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:2.7.10.1 (ERK)
95,504 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurofibromatosis type 1 (NF1), a common autosomal dominant disorder caused by loss of the NF1 gene, is characterized clinically by neurofibromas and more rarely by neurofibrosarcomas. Neurofibromin, the protein encoded by NF1, possesses an intrinsic GTPase accelerating activity for the Ras proto-oncogene. Through this activity, it is a negative regulator of Ras. The Pak protein kinase is a candidate for a downstream signaling protein that may mediate Ras signals because it is activated by Rac and Cdc42, two small G proteins required for Ras signaling. Here, we use Pak mutants to explore the role of Pak in Ras signaling in Schwann cells, the cells affected in NF1. Whereas an activated Pak mutant does not transform cells, dominant negative Pak mutants are potent inhibitors of Ras transformation of rat Schwann cells and of a neurofibrosarcoma cell line from an NF1 patient. Although activated Pak stimulated jun-N-terminal kinase, inhibition of Ras transformation by dominant negative Pak did not require inhibition of jun-N-terminal kinase. Instead, the Pak mutants appeared to inhibit transformation by preventing Ras activation of the ERK/mitogen-activated protein kinase cascade. These results have implications for our understanding of NF1 because a neurofibrosarcoma cell line derived from a patient with NF1 was reverted by stable expression of the Pak dominant negative mutants.
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PMID:A role for Pak protein kinases in Schwann cell transformation. 956 Feb 42

In the present study we investigated the expression of the ERBB2 protein and neurofibromin in human benign and malignant Schwann cell tumors, traumatic neuromas and peripheral nerves without pathological findings. By immunohistochemistry and Western analysis ERBB2 expression was not detectable in normal nerves but in proliferating Schwann cells of traumatic neuromas. While none of the malignant schwannomas exhibited ERBB2 expression, weak expression was seen in a small proportion of the benign schwannomas. Low levels of neurofibromin were detectable in normal nerves but not in traumatic neuromas or tumors. These data indicate an inverse expression pattern of ERBB2 and neurofibromin in human non-neoplastic Schwann cells, but not in neurinoma cells.
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PMID:Expression of the ERBB2/neu and neurofibromatosis type 1 gene products in reactive and neoplastic schwann cell proliferation. 982 45

Neural crest-derived melanocyte precursors (MPs) in avian and murine embryos emerge from the dorsal neural tube into a migration staging area (MSA). MPs subsequently migrate from the MSA on a dorsolateral pathway between the dermamyotome and the overlying epithelium. In mouse embryos, MPs express the receptor tyrosine kinase, KIT, and require its cognate ligand, Mast cell growth factor (MGF), for survival and differentiation. Prior to the onset of MP migration, MGF is expressed on the dorsolateral pathway at some distance from cells in the MSA and appears to be required for normal MP development. To learn if MGF is required solely for MP survival on this pathway, or if it also provides directional cues for migration, we uncoupled survival from chemoattractive or motogenic functions of this ligand using mice that carry a targeted mutation at the Neurofibromin (Nf1) locus and consequently lack RAS-GAP function. We show that Nf1-mutant MPs survive in the absence of MGF in vitro and in vivo and that Nf1-mutant MPs disperse normally on the lateral migration pathway in the presence of MGF. In contrast, Nf1-mutant MPs persist in the location of the MSA but are not observed on the lateral migration pathway in double-mutant mice that also lack MGF. We conclude that MGF/KIT function provides a signal required for directed migration of the MPs on the lateral pathway in vivo, independent of its function in survival. We further suggest that the MGF mediates MP migration through a signaling pathway that does not involve RAS.
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PMID:Analysis of melanocyte precursors in Nf1 mutants reveals that MGF/KIT signaling promotes directed cell migration independent of its function in cell survival. 1140 6

