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)

Investigations into molecular mechanisms in vertebrates have examined which growth factors regulate many of the essential underlying cellular processes in development. Growth factors regulate cell proliferation and differentiation through diverse signaling pathways like the MEK (mitogen-activated protein kinase) and ERK (extracellular signal-regulated kinase) pathway. The MEK and ERK pathway can interact with the PI3K (phosphatidylinositol-3-kinase) and PTEN (phosphatase and tensin homologues deleted on chromosome 10) signaling pathway. Interactions between these pathways during development have been extensively studied in many organs; however, the importance of these pathways in oral development is not well known. In this study, we examined the expression of the phosphorylated forms of ERK (pERK), MEK (pMEK), PTEN (pPTEN) and PI3K during mouse development from E13.5 to E16.5. We found unique and overlapping expression of these factors in the craniofacial region, with pERK and pPTEN showing opposing activation patterns in both the tooth and the tongue.
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PMID:Expression of phosphorylated forms of ERK, MEK, PTEN and PI3K in mouse oral development. 1820 67

The classification of human tumors based on molecular criteria offers tremendous clinical potential; however, discerning critical and "druggable" effectors on a large scale will also require robust experimental models reflective of tumor genomic diversity. Here, we describe a comprehensive genomic analysis of 101 melanoma short-term cultures and cell lines. Using an analytic approach designed to enrich for putative "driver" events, we show that cultured melanoma cells encompass the spectrum of significant genomic alterations present in primary tumors. When annotated according to these lesions, melanomas cluster into subgroups suggestive of distinct oncogenic mechanisms. Integrating gene expression data suggests novel candidate effector genes linked to recurrent copy gains and losses, including both phosphatase and tensin homologue (PTEN)-dependent and PTEN-independent tumor suppressor mechanisms associated with chromosome 10 deletions. Finally, sample-matched pharmacologic data show that FGFR1 mutations and extracellular signal-regulated kinase (ERK) activation may modulate sensitivity to mitogen-activated protein kinase/ERK kinase inhibitors. Genetically defined cell culture collections therefore offer a rich framework for systematic functional studies in melanoma and other tumors.
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PMID:Modeling genomic diversity and tumor dependency in malignant melanoma. 1824 65

LPS stimulation of monocytes/macrophages induces the expression of genes encoding proinflammatory cytokines and the procoagulant protein, tissue factor. Induction of these genes is mediated by various signaling pathways, including mitogen-activated protein kinases, and several transcription factors, including Egr-1, AP-1, ATF-2, and NF-kappaB. We used a genetic approach to determine the role of the phosphatidylinositol-3-kinase (PI3K)-protein kinase B (Akt) pathway in the regulation of LPS signaling and gene expression in isolated macrophages and in mice. The PI3K-Akt pathway is negatively regulated by the phosphatase and tensin homologue (PTEN). We used peritoneal exudate cells from Pik3r1-deficient mice, which lack the p85alpha regulatory subunit of PI3K and have reduced PI3K activity, and peritoneal macrophages from PTEN(flox/flox)/LysMCre mice (PTEN(-/-)), which have increased Akt activity. Analysis of LPS signaling in Pik3r1(-/-) and PTEN(-/-) cells indicated that the PI3K-Akt pathway inhibited activation of the ERK1/2, JNK1/2, and p38 mitogen-activated protein kinases and reduced the levels of nuclear Egr-1 protein and phosphorylated ATF-2. Modulating the PI3K-Akt pathway did not affect LPS-induced degradation of IkappaBalpha or NF-kappaB nuclear translocation. LPS induction of TNF-alpha, IL-6, and tissue factor gene expression was increased in Pik3r1(-/-) peritoneal exudate cells and decreased in PTEN(-/-) peritoneal macrophages compared with wild-type (WT) cells. Furthermore, LPS-induced inflammation and coagulation were enhanced in WT mice containing Pik3r1(-/-) bone marrow compared with WT mice containing WT bone marrow and in mice lacking the p85alpha subunit in all cells. Taken together, our results indicate that the PI3K-Akt pathway negatively regulates LPS signaling and gene expression in monocytes/macrophages.
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PMID:Genetic analysis of the role of the PI3K-Akt pathway in lipopolysaccharide-induced cytokine and tissue factor gene expression in monocytes/macrophages. 1832 34

