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)

Malformations of cortical development are increasingly recognized as causes of mental retardation and epilepsy. However, little is known about the molecular and biochemical signals that control the proliferation, migration, and organization of the cells involved in normal cerebral cortical development. Analysis of genes required for cortical development will help elucidate the pathogenesis of some epilepsies. In humans, two striking examples of abnormal cortical development, with varying degrees of epilepsy and mental retardation, are 'double cortex' and lissencephaly. Double cortex (DC), also known as subcortical band heterotopia, shows an abnormal band of neurons in the white matter underlying a relatively normal cortex. In pedigrees, DC often occurs in females, whereas affected males show more severe lissencephaly (XLIS), i.e. an abnormally thick cortex with decreased or absent surface convolutions. We and others have identified a novel brain specific gene, doublecortin, that is mutated in Double Cortex/X-linked lissencephaly (DC/XLIS) patients. Although the cellular function of doublecortin (DCX) is unknown, sequence analysis reveals a cytoplasmic protein with potential MAP kinase phosphorylation sites, as well as a site that is likely to be phosphorylated by c-Abl, suggesting that doublecortin functions as an intracellular signaling molecule critical for the migration of developing neurons. Interestingly, the scrambler mouse mutant demonstrates abnormal lamination with some similarity to lissencephaly and reflects a mutation in the murine homolog of the Drosophila disabled gene, mdab1, which binds c-Abl. Although a direct interaction between doublecortin and mDab1 has not been demonstrated, it is plausible that these two proteins may be part of a common signaling pathway. Therefore, abnormalities in signal transduction may be an underlying mechanism for the neuronal migration defects in DC/XLIS and the scrambler mouse, but further research is necessary to determine how such abnormalities give rise to cortical malformations and epilepsy.
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PMID:Genes that regulate neuronal migration in the cerebral cortex. 1051 62

The neural cell adhesion molecule L1 mediates the axon outgrowth, adhesion, and fasciculation necessary for proper development of synaptic connections. Mutations of human L1 cause an X-linked mental retardation syndrome termed CRASH (corpus callosum hypoplasia, retardation, aphasia, spastic paraplegia, and hydrocephalus), and L1 knock-out mice display defects in neuronal process extension resembling the CRASH phenotype. Little is known about the biochemical or cellular mechanism by which L1 performs neuronal functions. Here it is demonstrated that clustering of L1 with antibodies or L1 protein in rodent B35 neuroblastoma and cerebellar neuron cultures induced the phosphorylation/activation of the mitogen-activated protein kinases (MAPKs) and extracellular signal-regulated kinases 1 and 2. MAPK activation was essential for L1-dependent neurite outgrowth, because chemical inhibitors [2-(2'-amino-3'-methoxyphenyl)-oxanaphthalen-4-one and 1,4-diamino-2, 3-dicyano-1,4-bis(2-aminophenylthio)butadiene] of the MAPK kinase MEK strongly suppressed neurite outgrowth by cerebellar neurons on L1. The nonreceptor tyrosine kinase pp60(c-src) was required for L1-triggered MAPK phosphorylation, as shown in src-minus cerebellar neurons and by expression of the kinase-inactive mutant Src(K295M) in B35 neuroblastoma cells. Phosphatidylinositol 3-kinase (PI3-kinase) and the small GTPase p21(rac) were identified as signaling intermediates to MAPK by phosphoinositide and Rac-GTP assays and expression of inhibitory mutants. Antibody-induced endocytosis of L1, visualized by immunofluorescence staining and confocal microscopy of B35 cells, was blocked by expression of kinase-inactive Src(K295M) and dominant-negative dynamin(K44A) but not by inhibitors of MEK or PI3-kinase. Dynamin(K44A) also inhibited L1 antibody-triggered MAPK phosphorylation. This study supports a model in which pp60(c-src) regulates dynamin-mediated endocytosis of L1 as an essential step in MAPK-dependent neurite outgrowth on an L1 substrate.
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PMID:A MAP kinase-signaling pathway mediates neurite outgrowth on L1 and requires Src-dependent endocytosis. 1081 53

X-linked mental retardation is a very common condition that affects approximately 1 in 600 males. Despite recent progress, in most cases the molecular defects underlying this disorder remain unknown. Recently, a study using the candidate gene approach demonstrated the presence of mutations in PAK3 (p21-activating kinase) associated with nonspecific mental retardation. PAK3 is a member of the larger family of PAK genes. PAK proteins have been implicated as critical downstream effectors that link Rho-GTPases to the actin cytoskeleton and to MAP kinase cascades, including the c-Jun amino-terminal kinase (JNK) and p38. We screened 12 MRX pedigrees that map to a large region overlying Xq21-q24. Mutation screening of the whole coding region of the PAK3 gene was performed by using a combination of denaturing gradient gel electrophoresis and direct sequencing. We have identified a novel missense mutation in exon 2 of PAK3 gene (R67C) in MRX47. This confirms the involvement of PAK3 in MRX following the report of a nonsense mutation recently reported in MRX30. In the MRX47 family, all affected males show moderate to severe mental retardation. No seizures, statural growth deficiency, or minor facial or other abnormal physical features were observed. This mutation R67C is located in a conserved polybasic domain (AA 66-68) of the protein that is predicted to play a major role in the GTPases binding and stimulation of Pak activity.
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PMID:Missense mutation in PAK3, R67C, causes X-linked nonspecific mental retardation. 1094 56

