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)

The activity of the N-terminal activation function AF-1 of RAR alpha1 is abrogated upon mutation of a phosphorylatable serine residue (Ser-77). Recombinant RAR alpha was phosphorylated by a variety of proline-directed protein kinases in vitro. However, only the coexpression of cdk7 stimulated Ser-77 phosphorylation in vivo and enhanced transactivation by RAR alpha, but not by a S77A RAR mutant. Both free CAK (cdk7, cyclin H, MAT1) and the CAK-containing general transcription factor TFIIH phosphorylated Ser-77 in vitro. Furthermore RAR alpha bound free CAK and purified TFIIH in vitro, and RAR alpha-TFIIH complexes could be isolated from HeLa nuclear extracts. These findings represent the first example of activation of a transactivator through binding to and phosphorylation by a general transcription factor.
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PMID:Stimulation of RAR alpha activation function AF-1 through binding to the general transcription factor TFIIH and phosphorylation by CDK7. 923 Mar 6

Eph-related receptor tyrosine kinases have been implicated in the control of axonal navigation and fasciculation. To investigate the biochemical mechanisms underlying such functions, we have expressed the EphB2 receptor (formerly Nuk/Cek5/Sek3) in neuronal NG108-15 cells, and have observed the tyrosine phosphorylation of multiple cellular proteins upon activation of EphB2 by its ligand, ephrin-B1 (formerly Elk-L/Lerk2). The activated EphB2 receptor induced the tyrosine phosphorylation of a 62-64 kDa protein (p62[dok]), which in turn formed a complex with the Ras GTPase-activating protein (RasGAP) and SH2/SH3 domain adaptor protein Nck. RasGAP also bound through its SH2 domains to tyrosine-phosphorylated EphB2 in vitro, and complexed with activated EphB2 in vivo. We have localized an in vitro RasGAP-binding site to conserved tyrosine residues Y604 and Y610 in the juxtamembrane region of EphB2, and demonstrated that substitution of these amino acids abolishes ephrin-B1-induced signalling events in EphB2-expressing NG108-15 cells. These tyrosine residues are followed by proline at the + 3 position, consistent with the binding specificity of RasGAP SH2 domains determined using a degenerate phosphopeptide library. These results identify an EphB2-activated signalling cascade involving proteins that potentially play a role in axonal guidance and control of cytoskeletal architecture.
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PMID:Juxtamembrane tyrosine residues couple the Eph family receptor EphB2/Nuk to specific SH2 domain proteins in neuronal cells. 923 98

Several mutations involving the fibroblast growth factor receptor (FGFR) gene family have been identified in association with phenotypically distinct forms of craniosynostosis. One such point mutation, resulting in the substitution of proline by arginine in a critical region of the linker region between the first and second immunoglobulin-like domains, is associated with highly specific phenotypic consequences in that mutation at this point in FGFR1 results in Pfeiffer syndrome and analogous mutation in FGFR2 results in Apert syndrome. We now show that a much more variable clinical presentation accompanies analogous mutation in the FGFR3 gene. Specifically, mental retardation, apparently unrelated to the management of the craniosynostosis, appears to be a variable clinical consequence of this FGFR3 mutation.
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PMID:Craniosynostosis associated with FGFR3 pro250arg mutation results in a range of clinical presentations including unisutural sporadic craniosynostosis. 927 53

Two isolates of pea seed-borne mosaic potyvirus, DPD1 and NY, which both infect pea (Pisum sativum) systemically, differ in their ability to move long distance in Chenopodium quinoa. DPD1 spreads to uninoculated leaves, whereas NY is restricted to the inoculated leaves. The NY isolate was found to move from cell to cell infecting all parts of the inoculated leaves, including the petiole. The coat protein (CP) coding region was identified as the determinant of long-distance movement. Virus chimeras containing the CP coding sequence of NY were restricted to inoculated leaves, whereas chimeras containing the CP coding sequence of DPD1 infected C. quinoa systemically. Mutational analysis of the CP demonstrated that changing the serine at position 47 of the NY CP to proline was sufficient to permit systemic spread of the NY(S47P) mutant. The reverse mutant, DPD1(P47S), in which the proline at position 47 of the CP was changed to serine, was restricted to inoculated leaves. The movement characteristics and CP sequences of 10 additional PSbMV isolates were determined. All isolates caused systemic infection in pea. In C. quinoa 6 of the isolates that were restricted to inoculated leaves had a serine at position 47. Two isolates that infected C. quinoa systemically had a proline at position 47. Two isolates, S6 and NEP-1, infected C. quinoa systemically, but had a serine at position 47 of the CP. This shows that although a proline/serine difference at position 47 of the CP determined systemic spread of the isolates DPD1 and NY, this amino acid alone does not govern the spread of PSbMV in C. quinoa.
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PMID:A single conserved amino acid in the coat protein gene of pea seed-borne mosaic potyvirus modulates the ability of the virus to move systemically in Chenopodium quinoa. 949 5