Diglycerides (DGs) are phospholipid-derived second messengers that regulate PKC-dependent signaling pathways. Distinct species of DGs are generated from inflammatory cytokines and growth factors. Growth factors increase diacyl- but not ether-linked DG species, whereas inflammatory cytokines predominately generate alkyl, acyl- and alkenyl, acyl-linked DG species in rat mesenchymal cells. These DG species have been shown to differentially regulate protein kinase C (PKC) isotypes. Ester-linked diacylglycerols activate PKC-epsilon and cellular proliferation in contrast to ether-linked DGs, which lead to growth arrest through the inactivation of PKC-epsilon. It is now hypothesized that ether-linked DGs inhibit mitogenesis through the inactivation of ERK and/or Akt signaling cascades. We demonstrate that cell-permeable ether-linked DGs reduce vascular smooth muscle cell growth by inhibiting platelet-derived growth factor-stimulated ERK in a PKC-epsilon-dependent manner. This inhibition is specific to the ERK pathway, since ether-linked DGs do not affect growth factor-induced activation of other family members of the MAPKs, including p38 MAPK and c-Jun NH(2)-terminal kinases. We also demonstrate that ether-linked DGs reduce prosurvival phosphatidylinositol 3-kinase (PI3K)/Akt signaling, independent of PKC-epsilon, by diminishing an interaction between the subunits of PI3K and not by affecting protein phosphatase 2A or lipid (phosphatase and tensin homologue deleted in chromosome 10) phosphatases. Taken together, our studies identify ether-linked DGs as potential adjuvant therapies to limit vascular smooth muscle migration and mitogenesis in atherosclerotic and restenotic models.
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PMID:Ether-linked diglycerides inhibit vascular smooth muscle cell growth via decreased MAPK and PI3K/Akt signaling. 1872 71

Granulosa cells proliferate and then undergo differentiation; an inverse relationship between these processes is observed during terminal follicular growth. During terminal follicular growth and initial luteinization, there is a necessary transition of granulosa cells to a less proliferative and highly steroidogenic form in response to LH. Although the expression of several molecules has been reported to be up-regulated by LH, proliferation/differentiation transition is not fully understood. Here, we show that the expression of a tumor suppressor, phosphatase and tensin homologue deleted on chromosome 10 (PTEN) was induced with human chorionic gonadotropin (hCG) treatment in human luteinized granulosa cells. Pretreatment with hCG attenuated insulin-like growth factor (IGF)-1-induced phosphorylation of AKT and cell proliferation, not phosphorylation of ERK1/2. Moreover, suppression of hCG-induced PTEN expression with siRNA increased AKT phosphorylation and cell proliferation in response to IGF1. We also demonstrate that a PI3K inhibitor, LY294002, not a MEK inhibitor, PD98059, inhibited IGF1-induced cell proliferation. In conclusion, PTEN induced to express by hCG in luteinized granulosa cells that inactivates AKT, not ERK, and attenuates IGF1-induced cell proliferation. PTEN expression may be a trigger for proliferation/differentiation transition in human granulosa cells.
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PMID:IGF1-induced AKT phosphorylation and cell proliferation are suppressed with the increase in PTEN during luteinization in human granulosa cells. 1922 41