Members of the AF4/FMR2 family of nuclear proteins are involved in human diseases such as acute lymphoblastic leukemia and mental retardation. Here we report the identification and characterization of the Drosophila lilliputian (lilli) gene, which encodes a nuclear protein related to mammalian AF4 and FMR2. Mutations in lilli suppress excessive neuronal differentiation in response to a constitutively active form of Raf in the eye. In the wild type, Lilli has a partially redundant function in the Ras/MAPK pathway in differentiation but it is essential for normal growth. Loss of Lilli function causes an autonomous reduction in cell size and partially suppresses the increased growth associated with loss of PTEN function. These results suggest that Lilli acts in parallel with the Ras/MAPK and the PI3K/PKB pathways in the control of cell identity and cellular growth.
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PMID:Lilliputian: an AF4/FMR2-related protein that controls cell identity and cell growth. 1117 3

The L1 adhesion molecule regulates axon growth and is mutated in the X-linked mental retardation syndrome CRASH (acronym for corpus callosum agenesis, retardation, aphasia, spastic paraplegia, hydrocephalus). A novel role for L1 as a potentiator of neuronal cell migration to extracellular matrix proteins through beta1 integrins and intracellular signaling to mitogen-activated protein (MAP) kinase was identified. L1 potentiated haptotactic migration of B35 neuroblastoma cells toward fibronectin, vitronectin, and laminin through the signaling intermediates c-Src, phosphatidylinositol-3 kinase, and MAP kinase. L1 potentiated migration toward fibronectin through alpha5beta1 integrin in human embryonic kidney 293 cells and depended on determinants of L1 endocytosis: dynamin I, c-Src, and the AP2/clathrin binding site (Arg-Ser-Leu-Glu) in the neuronal splice form of L1. L1 clustering on the cell surface enhanced the internalization of activated beta1 integrins and L1 into distinct endocytic vesicles. L1-potentiated migration, enhancement of beta1 integrin endocytosis, and activation of MAP kinase were coordinately inhibited by mutation of an RGD sequence in the sixth immunoglobulin-like domain of L1. Moreover, three CRASH mutations in the L1 cytoplasmic domain (1194L, S1224L, Y1229H), two of which interfere with ankyrin association, inhibited L1-potentiated migration and MAP kinase activation. Function-blocking antibodies to L1 and beta1 integrin retarded the migration of 5-bromo-2'-deoxyuridine-labeled mouse cerebellar granule cells in slice cultures, underscoring the potential physiological relevance of these findings. These studies suggest that L1 functionally interacts with beta1 integrins to potentiate neuronal migration toward extracellular matrix proteins through endocytosis and MAP kinase signaling, and that impairment of this function by L1 cytoplasmic domain mutations may contribute to neurological deficits in CRASH.
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PMID:The neural cell adhesion molecule L1 potentiates integrin-dependent cell migration to extracellular matrix proteins. 1207 89

Myotonic dystrophy (DM) is a dominant neuromuscular disorder caused by the expansion of trinucleotide CTG repeats in the 3-untranslated region (3'-UTR) of the MtPK gene. Although DM-associated mental retardation suggests that neuronal functions are disturbed by the expansion mutation, the effect of this alteration in neuronal cells has not been approached. In this study we established stable transfectans of PC12 neuronal cell line expressing the reporter gene CAT alone (empty-vector clone) or fused to the MtPK 3'-UTR with 5, 60, or 90 CTG repeats (CTG5, CTG60, and CTG90 clones, respectively). CTG90 cells exhibited a suppression of NGF-induced neuronal differentiation while empty-vector, CTG5 and CTG60 clones differentiated normally. CTG90 cells displayed normal activation of early differentiation markers, ERK1/2, but the up-regulation of the late marker MAP2 was dramatically reduced. Our neuronal cell system provides the first information of how the mutant MtPK 3'-UTR mRNA affects neuronal functions.
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PMID:Expanded CTG repeats inhibit neuronal differentiation of the PC12 cell line. 1215 Sep 45

