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)

Hirschsprung disease (HSCR), or aganglionic megacolon, is the most common cause of congenital intestinal obstruction. Two different loci have been found to be tightly linked to HSCR on chromosomes 10 and 13, respectively. Recently, mutations in the RET protooncogene on chromosome 10q11.2 were identified in several HSCR patients. In addition, a missense mutation in the endothelin-B receptor (EDNRB) gene on chromosome 13q22 was found in an inbred Mennonite kindred affected by HSCR and associated abnormalities, demonstrating the involvement of EDNRB in HSCR pathogenesis. To test whether mutations in the EDNRB gene could account for Hirschsprung in patients from non-inbred populations, we analysed DNA samples from 17 probands of Italian origin with HSCR. We have identified two novel EDNRB mutations: a missense mutation in a sporadic case, S305N, which leads to a change of a serine to an asparagine, disrupting a putative phosphorylation site; and a single nucleotide deletion in a familial case, N378I, resulting in a truncated protein. Both mutations were found in one of the healthy parents, and neither of these mutations were found in any of the normal individuals tested. These data confirm the involvement of EDNRB in HSCR pathogenesis and demonstrate that EDNRB mutations could contribute to HSCR disease in non-inbred populations.
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PMID:Endothelin-B receptor mutations in patients with isolated Hirschsprung disease from a non-inbred population. 885 59

We isolated a cDNA clone, Elk-3, that encodes a novel Ets transcription factor from 16-day mouse embryos. The deduced amino acid sequence of the protein was homologous to human ELK-1 and SAP-1. This protein, ELK-1, and SAP-1 shared some unique structural properties such as an Ets DNA-binding site in the amino-terminal region, a serum response factor interacting domain and phosphorylation sites of serine or threonine residues in the carboxy-terminal region. Northern blotting weakly revealed that two transcripts of 4 and 2.1 kb are expressed in the adult ovary and lung and a 2.1-kb transcript predominated in 8- to 14-day embryos. We assayed the transcriptional activities of Elk-3 protein on the cytokeratin EndoA enhancer containing Ets binding sites in endodermal cells. Elk-3 protein strongly repressed enhancer activity but did not affect the activity of the basal promoter in the absence of the enhancer. Furthermore, Elk-3 can suppress the activity of Ets-2 as the transcriptional activator on the EndoA enhancer. These data suggested that the Elk-3 gene product plays a role in transcriptional regulation during embryogenesis.
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PMID:Molecular cloning of Elk-3, a new member of the Ets family expressed during mouse embryogenesis and analysis of its transcriptional repression activity. 889 57

Receptor serine-threonine kinases (RSTK) mediate inhibitory as well as stimulatory signals for growth and differentiation by binding to members of the transforming growth factor-beta (TGF-beta) superfamily. Over 12 different RSTKs have been isolated so far, displaying wide expression in peripheral tissues and in the nervous system. Here we report the isolation and characterization of a novel type I RSTK termed activin receptor-like kinase-7 (ALK-7) that, unlike other members of this receptor family, is predominantly expressed in the adult central nervous system. The ALK-7 gene encodes a 55-kDa cell-surface protein that exhibits up to 78% amino acid sequence identity in the kinase domain to previously isolated type I receptors for TGF-beta and activin. In the extracellular domain, however, ALK-7 is more divergent, displaying comparable similarities with all members of the ALK subfamily. RNase protection and in situ hybridization studies demonstrated a highly specific mRNA distribution restricted to neurons in several regions of the adult rat central nervous system, including cerebellum, hippocampus, and nuclei of the brainstem. Receptor reconstitution and cross-linking experiments indicated that ALK-7 can form complexes with type II RSTKs for TGF-beta and activin in a ligand-dependent manner, although direct binding of ALK-7 to ligand in these complexes could not be demonstrated. The specific expression pattern of ALK-7, restricted to the postnatal central nervous system, indicates that this receptor may play an important role in the maturation and maintenance of several neuronal subpopulations.
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PMID:A novel type I receptor serine-threonine kinase predominantly expressed in the adult central nervous system. 894 33

The causative relationship between several of the syndromic forms of craniosynostosis and mutations in the fibroblast growth factor receptor (FGFR) loci is now well established. However, within the group of patients with craniosynostosis, there are several families and sporadic cases whose clinical features differ in variable degrees from the classically described syndromes of craniosynostosis. In this communication we present novel FGFR2 mutations associated with a spectrum of craniosyostosis phenotypes in 4 sporadic cases and in one family in which craniosynostosis segregates. The mutation and phenotype data presented emphasise the clinical variability of mutations at this locus and underline the plasticity of the phenotype-genotype relationship in this important group of congenital malformation syndromes. Mutations found were tyrosine 105 to cysteine, glycine 338 to glutamic acid, serine 351 to cysteine and glycine 384 to arginine. These are the first reported mutations in the first immunoglobulin-like loop (tyrosine 105 to cysteine) and the transmembrane domain (glycine 384 to arginine) of FGFR2, providing further insights into the mechanism of abnormal receptor function in FGFR2 mutations.
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PMID:Spectrum of craniosynostosis phenotypes associated with novel mutations at the fibroblast growth factor receptor 2 locus. 894 74

Human heat shock transcription factor 1 (HSF1) is responsible for stress-induced transcription of heat shock protein genes. The activity of the HSF1 transcriptional activation domains is modulated by a separate regulatory domain, which confers repression at control temperature and heat inducibility. We show here that two specific proline-directed serine motifs are important for function of the regulatory domain: Mutation of these serines to alanine derepresses HSF1 activity at control temperature, and mutation to glutamic acid, mimicking a phosphorylated serine, results in normal repression at control temperature and normal heat shock inducibility. Tryptic mapping shows that these serines are the major phosphorylation sites of HSF1 at control temperature in vivo. Stimulation of the Raf/ERK pathway in vivo results in an increased level of phosphorylation of these major sites and the regulatory domain is an excellent substrate in vitro for the mitogen-activated MAPK/ERK. We conclude that phosphorylation of the regulatory domain of HSF1 decreases the activity of HSF1 at control temperature, and propose a mechanism for modification of HSF1 activity by growth control signals.
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PMID:Repression of human heat shock factor 1 activity at control temperature by phosphorylation. 894 18