Transmission of zucchini yellow mosaic virus (ZYMV) by aphids was examined by introducing mutations within the highly conserved proline-threonine-lysine (PTK) motif of the helper component proteinase (HC-Pro) using a cDNA full-length clone. Replacement of proline by alanine (ATK) in the PTK motif abolished transmission almost completely both from plants and from membranes. Substitution of the basic lysine by glutamic acid (PTE) did not reduce the rate of transmission compared with the wild-type. Replacement of threonine by valine (PVK) or serine (PSK) resulted in a rate of transmission that was lower than that of the wild-type. The rate was lower for PSK than for PVK. Western blot comparison did not permit attribution of HC-Pro functionality in transmission to its level in the host. The HC-Pro of strains that effected transmission (with the wild-type PTK motif, and with the mutated PTE and PVK motifs) could also bind in vitro to virions of ZYMV. HC-Pro with a PSK motif, which was less effective in assisting transmission, could bind only weakly to virions, while HC-Pro of the almost non-transmissible strains (with PAK and ATK motifs) did not bind at all. Interestingly, positive binding was recorded for transmission-defective ZYMV-Ct, which has a PTK motif but has glutamic acid instead of lysine in the lysine-leucine-serine-cysteine (KLSC) motif. These findings support the 'bridge hypothesis', and confirm the binding of the HC-Pro to the virion. The possible role of the PTK and KLSC motifs in binding to the virus and to the mouthparts of the aphid is discussed.
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PMID:Mutations in the HC-Pro gene of zucchini yellow mosaic potyvirus: effects on aphid transmission and binding to purified virions. 956 86

Computer analysis of protein phosphorylation site sequences revealed that transcriptional factors and viral oncoproteins are prime targets for regulation of proline-directed protein phosphorylation, suggesting an association of the proline-directed protein kinase (PDPK) family with neoplastic transformation and tumorigenesis. In this report, an immunoprecipitate activity assay of proline-directed protein kinase F(A)/glycogen synthase kinase-3alpha (PDPK F(A)/GSK-3alpha) has been optimized to demonstrate significantly increased (p < 0.01) activity in poorly differentiated human prostate carcinoma PC-3 cells (55.5+/-3.8 units/mg) when compared to well-differentiated LNCaP cells (28.1+/-2.3 units/mg). Immunoblotting analysis revealed that increased activity of this PDPK in PC-3 cells is due not to overexpression of the protein, but to enhanced tyrosine phosphorylation of the kinase. When treated with genistein (a protein tyrosine kinase PTK inhibitor), the enhanced tyrosine phosphorylation/activation of the kinase in PC-3 cells can be blocked. Conversely, when treated with vanadate (a protein tyrosine phosphatase PTP inhibitor), the phosphotyrosine content of PDPK F(A)/GSK-3alpha in LNCaP cells can be promoted to the level of PC-3 cells. In sharp contrast, the PTK inhibitor has little effect on the tyrosine phosphorylation level of the kinase in LNCaP cells, whereas the PTP inhibitor has little effect on the tyrosine phosphorylation level of the kinase in PC-3 cells. Taken together, the results provide initial evidence that the tyrosine phosphorylation/activation levels of this oncogenic PDPK can be differentially regulated in well- and poorly differentiated prostate carcinoma cells.
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PMID:Differential tyrosine phosphorylation/activation of oncogenic proline-directed protein kinase F(A)/GSK-3alpha in well and poorly differentiated human prostate carcinoma cells. 961 86

Hereditary or primary lymphedema is a developmental disorder of the lymphatic system which leads to a disabling and disfiguring swelling of the extremities. Hereditary lymphedema generally shows an autosomal dominant pattern of inheritance with reduced penetrance, variable expression and variable age at onset. Three multigeneration families demonstrating the phenotype of hereditary lymphedema segregating as an autosomal dominant trait with incomplete penetrance were genotyped for 366 autosomal markers. Linkage analysis yielded a two-point LOD score of 6.1 at straight theta = 0. 0 for marker D5S1354 and a maximum multipoint LOD score of 8.8 at marker D5S1354 located at chromosome 5q34-q35. Linkage analysis in two additional families using markers from the linked region showed one family consistent for linkage to distal chromosome 5. In the second family, linkage to 5q was excluded for all markers in the region with LOD scores Z < -2.0. The vascular endothelial growth factor C receptor ( FLT4 ) was mapped to the linked region, and partial sequence analysis identified a G-->A transition at nucleotide position 3360 of the FLT4 cDNA, predicting a leucine for proline substitution at residue 1126 of the mature receptor in one nuclear family. This study localizes a gene for primary lymphedema to distal chromosome 5q, identifies a plausible candidate gene in the linked region, and provides evidence for a second, unlinked locus for primary lymphedema.
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PMID:Hereditary lymphedema: evidence for linkage and genetic heterogeneity. 981 24

