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 features of three distinct protein phosphorylation cascades in mammalian cells are becoming clear. These signalling pathways link receptor-mediated events at the cell surface or intracellular perturbations such as DNA damage to changes in cytoskeletal structure, vesicle transport and altered transcription factor activity. The best known pathway, the Ras-->Raf-->MEK-->ERK cascade [where ERK is extracellular-signal-regulated kinase and MEK is mitogen-activated protein (MAP) kinase/ERK kinase], is typically stimulated strongly by mitogens and growth factors. The other two pathways, stimulated primarily by assorted cytokines, hormones and various forms of stress, predominantly utilize p21 proteins of the Rho family (Rho, Rac and CDC42), although Ras can also participate. Diagnostic of each pathway is the MAP kinase component, which is phosphorylated by a unique dual-specificity kinase on both tyrosine and threonine in one of three motifs (Thr-Glu-Tyr, Thr-Phe-Tyr or Thr-Gly-Tyr), depending upon the pathway. In addition to activating one or more protein phosphorylation cascades, the initiating stimulus may also mobilize a variety of other signalling molecules (e.g. protein kinase C isoforms, phospholipid kinases, G-protein alpha and beta gamma subunits, phospholipases, intracellular Ca2+). These various signals impact to a greater or lesser extent on multiple downstream effectors. Important concepts are that signal transmission often entails the targeted relocation of specific proteins in the cell, and the reversible formation of protein complexes by means of regulated protein phosphorylation. The signalling circuits may be completed by the phosphorylation of upstream effectors by downstream kinases, resulting in a modulation of the signal. Signalling is terminated and the components returned to the ground state largely by dephosphorylation. There is an indeterminant amount of cross-talk among the pathways, and many of the proteins in the pathways belong to families of closely related proteins. The potential for more than one signal to be conveyed down a pathway simultaneously (multiplex signalling) is discussed. The net effect of a given stimulus on the cell is the result of a complex intracellular integration of the intensity and duration of activation of the individual pathways. The specific outcome depends on the particular signalling molecules expressed by the target cells and on the dynamic balance among the pathways.
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PMID:Signal-transducing protein phosphorylation cascades mediated by Ras/Rho proteins in the mammalian cell: the potential for multiplex signalling. 883 13

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

We investigated the possible role of the RET proto-oncogene, which has recently been identified as the susceptibility gene for multiple endocrine neoplasia type 2, in the development of sporadic neuroendocrine tumors from different locations. DNA extracted from paraffin-embedded specimens of 112 neuroendocrine tumors was screened for somatic RET point mutations in exons 10, 11, 13, 15, and 16, where recently oncogenic mutations have been described in a subset of sporadic medullary thyroid carcinomas and pheochromocytomas. Methods employed included nonisotopic PCR-based single strand conformation polymorphism (PCR-SSCP) analysis, heteroduplex gel electrophoresis, and restriction enzyme digestion. The nucleotide sequence of samples with aberrant band patterns was identified by nonisotopic direct sequencing of PCR-amplified DNA. Forty-four percent (7/16) of sporadic medullary thyroid carcinomas and 15% (3/20) of pheochromocytomas contained a somatic, heterozygous point mutation at codon 918 of exon 16 (ATG --> ACG) causing a Met --> Thr substitution. None of the remaining 4 parathyroid adenomas, 8 pituitary adenomas, 17 pancreatic neuroendocrine tumors, 11 pulmonary and 10 gastrointestinal carcinoids, 7 small cell lung carcinomas, 5 neuroblastomas, 10 malignant melanomas, or 4 schwannomas contained mutations in any of the five RET exons tested. Although the numbers of each investigated neuroendocrine tumor type are small, our data indicate that oncogenic RET proto-oncogene mutations are involved in the formation of a subset of sporadically occurring medullary thyroid carcinomas and pheochromocytomas but do not appear to be generally important in the formation of other types of sporadically occurring neuroendocrine tumors.
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PMID:RET proto-oncogene point mutations in sporadic neuroendocrine tumors. 896 26