Neural cell adhesion molecules of the immunoglobulin superfamily are multidomain proteins involved in important cellular events pertinent to development and adult neurological function. This review attempts to give a concise overview of the complex intracellular signaling pathways enabling neural cell adhesion molecules NCAM and L1 to regulate axon growth, guidance, and synaptic plasticity. Recent research findings suggest that these molecules signal in part through integrins leading to cytoskeletal rearrangements locally in the growth cone or cell leading edge, and to MAP kinase, which has the potential to cause gene expression changes in the nucleus. Abnormal expression of NCAM on human chromosome 11q23 has been linked to schizophrenia in humans, a multigenic disease believed to be of neurodevelopmental origin. L1 at Xq28 is the target for mutation in a complex mental retardation disorder termed the L1 syndrome (also sometimes referred to as CRASH syndrome). Thus a full understanding of the mechanism of NCAM and L1 function will contribute to understanding both normal brain development and pathologies associated with cognitive dysfunction in schizophrenia and mental retardation.
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PMID:Cellular signalling mechanisms of neural cell adhesion molecules. 1270 44

Exposure to ethanol during pregnancy is detrimental to fetal development, and individuals affected by the fetal alcohol syndrome present a number of CN system dysfunctions including microencephaly and mental retardation. Recently, it has been suggested that ethanol-induced inhibition of glial cell proliferation may be relevant in the causation of microencephaly. In this study, we measured the developmental changes of MAPK (ERKl/2) and p70S6 kinase, which are considered to play a prominent role in cell proliferation, and their phosphorylated proteins in rat brain, and examined the effects of in vivo ethanol administration. MAPK and phospho-MAPK increased gradually after birth, and reached adult levels on postnatal day 21. In contrast, levels of both p70S6 kinase and phospho-p70S6 kinase decreased after birth. Exposure to ethanol (2-6 g/kg, from postnatal day 4 to 7) had no effects on MAPK or p70S6 kinase levels, but caused a dose-dependent decrease of both phosphoproteins. These results suggest that phosphorylation of MAPK and p70S6 kinase may represent relevant targets for the developmental neurotoxicity of ethanol, and may be involved in microencephaly.
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PMID:In vivo ethanol decreases phosphorylated MAPK and p70S6 kinase in the developing rat brain. 1287 81

The FMR2 gene is dysregulated by the fragile X E triplet repeat expansion in patients with FRAXE mental retardation syndrome. A CCG triplet, located in the 5' untranslated region of the FRAXE gene undergoes expansion and methylation in these patients, eliminating detectable gene transcription. FRAXE syndrome is distinct from fragile X syndrome, a more common genetic form of mental retardation caused by expansion and methylation of a similar repeat in the FMR1 gene located 600 kb proximal to FRAXE. FRAXE syndrome is rare, and patients' phenotypes are highly variable, leading to difficulties with predicting specific FMR2 functions based on the human disease. Recently, Lilliputian(Lilli), a Drosophila FMR2 orthologue, was identified; this gene has been linked with several signal transduction pathways, including the transforming growth factor-beta (TGF-beta) pathway, the Raf/MEK/MAP kinase (MAPK) pathway, and the P13K/PKB pathway. Mutation of Lilli shows defects in germinal band extension, cytoskeletal structure, cell growth, and organ development. The Lilli gene suggests possible functions for FMR2 (and related genes) in humans and mice, but cannot predict specific functions. Modeling FMR2 mutation in the mouse will be useful to understand specific functions of this gene in vertebrates. This review presents what has been learned thus far from the FMR2 knockout mouse model and suggests future studies on this model in order to compare it with the human FRAXE mental retardation disorder, Lilli mutants in Drosophila and other mouse models of genes in this family.
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PMID:FMR2 function: insight from a mouse knockout model. 1452 73

Tuberous sclerosis complex (TSC) is a tumor suppressor gene syndrome with manifestations that can include seizures, mental retardation, autism, and tumors in the brain, retina, kidney, heart, and skin. The products of the TSC1 and TSC2 genes, hamartin and tuberin, respectively, heterodimerize and inhibit the mammalian target of rapamycin (mTOR). We found that tuberin expression increases p42/44 MAPK phosphorylation and B-Raf kinase activity. Short interfering RNA down-regulation of tuberin decreased the p42/44 MAPK phosphorylation and B-Raf activity. Expression of Rheb, the target of the GTPase-activating domain of tuberin, inhibited wild-type B-Raf kinase but not activated forms of B-Raf. The interaction of endogenous Rheb with B-Raf was enhanced by serum and by Ras overexpression. A farnesylation-defective mutant of Rheb co-immunoprecipitated with and inhibited B-Raf but did not activate ribosomal protein S6 kinase, indicating that farnesylation is not required for B-Raf inhibition by Rheb and that B-Raf inhibition and S6 kinase activation are separable activities of Rheb. Consistent with this, inhibition of B-Raf and p42/44 MAPK by Rheb was resistant to rapamycin in contrast to Rheb activation of S6 kinase, which is rapamycin-sensitive. Taken together these data demonstrate that inhibition of B-Raf kinase via Rheb is an mTOR-independent function of tuberin.
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PMID:Regulation of B-Raf kinase activity by tuberin and Rheb is mammalian target of rapamycin (mTOR)-independent. 1515 Feb 71


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