The neural crest gives rise to numerous cell types, including Schwann cells, neurons, and melanocytes. The extent to which adult neural crest-derived cells retain plasticity has not been tested previously. We report that cutting adult mouse sciatic nerve induces pigmentation around nerve fascicles, among muscle bundles, and in the hypodermis. Pigmented cells are derived from adult nerve, because pigmentation occurs even when nerve fragments are grafted into tyrosinase null albino mice. Pigmentation defects are pervasive in patients with neurofibromatosis type 1 (NF1). Mice hemizygous for Nf1 mutations show enhanced pigmentation after nerve lesion and occasionally form pigmented and unpigmented tumors. The Nf1 nerve and the Nf1 host environment both contribute to enhanced pigmentation. Grafted purified Nf1 mutant glial cells [S100(+)-p75NGFR(+)-GFAP(+)-EGFR(+) or S100(+)-p75NGFR(+)-GFAP(+)-EGFR(-)] mimic nerve-derived pigmentation. The NF1 protein, neurofibromin, is a Ras-GAP that acts downstream of a few defined receptor tyrosine kinases, including [beta-common (beta(c))] the shared common receptor for granulocyte and monocyte colony-stimulating factor, interleukin-3 (IL3), and IL5. Cytokines in the environment have the potential to suppress pigmentation as shown by nerve injury experiments in null mice; when is beta(c) absent or Nf1 is mutant, melanogenesis is increased. Thus, the adult nerve glial cell phenotype is maintained after nerve injury by response to cytokines, through neurofibromin.
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PMID:A novel cytokine pathway suppresses glial cell melanogenesis after injury to adult nerve. 1242 39

Mutations in the NF1 tumor suppressor underlie the familial tumor predisposition syndrome neurofibromatosis type I. Although its encoded protein, neurofibromin, functions as a Ras-GTPase activating protein (GAP), nothing is known about how it is normally regulated or its precise role in controlling Ras signaling pathways. We show here that neurofibromin is dynamically regulated by the ubiquitin-proteasome pathway. Degradation is rapidly triggered in response to a variety of growth factors and requires sequences adjacent to the catalytic GAP-related domain of neurofibromin. However, whereas degradation is rapid, neurofibromin levels are re-elevated shortly after growth factor treatment. Accordingly, Nf1-deficient mouse embryonic fibroblasts (MEFs) exhibit an enhanced activation of Ras, prolonged Ras and ERK activities, and proliferate in response to subthreshold levels of growth factors. Thus, the dynamic proteasomal regulation of neurofibromin represents an important mechanism of controlling both the amplitude and duration of Ras-mediated signaling. Furthermore, this previously unrecognized Ras regulatory mechanism may be exploited therapeutically.
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PMID:Dynamic regulation of the Ras pathway via proteolysis of the NF1 tumor suppressor. 1260 Sep 38

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors of the gastrointestinal tract. KIT and PDGFRA activating mutations are the oncogenic mechanisms in most sporadic GISTs. In addition to sporadic occurrences, GISTs are increasingly being recognized in association with neurofibromatosis type 1 (NF1), yet the underlying pathogenic mechanism remains elusive. To gain an insight into the mechanisms underlying GIST formation in NF1 patients, we studied seven GISTs from three NF1 patients with a combination of different techniques: mutation analysis (KIT, PDGFRA and NF1), western blotting, array CGH and ex vivo imatinib response experiments. We demonstrate that (i) the NF1-related GISTs do not have KIT or PDGFRA mutations, (ii) the molecular event underlying GIST development in this patient group is a somatic inactivation of the wild-type NF1 allele in the tumor and (iii) inactivation of neurofibromin is an alternate mechanism to (hyper) activate the MAP-kinase pathway, while the JAK-STAT3 and PI3K-AKT pathways are less activated in NF1-related GIST compared with sporadic GISTs. In conclusion, we report for the first time the molecular pathogenesis of GISTs in NF1 individuals and demonstrate that this type of tumor clearly belongs to the spectrum of clinical symptoms in NF1.
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PMID:Molecular pathogenesis of multiple gastrointestinal stromal tumors in NF1 patients. 1646 35

Patients with neurofibromatosis type 1 (NF1), resulting from neurofibromin gene mutations, frequently suffer from deficits in learning and spatial memory. Mice heterozygous for functional deletion of the NF1 gene (NF1(+/-) mice) also exhibit compromised spatial learning, and deficits in early-stage hippocampal long-term potentiation (LTP). Neurofibromin is a multifunctional protein which acts in part as an inhibitory constraint on Ras signalling, and the deficits in early-stage LTP and spatial learning have been linked to Ras hyperactivation. However, the downstream targets of Ras hyperactivation that lead to cognitive disruption are unknown. The levels of activity of signalling molecules potentially downstream of Ras were therefore studied in NF1(+/-) mice. Elevated phospho-ERK (pERK) levels were observed in the hippocampi from NF1(+/-) mice, while phospho-Akt/PKB (pAkt) and phospho-eIF4E (peIF4E) levels were unchanged relative to wild-type mice. Hippocampal levels of phospho-CREB (pCREB) were also increased, suggesting potential changes in late-phase LTP in NF1(+/-) mice. Indeed, LTP was found to be impaired for at least 4 h following induction in NF1(+/-) mice, linking neurofibromin function with the long-term maintenance of LTP. Remarkably, U0126, an inhibitor of ERK activation, at doses which reduced the hyperactive pERK levels in NF1(+/-) mice to the levels observed in control mice, caused a reduction in the deficits in early-phase LTP and completely rescued the long-term LTP deficits. In contrast to the abundant evidence that reductions in ERK activity lead to impaired plasticity, these data indicate that ERK hyperactivation in a partial model of type 1 neurofibromatosis leads to deficits in long-lasting hippocampal plasticity.
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PMID:Restored plasticity in a mouse model of neurofibromatosis type 1 via inhibition of hyperactive ERK and CREB. 1724 Dec 71