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

Germline mutations of the RET proto-oncogene, which codes for a receptor tyrosine kinase, cause multiple endocrine neoplasia type 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). MEN 2 mutations have been shown to result in RET oncogenic activation. The RET gene encodes several isoforms whose biological properties, when altered by MEN 2 mutations, have not been thoroughly addressed yet. In this study, we have introduced a MEN 2A mutation (Cys634-->Arg) and the unique MEN 2B mutation (Met918-->Thr) in two RET isoforms of 1114 and 1072 amino acids which differ in the carboxy-terminus part. Herein, we report that each RET isoform activated by MEN 2A or MEN 2B mutation was transforming in fibroblasts and induced neuronal differentiation of pheochromocytoma PC12 cells. However, among the different RET-MEN 2 mutants, the long RET isoform activated by the MEN 2B mutation stimulated the most prominent neurite outgrowth in PC12 cells, while the short RET isoform counterpart elicited a very weak differentiation effect in PC12 cells. We further demonstrate that the morphological changes of PC12 cells caused by constitutively activated RET oncoproteins involved the engagement of a Ras-dependent pathway. These findings provide evidence that the biological properties of RET-MEN 2 mutants depend on the interplay between the RET isoforms and the nature of the activating MEN 2 mutation.
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PMID:Distinct biological properties of two RET isoforms activated by MEN 2A and MEN 2B mutations. 901 12

Recombinant mouse perlecan domain 1(173 residues) was produced in transfected embryonic kidney cells and purified from the culture medium on DEAE-cellulose. It was shown to be modified by glycosaminoglycans and could be partially separated into two protein pools which were either substituted with heparan sulfate (fragment IA) or, to a smaller extent (20%), with chondroitin/dermatan sulfate or a mixture of both glycosaminoglycans (fragment IB). The average molecular mass of the glycosaminoglycans was about 8-10 kDa and, thus, smaller than in tissue-derived perlecans. Sequence and carbohydrate analyses localized the heparan sulfate attachment site to three Ser residues within SGD consensus sequences. Furthermore, the N-terminal part of fragment IA contained six Thr/Ser residues substituted by branched galactosamine-containing oligosaccharides and an N-substituted Asn residue. Fragment I was also shown to contain unique immunological epitopes which are not dependent on glycosaminoglycans and are shared by tissue-derived perlecan. Circular dichroism demonstrated a distinct alpha helix (20%) and beta structure (60%) in fragment IA, consistent with predictions of a novel SEA protein module located in the C-terminal part of domain I.
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PMID:Characterization of recombinant perlecan domain I and its substitution by glycosaminoglycans and oligosaccharides. 903 Jul 29

Multiple endocrine neoplasia type 2 (MEN 2) is a cancer syndrome which comprises three related disorders, MEN type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC), MEN 2A is characterized by the association of MTC, a tumour arising from thyroid C-cells, pheochromocytoma and parathyroid hyperplasia. In addition to the thyroid cancer, MEN 2B associates pheochromocytoma, mucosal neuromas, ganglioneuromatosis of the digestive tract and skeletal abnormalities. In FMTC, the MTC is the sole clinical manifestation. MEN 2 is a dominantly inherited neural crest disorder caused by germline mutations of the RET proto-oncogene. The RET gene encodes a receptor tyrosine kinase, which displays a cadherin-like domain and a cysteine rich motif in its extracellular part. Missense mutations at one of five cysteines clustered in the extra-cytoplasmic domain of RET have been identified in the majority of the MEN 2A families and in two-thirds of FMTC. A single point mutation leading to the replacement of a methionine by a threonine within the tyrosine kinase domain has been detected in almost all cases of MEN 2B. We have screened 170 french MEN 2 families and a germline mutations in the RET gene have been identified in 92% of cases. Moreover, we confirmed the significant correlation between the nature, the position of the RET mutations and the clinical phenotype. The accurate identification by DNA testing of individual predisposed to MEN 2 suggests new protocols of treatment. Thyroidectomy as early as 6 years of age in individuals with MEN 2 mutations has been recently advocated by clinicians. We further provide evidence that MEN 2A and MEN 2B mutations convert the RET proto-oncogene in a dominantly-acting transforming gene due to the ligand-independent constitutive activation of the tyrosine kinase. Finally, we have constructed transgenic mice carrying the RET gene carrying a MEN 2A mutation fused to the calcitonin gene related peptide/calcitonin promoter. Animals of three independent transgenic lines developed C-cell hyperplasia and subsequently MTC with a complete penetrance. Taken together, these findings indicate that MEN 2A form of RET is oncogenic in thyroid C-cells, and suggest that these transgenic animals should prove a valuable model for hereditary MTC. Future work should yield insights in the signaling pathways subverted by the RET-MEN 2 proteins.
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PMID:[Neural crest and multiple endocrinopathies]. 907 21

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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