In this study we show that one of these potential targets, the ERK1/2, is indeed a direct DEP-1 substrate in vivo. Pulldown and in vitro dephosphorylation assays confirmed our prediction and demonstrated an overall specificity of DEP-1 in targeting the phosphorylated tyrosine 204 of ERK1/2. After epidermal growth factor stimulation, the phosphorylation of the activation loop of ERK1/2 can be modulated by changing the concentration of DEP-1, without affecting the activity of the upstream kinase MEK. In addition, we show that DEP-1 contains a KIM-like motif to recruit ERK1/2 proteins by a docking mechanism mediated by the common docking domain in ERK1/2. ERK proteins that are mutated in the conserved docking domain become insensitive to DEP-1 de-phosphorylation. Overall this study provides novel insights into the anti-proliferative role of this phosphatase and proposes a new mechanism that may also be relevant for the regulation of density-dependent growth inhibition.
 ...
PMID:Tumor suppressor density-enhanced phosphatase-1 (DEP-1) inhibits the RAS pathway by direct dephosphorylation of ERK1/2 kinases. 1949 14

Adequate fetal growth depends on placental transfer of nutrients and gases from the mother; thus, as pregnancy progresses, the placenta must grow to meet the increasing demands of the developing fetus. IGFs control proliferation, differentiation, and survival of trophoblast in first-trimester placenta via intracellular tyrosine kinase signaling cascades, the activation of which is also regulated by tyrosine phosphatases. The protein-tyrosine phosphatase, Src homology-2 domain containing protein tyrosine phosphatase (SHP)-2, is crucial for mouse placental development and is known to mediate IGF actions in other systems. In this study we examined the role of SHP-2 in regulating IGF-mediated proliferation in human trophoblast. Immunohistochemical analysis demonstrated that SHP-2 is expressed strongly in cytotrophoblast and only weakly in syncytium. After small interfering RNA-mediated knockdown of SHP-2 in BeWo choriocarcinoma cells and human first-trimester placental explants, IGF-induced trophoblast proliferation, examined using immunohistochemical analysis of Ki67 and 5-bromo-2'-deoxyuridine incorporation, was significantly reduced (P < 0.05). Kinase activation assays suggested that SHP-2 interacts with the MAPK pathway to mediate these effects. Markers of trophoblast differentiation were elevated after SHP-2 knockdown. This study demonstrates a role for tyrosine phosphatases in human trophoblast and establishes SHP-2 as a component of the IGF signaling pathway that is required for normal placental growth.
 ...
PMID:The protein-tyrosine phosphatase, SRC homology-2 domain containing protein tyrosine phosphatase-2, is a crucial mediator of exogenous insulin-like growth factor signaling to human trophoblast. 1958 68

T cells express diverse antigen-specific receptors and are required for eradicating pathogens and transformed cells. T cells expressing CD4 acquire helper effector functions and those expressing CD8 exert cytotoxic activity after antigen recognition. The protein-tyrosine phosphatase, receptor type kappa (PTPRKappa) is mutated in LEC rats, resulting in impaired CD4(+) T cell development in the thymus. However, the molecular mechanism of PTPRK controlling CD4(+) T cell development remains unclear. We demonstrate herein that inhibition of PTPRK by transducing a dominant negative form of the intracellular domain of PTPRK (PTPRK-ICD-DN) in bone marrow-derived stem cells suppresses the development of CD4(+) T cells. The inhibition of PTPRK by PTPRK-ICD-DN or short-hairpin RNA for PTPRK attenuates ERK1/2 phosphorylation in T cells after PMA and ionomycin stimulation. Total thymocytes from LEC rats also showed weaker phosphorylation of ERK1/2 after PMA and ionomycin stimulation than control thymocytes. Furthermore, inhibition of PTPRK by PTPRK-ICD-DN suppressed MEK1/2 and c-Raf phosphorylation, which is required for ERK1/2 phosphorylation. These data indicate that PPTRK positively regulates ERK1/2 phosphorylation, which impacts CD4(+) T cell development.
 ...
PMID:Protein-tyrosine phosphatase-kappa regulates CD4+ T cell development through ERK1/2-mediated signaling. 1980 Mar 17

The present study examined whether chronic treatment with angiotensin (ANG)-(1-7) reduces cardiac remodeling and inhibits growth-promoting signaling pathways in the heart of fructose-fed rats (FFR), an animal model of insulin resistance. Sprague-Dawley rats were fed either normal rat chow (control) or the same diet plus 10% fructose in drinking water. For the last 2 wk of a 6-wk period of the corresponding diet, control and FFR were implanted with osmotic pumps that delivered ANG-(1-7) (100 ng.kg(-1).min(-1)). A subgroup of each group of animals (control or FFR) underwent a sham surgery. We determined heart weight, myocyte diameter, interstitial fibrosis, and perivascular collagen type III deposition as well as the phosphorylation degree of ERK1/2, JNK1/2, and p38MAPK. FFR showed a mild hypertension that was significantly reduced after ANG-(1-7) treatment. Also, FFR displayed higher ANG II circulating and local levels in the heart that remained unaltered after chronic ANG-(1-7) infusion. An increased heart-to-body weight ratio, myocyte diameter, as well as left ventricular fibrosis and perivascular collagen type III deposition were detected in the heart of FFR. Interestingly, significant improvements in these cardiac alterations were obtained after ANG-(1-7) treatment. Finally, FFR that received ANG-(1-7) chronically displayed significantly lower phosphorylation levels of ERK1/2, JNK1/2, and p38MAPK. The beneficial effects obtained by ANG-(1-7) were associated with normal values of Src-homology 2-containing protein-tyrosine phosphatase-1 (SHP-1) activity in the heart. In conclusion, chronic ANG-(1-7) treatment ameliorated cardiac hypertrophy and fibrosis and attenuated the growth-promoting pathways in the heart. These findings show an important protective role of ANG-(1-7) in the heart of insulin-resistant rats.
 ...
PMID:Angiotensin-(1-7) improves cardiac remodeling and inhibits growth-promoting pathways in the heart of fructose-fed rats. 2006 44

The involvement of macrophages (Mvarphis) as host, accessory, and effector cells in the development of infectious diseases, together with their central role in iron homeostasis, place these immune cells as key players in the interface between iron and infection. Having previously shown that the functional expression of NRAMP-1 results in increased protein phosphorylation mediated in part by an iron-dependent inhibition of Mvarphi protein-tyrosine phosphatase (PTP) activity, we sought to study the mechanism(s) underlying this specific event. Herein we have identified the mononuclear dicitrate iron complex [Fe(cit)(2)H(4-x)]((1+x)-) as the species responsible for the specific inhibition of Mvarphi PTP activity. By using biochemical and computational approaches, we show that [Fe(cit)(2)](5-) targets the catalytic pocket of the PTP SHP-1, competitively inhibiting its interaction with an incoming phosphosubstrate. In vitro and in vivo inhibition of PTP activity by iron-citrate results in protein hyperphosphorylation and enhanced MAPK signaling in response to LPS stimulation. We propose that iron-citrate-mediated PTP inhibition represents a novel and biologically relevant regulatory mechanism of signal transduction.
 ...
PMID:Protein tyrosine phosphatases are regulated by mononuclear iron dicitrate. 2051 8


<< Previous 1 2 3 4 5 6 7 8 9 10 Next >>