DUSPs (dual-specificity phosphatases) are a heterogeneous group of protein phosphatases that can dephosphorylate both phosphotyrosine and phosphoserine/phosphothreonine residues within the one substrate. DUSPs have been implicated as major modulators of critical signalling pathways that are dysregulated in various diseases. DUSPs can be divided into six subgroups on the basis of sequence similarity that include slingshots, PRLs (phosphatases of regenerating liver), Cdc14 phosphatases (Cdc is cell division cycle), PTENs (phosphatase and tensin homologues deleted on chromosome 10), myotubularins, MKPs (mitogen-activated protein kinase phosphatases) and atypical DUSPs. Of these subgroups, a great deal of research has focused on the characterization of the MKPs. As their name suggests, MKPs dephosphorylate MAPK (mitogen-activated protein kinase) proteins ERK (extracellular-signal-regulated kinase), JNK (c-Jun N-terminal kinase) and p38 with specificity distinct from that of individual MKP proteins. Atypical DUSPs are mostly of low-molecular-mass and lack the N-terminal CH2 (Cdc25 homology 2) domain common to MKPs. The discovery of most atypical DUSPs has occurred in the last 6 years, which has initiated a large amount of interest in their role and regulation. In the past, atypical DUSPs have generally been grouped together with the MKPs and characterized for their role in MAPK signalling cascades. Indeed, some have been shown to dephosphorylate MAPKs. The current literature hints at the potential of the atypical DUSPs as important signalling regulators, but is crowded with conflicting reports. The present review provides an overview of the DUSP family before focusing on atypical DUSPs, emerging as a group of proteins with vastly diverse substrate specificity and function.
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PMID:Dual-specificity phosphatases: critical regulators with diverse cellular targets. 1922 21

Hypoxia-inducible factor 1 alpha (HIF-1 alpha) is upregulated by hypoxia and oncogenic signalling in many solid tumours. Its regulation and function in thyroid carcinomas are unknown. We evaluated the regulation of HIF-1 alpha and target gene expression in primary thyroid carcinomas and thyroid carcinoma cell lines (BcPAP, WRO, FTC-133 and 8505c). HIF-1 alpha was not detectable in normal tissue but was expressed in thyroid carcinomas. Dedifferentiated anaplastic tumours (ATCs) exhibited high levels of nuclear HIF-1 alpha staining. The HIF-1 target glucose transporter 1 was expressed to a similar level in all tumour types, whereas carbonic anhydrase-9 was significantly elevated in ATCs. In vitro studies revealed a functionally active HIF-1 alpha pathway in thyroid cells with transcriptional activation observed after graded hypoxia (1% O(2), anoxia) or treatment with a hypoxia mimetic cobalt chloride. High basal and hypoxia-induced expression of HIF-1 alpha in FTC-133 cells that harbour a phosphatase and tensin homologue (PTEN) mutation was reduced by introduction of wild-type PTEN. Similarly, pharmacological inhibition of the phosphoinositide 3-kinase (PI3K) pathway using LY294002 inhibited HIF-1 alpha and HIF-1 alpha targets in all cell lines, including those with B-RAF mutations (BcPAP and 8505c). In contrast, the effects of inhibition of the RAF/MEK/extracellular signal-regulated kinase pathway were restricted by environmental condition and B-RAF mutation status. HIF-1 is functionally expressed in thyroid carcinomas and is regulated not only by hypoxia but also via growth factor signalling pathways and, in particular, the PI3K pathway. Given the strong association of HIF-1 alpha with an aggressive disease phenotype and therapeutic resistance, this pathway may be an attractive target for improved therapy in thyroid carcinomas.
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PMID:Expression of hypoxia-inducible factor 1 alpha in thyroid carcinomas. 1980 99