We uncovered a role for ERK signaling in GABA release, long-term potentiation (LTP), and learning, and show that disruption of this mechanism accounts for the learning deficits in a mouse model for learning disabilities in neurofibromatosis type I (NF1). Our results demonstrate that neurofibromin modulates ERK/synapsin I-dependent GABA release, which in turn modulates hippocampal LTP and learning. An Nf1 heterozygous null mutation, which results in enhanced ERK and synapsin I phosphorylation, increased GABA release in the hippocampus, and this was reversed by pharmacological downregulation of ERK signaling. Importantly, the learning deficits associated with the Nf1 mutation were rescued by a subthreshold dose of a GABA(A) antagonist. Accordingly, Cre deletions of Nf1 showed that only those deletions involving inhibitory neurons caused hippocampal inhibition, LTP, and learning abnormalities. Importantly, our results also revealed lasting increases in GABA release triggered by learning, indicating that the mechanisms uncovered here are of general importance for learning.
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PMID:Neurofibromin regulation of ERK signaling modulates GABA release and learning. 1898 65

Lack of expression of neurofibromin in neurofibromatosis 1 and its lethal derivative, malignant peripheral nerve sheath tumors (MPNSTs), is thought to result in the overactivation of the Ras signaling pathway. Our previous studies have shown that cells with overactivation in the Ras pathway are more permissive to infection with herpes simplex virus 1 and its mutant version R3616. In this study, we show that among five different mouse MPNST cell lines, only the ones with elevated levels of Ras signaling are highly permissive to infection with oncolytic herpes G207. Specific inhibitors of the Ras, ERK, and JNK pathways all reduced the synthesis of viral proteins in MPNST cells. The cell lines that contained lower levels of Ras and decreased activation of downstream signaling components underwent an enhancement in apoptosis upon exposure to G207. Additionally, mouse SW10 Schwann cells were able to become infected by parental herpes but were found to be resistant to G207. The immortalization of these cell lines with the expression of SV40 large T antigen increased the levels of Ras activation and permissiveness to oncolytic herpes. A Ras/Raf kinase inhibitor reduced the synthesis of both herpes simplex virus-1 and G207 proteins in SW10 cells. The results of this study, therefore, introduce Ras signaling as a divergent turning point for the response of MPNST cells to an assault by oncolytic herpes.
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PMID:Ras signaling influences permissiveness of malignant peripheral nerve sheath tumor cells to oncolytic herpes. 1898 3

Neurofibromatosis type 1 (NF1) patients develop neurofibromas, tumors of Schwann cell origin, as a result of loss of the Ras-GAP neurofibromin. In normal nerves, Schwann cells are found tightly associated with axons, while loss of axonal contact is a frequent and important early event in neurofibroma development. However, the molecular basis of this physical interaction or how it is disrupted in cancer remains unclear. Here we show that loss of neurofibromin in Schwann cells is sufficient to disrupt Schwann cell/axonal interactions via up-regulation of the Ras/Raf/ERK signaling pathway. Importantly, we identify down-regulation of semaphorin 4F (Sema4F) as the molecular mechanism responsible for the Ras-mediated loss of interactions. In heterotypic cocultures, Sema4F knockdown induced Schwann cell proliferation by relieving axonal contact-inhibitory signals, providing a mechanism through which loss of axonal contact contributes to tumorigenesis. Importantly, Sema4F levels were strongly reduced in a panel of human neurofibromas, confirming the relevance of these findings to the human disease. This work identifies a novel role for the guidance-molecules semaphorins in the mediation of Schwann cell/axonal interactions, and provides a molecular mechanism by which heterotypic cell-cell contacts control cell proliferation and suppress tumorigenesis. Finally, it provides a new approach for the development of therapies for NF1.
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PMID:NF1 loss disrupts Schwann cell-axonal interactions: a novel role for semaphorin 4F. 1905 85


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