KIT receptor kinase activity is repressed, prior to stem cell factor binding, by unknown structural constraints. Using site-directed mutagenesis, we examined the role of KIT intracellular juxtamembrane residues Met-552 through Ile-563 in controlling receptor autophosphorylation. Alanine substitution for Tyr-553, Trp-557, Val-559, or Val-560, all sitting along the hydrophobic side of an amphipathic alpha-helix (Tyr-553-Ile-563) predicted by the Chou-Fasman algorithm, resulted in substantially increased spontaneous receptor phosphorylation, revealing inhibitory roles for these residues. Alanine substitution for other residues, most of which are on the hydrophilic side of the helix, caused no or slightly increased basal receptor phosphorylation. Converting Tyr-553 or Trp-557 to phenylalanine generated slight or no elevation, respectively, in basal KIT phosphorylation, indicating that the phenyl ring of Tyr-553 and the hydrophobicity of Trp-557 are critical for the inhibition. Although alanine substitution for Lys-558 had no effect on receptor phosphorylation, its substitution with proline produced high spontaneous receptor phosphorylation, suggesting that the predicted alpha-helical conformation is involved in the inhibition. A synthetic peptide comprising Tyr-553 through Ile-563 showed circular dichroism spectra characteristic of alpha-helix, supporting the structural prediction. Thus, the KIT intracellular juxtamembrane region contains important residues which, in a putative alpha-helical conformation, exert inhibitory control on the kinase activity of ligand-unoccupied receptor.
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PMID:Inhibition of spontaneous receptor phosphorylation by residues in a putative alpha-helix in the KIT intracellular juxtamembrane region. 1022 3

Several mutations were identified in the kinase domain of the RET proto-oncogene in patients with multiple endocrine neoplasia (MEN) 2B, familial medullary thyroid carcinoma (FMTC) or sporadic medullary thyroid carcinoma. We introduced seven mutations (glutamic acid 768-->aspartic acid (E768D), valine 804-->leucine (V804L), alanine 883-->phenylalanine (A883F), serine 891-->alanine (S891A), methionine 918-->threonine (M918T), alanine 919-->proline (A919P) and E768D/A919P) into the short and long isoforms of RET cDNA and transfected the mutant cDNAs into NIH3T3 cells. The transforming activity of the long isoform of Ret with each mutation was much higher that that of its short isoform. Based on the levels of the transforming activity, these mutant RET genes were classified into two groups; a group with high transforming activity (A883F, M918T and E768D/A919P) and a group with low transforming activity (E768D, V804L, S891A and A919P) (designated high group and low group). Interestingly, the level of transforming activity correlated with clinical phenotypes; high group Ret with the A883F or M918T mutation and low group Ret with the E768D, V804L or S891A mutation were associated with the development of MEN 2B and FMTC, respectively. In addition, we found that substitution of phenylalanine for tyrosine 905 present in the kinase domain abolished both transforming and autophosphorylation activities of low group Ret whereas it did not affect the activities of high group Ret.
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PMID:Biological and biochemical properties of Ret with kinase domain mutations identified in multiple endocrine neoplasia type 2B and familial medullary thyroid carcinoma. 1044 57

Amino acid starvation markedly stimulates the activity of system A, a widely distributed transport route for neutral amino acids. The involvement of MAPK (mitogen-activated protein kinase) pathways in this adaptive increase of transport activity was studied in cultured human fibroblasts. In these cells, a 3-fold stimulation of system A transport activity required a 6-h amino acid-free incubation. However, a rapid tyrosine phosphorylation of ERK (extracellular regulated kinase) 1 and 2, and JNK (Jun N-terminal kinase) 1, but not of p38, was observed after the substitution of complete medium with amino acid-free saline solution. ERK1/2 activity was 4-fold enhanced after a 15-min amino acid-free incubation and maintained at stimulated values thereafter. A transient, less evident stimulation of JNK1 activity was also detected, while the activity of p38 was not affected by amino acid deprivation. PD98059, an inhibitor of ERK1/2 activation, completely suppressed the adaptive increase of system A transport activity that, conversely, was unaffected by inhibitors of other transduction pathways, such as rapamycin and wortmannin, as well as by chronic treatment with phorbol esters. In the presence of either L-proline or 2-(methylaminoisobutyric) acid, two substrates of system A, the transport increase was prevented and no sustained stimulation of ERK1/2 was observed. To identify the stimulus that maintains MAPK activation, cell volume was monitored during amino acid-free incubation. It was found that amino acid deprivation caused a progressive cell shrinkage (30% after a 6-h starvation). If proline was added to amino acid-starved, shrunken cells, normal values of cell volume were rapidly restored. However, proline-dependent volume rescue was hampered if cells were pretreated with PD98059. It is concluded that (a) the triggering of adaptive increase of system A activity requires a prolonged activation of ERK1 and 2 and that (b) cell volume changes, caused by the depletion of intracellular amino acid pool, may underlie the activation of MAPKs.
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PMID:Adaptive increase of amino acid transport system A requires ERK1/2 activation. 1050 37


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