Many cancers, including breast cancer, harbor loss-of-function mutations in the catalytic domain of phosphatase and tensin homologue deleted on chromosome 10 (PTEN) or have reduced PTEN expression through loss of heterozygosity and/or epigenetic silencing mechanisms. However, specific phenotypic effects of PTEN inactivation in human cancer cells remain poorly defined without a direct causal connection between the loss of PTEN function and the development or progression of cancer. To evaluate the biological and clinical relevance of reduced or deleted PTEN expression, a novel in vitro model system was generated using human somatic cell knockout technologies. Targeted homologous recombination allowed for a single and double allelic deletion, which resulted in reduced and deleted PTEN expression, respectively. We determined that heterozygous loss of PTEN in the nontumorigenic human mammary epithelial cell line MCF-10A was sufficient for activation of the phosphoinositide 3-kinase/AKT and mitogen-activated protein kinase pathways, whereas the homozygous absence of PTEN expression led to a further increased activation of both pathways. The deletion of PTEN was able to confer growth factor-independent proliferation, which was confirmed by the resistance of the PTEN(-/-) MCF-10A cells to small-molecule inhibitors of the epidermal growth factor receptor. However, neither heterozygous nor homozygous loss of PTEN expression was sufficient to promote anchorage-independent growth, but the loss of PTEN did confer apoptotic resistance to cell rounding and matrix detachment. Finally, MCF-10A cells with the reduction or loss of PTEN showed increased susceptibility to the chemotherapeutic drug doxorubicin but not paclitaxel.
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PMID:Deletion of PTEN promotes tumorigenic signaling, resistance to anoikis, and altered response to chemotherapeutic agents in human mammary epithelial cells. 1984 59

Oncogenic Ras mutations render the protein constitutively active and promote tumorigenesis via chronic stimulation of effector pathways. In A549 lung adenocarcinoma approx. 50% of the total Ras population is constitutively active, yet these cells display only weak activation of the effectors: ERK1/2 (extracellular-signal-regulated kinase 1/2) and Akt. In order to identify key negative regulators of oncogenic Ras signalling we performed a phosphatome RNAi (RNA interference) screen in A549 cells and ranked their effects on phosphorylation of Ser473 of Akt. As expected, the tumour suppressor PTEN (phosphatase and tensin homologue deleted on chromosome 10) emerged as a leading hit: knockdown elevated Akt activation to 70% of maximal generated by acute EGF (epidermal growth factor) stimulation. Importantly, we identified other phosphatases with similar potencies including PTPN2 (T-cell protein tyrosine phosphatase; also known as TC-PTP) and PTPRJ (protein tyrosine phosphatase receptor type J; also known as DEP-1/CD148). Potentiation of Akt phosphorylation by knockdown of PTEN or PTPRJ was contingent on the presence of oncogenic K-Ras. Our data reveal a synergy between oncogene function and the loss of a tumour suppressor within the same pathway that was necessary for full effector activation since each alone failed to elicit significant Akt phosphorylation. Taken together, these data reveal potent regulators of Akt signalling which contribute to ameliorating the consequences of oncogenic K-Ras activity.
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PMID:Phosphatome profiling reveals PTPN2, PTPRJ and PTEN as potent negative regulators of PKB/Akt activation in Ras-mutated cancer cells. 1992 11

Nogo-A is an oligodendroglial neurite outgrowth inhibitor, the deactivation of which enhances brain plasticity and functional recovery in animal models of stroke. Nogo-A's role in the reperfused brain tissue was still unknown. By using Nogo-A(-/-) mice and mice in which Nogo-A was blocked with a neutralizing antibody (11C7) that was infused into the lateral ventricle or striatum, we show that Nogo-A inhibition goes along with decreased neuronal survival and more protracted neurologic recovery, when deactivation is constitutive or induced 24 h before, but not after focal cerebral ischemia. We show that in the presence of Nogo-A, RhoA is activated and Rac1 and RhoB are deactivated, maintaining stress kinases p38/MAPK, SAPK/JNK1/2 and phosphatase-and-tensin homolog (PTEN) activities low. Nogo-A blockade leads to RhoA deactivation, thus overactivating Rac1 and RhoB, the former of which activates p38/MAPK and SAPK/JNK1/2 via direct interaction. RhoA and its effector Rho-associated coiled-coil protein kinase2 deactivation in turn stimulates PTEN, thus inhibiting Akt and ERK1/2, and initiating p53-dependent cell death. Our data suggest a novel role of Nogo-A in promoting neuronal survival by controlling Rac1/RhoA balance. Clinical trials should be aware of injurious effects of axonal growth-promoting therapies. Thus, Nogo-A antibodies should not be used in the very acute stroke phase.
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PMID:Role of Nogo-A in neuronal survival in the reperfused ischemic brain. 2008 69


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