The serine/threonine phosphatase inhibitor, okadaic acid (OA), exerted several insulin-like effects in rat adipose cells and was, in part, synergistic with insulin. OA stimulated glucose transport activity, altered the electrophoretic mobility of IRS-1, increased the phosphorylation of the MAP-kinases ERK 1 and 2 on tyrosine sites, markedly increased MAP kinase activity and also acted synergistically with insulin in activating these enzymes. However, OA did not increase PI 3-kinase activity or the tyrosine phosphorylation of key upstream proteins in insulin's signaling cascade. Staurosporine virtually completely inhibited the insulin-stimulated glucose transport and MAP kinase activation in spite of a maintained high PI 3-kinase activity. In contrast, the effects of OA alone or in the presence of insulin were less, or not at all, affected. These data suggest that OA exerts an insulin-like effect through a serine/threonine-related pathway which is distinct from, but converges with, that of insulin downstream PI 3-kinase and upon which staurosporine exerts an inhibitory effect.
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PMID:The inhibitory effect of staurosporine on insulin action is prevented by okadaic acid. Evidence for an important role of serine/threonine phosphorylation in eliciting insulin-like effects. 897 17

Integrins can trigger signals by activation of cytoplasmic tyrosine kinases, including pp125FAK. Preliminary evidence suggests that serine/threonine kinases such as ERKs may also be activated via integrins. Thus, there seems to be at least partial overlap between RTK signaling pathways and integrin signaling. In tumor cells, ectopic expression or over-expression of certain integrins such as alpha 5/beta 1 can result in reduced tumorigenesis. Presumably the effects of integrins on tumor growth are mediated by the integrin signaling pathway(s) involving FAK and ERKs. However, the precise mechanisms involved have not yet been elucidated.
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PMID:Integrin signals and tumor growth control. 898 69

DNA encoding the full-length Schistosoma mansoni epidermal growth factor receptor, SER, was obtained by combining partial cDNA clones. Three different anti-SER antibody preparations, specific either to the SER amino-terminus or the predicted ligand binding domain were generated with recombinant or synthetic peptides and purified by antigen affinity. Recombinant SER was expressed within insect cells using the baculovirus expression system and detected by each of the anti-SER antibodies as well as anti-phosphotyrosine antibodies. By in vitro phosphorylation of immunoprecipitated recombinant SER, the protein has been shown to be capable of tyrosine autophosphorylation but this activity is not affected by human epidermal growth factor. Native SER is detected as a 170 kDa protein in Western blots of S. mansoni adult worm membrane preparations. Adult worm sections, labeled with anti-SER antibodies, localize SER predominantly to the muscle of adult male and female worms. These results confirm a place for SER in the EGFR family of tyrosine kinases and strongly suggest that it participates in schistosome signal transduction, perhaps related to muscle development or function.
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PMID:The Schistosoma mansoni epidermal growth factor receptor homologue, SER, has tyrosine kinase activity and is localized in adult muscle. 901 Aug 37

Perlecan is primarily a heparan sulfate containing proteoglycan found in all basement membranes. Rotary shadowed images of perlecan show it to contain three glycosaminoglycan (GAG) side chains extending from one end of its core protein. Domain I is at the N terminus of perlecan and contains three closely spaced Ser-Gly-Asp sequences that may serve in GAG attachment. We evaluated the serines in these three sequences for GAG attachment by preparing a cDNA construct encoding for the N-terminal half (domains I, II, and III) of perlecan and then a series of constructs containing deletions and mutations within domain I of the domain I/II/III construct, expressing these constructs in COS-7 cells, and then analyzing the recombinant product for GAG side chains and GAG type. The results showed that all three serine residues in the Ser-Gly-Asp sequences in domain I can accept both chondroitin and heparan sulfate side chains but that a cluster of acidic residues N-terminal to these sequences is the primary determinant responsible for targeting these sites for heparan sulfate. Furthermore, there are two elements that can enhance heparan sulfate synthesis at a targeted site: 1) the presence of a the SEA module in the C-terminal region of domain I and 2) the presence of multiple acceptors in close proximity. These results indicate that the proportion of heparan and chondroitin sulfate at any one site in domain I of perlecan is regulated by multiple factors.
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PMID:Identification of sites in domain I of perlecan that regulate heparan sulfate synthesis. 902 Jan 50

Specific point-mutations of the RET receptor tyrosine kinase protooncogene are responsible for the inheritance of multiple endocrine neoplasia type 2A (MEN2A) and 2B (MEN2B), and familial medullary thyroid carcinoma (FMTC). MEN2B is caused by the substitution of methionine 918 by a threonine in the tyrosine kinase (TK) domain of RET. This mutation converts RET into a dominant transforming oncogene. We have substituted Met918 with four different residues and found that RET acquired transforming activity only when Met918 was substituted with a threonine. However, also when serine and valine, but not leucine or phenylalanine, were inserted in position 918, the RET TK function was activated and induced, especially in the case of the RET(918Ser), immmediate-early response genes. We conclude that the preservation of Met918 is critical for the control of RET kinase. However, only when a threonine residue is present in position 918, does RET efficiently couple with a transforming pathway.
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PMID:Only the substitution of methionine 918 with a threonine and not with other residues activates RET transforming potential. 907 1


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