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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)

How do distinct protein-tyrosine kinases activate specific down-stream events? Src-homology-2 (SH2) domains on tyrosine kinases or targets of tyrosine kinases recognize phosphotyrosine in a specific sequence context and thereby provide some specificity. The role of the catalytic site of tyrosine kinases in determining target specificity has not been fully investigated. Here we use a degenerate peptide library to show that each of nine tyrosine kinases investigated has a unique optimal peptide substrate. We find that the cytosolic tyrosine kinases preferentially phosphorylate peptides recognized by their own SH2 domains or closely related SH2 domains (group I; ref. 3), whereas receptor tyrosine kinases preferentially phosphorylate peptides recognized by subsets of group III SH2 domains. The importance of these findings for human disease is underscored by our observation that a point mutation in the RET receptor-type tyrosine kinase, which causes multiple endocrine neoplasia type 2B, results in a shift in peptide substrate specificity.
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PMID:Catalytic specificity of protein-tyrosine kinases is critical for selective signalling. 784 56

Germline mutations within one of six codons of the RET proto-oncogene account for the majority of cases of multiple endocrine neoplasia (MEN) type 2A and type 2B and familial medullary thyroid carcinoma (FMTC). MEN 2A and FMTC mutations characterised thus far occur exclusively in the cysteine-rich domain of the extracellular region of RET. We now report a missense mutation in the intracellular tyrosine kinase domain of RET in the germline of a family with FMTC that does not have a cysteine codon mutation. In this family, the mutation, which alters GAG (Glu) to GAC (Asp) at codon 768, segregates with the FMTC phenotype. The same mutation was also detected in sporadic MTC but not in corresponding constitutional DNA, confirming that it is likely to be of pathological significance rather than a rare polymorphism.
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PMID:A novel point mutation in the tyrosine kinase domain of the RET proto-oncogene in sporadic medullary thyroid carcinoma and in a family with FMTC. 784 75

Multiple endocrine neoplasia type 2 (MEN 2) is a dominantly inherited cancer syndrome which affects thyroid C cells, and with variable frequency, the adrenal medulla, parathyroid and enteric autonomic ganglia. The syndrome is due to germline mutation in the receptor tyrosine kinase gene, RET. We have recently shown an unexpected correlation between one particular RET mutation, cys634-->arg, and the probability of parathyroid involvement in families with MEN 2A. Here we use haplotype analysis in the families to show that this correlation is not explained by a single founder chromosome which carries both the cys634-->arg mutation and a separate allele conferring susceptibility to parathyroid abnormality, but is probably due to the cys634-->arg mutation itself. The results also indicate that new mutations to MEN 2 are not infrequent.
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PMID:Haplotype analysis of MEN 2 mutations. 784

Mutations in the RET protooncogene have recently been demonstrated in families with multiple endocrine neoplasia (MEN) types 2A and 2B. We have studied pheochromocytomas from 29 individuals who had no clinical evidence of MEN-2A or -2B to determine the frequency of germline and/or somatic mutations in exons 10, 11, and 16 of the RET protooncogene. Of the 29 tumors examined, 3 (10%) were found to have a mutation in 1 of the 3 exons. These mutations were not found in the DNA from the peripheral blood from these individuals, indicating that the mutations in the tumors were somatic in origin. Although we cannot exclude the possibility of mutations in other regions of the RET protooncogene, our data suggest that 1) individuals presenting with apparently sporadic pheochromocytomas are not likely to have undiagnosed MEN-2A or -2B; and 2) somatic mutations in exons 10, 11, and 16 in the RET protooncogene contribute to the process of tumorigenesis in a small percentage of sporadic pheochromocytomas.
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PMID:Mutations in the RET protooncogene in sporadic pheochromocytomas. 785 30

Multiple endocrine neoplasia type 2A (MEN2A) is a dominantly inherited cancer syndrome characterized by medullary thyroid carcinoma, pheochromocytoma, and parathyroid hyperplasia. The gene responsible for MEN2A was localized by linkage analysis to chromosome 10q11.2 in 1987, and recently mutations in RET, a proto-oncogene in the candidate region, were discovered in patients with MEN. The majority of mutations found so far in MEN2A patients have been located in nucleotide sequences encoding cysteine residues in the extracellular domain of RET. To characterize MEN2A germline alterations in the Japanese population, we screened DNA from eight unrelated patients for mutations in exons 10 and 11 of the RET proto-oncogene and found mutations in all eight patients, at codons 618, 620, or 634; each of these sites encodes a cysteine residue in the extracellular domain of RET. The mutations were confirmed in other affected individuals in the respective families by digestion of polymerase chain reaction (PCR) products containing the mutated codons with restriction enzymes (Rs alpha I, CfoI, or AluI) for which cleavage sites had been generated by the specific genetic alteration. These PCR-restriction enzyme systems will be useful for genetic diagnosis in members of families carrying these mutations.
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PMID:Germline mutations of the RET proto-oncogene in eight Japanese patients with multiple endocrine neoplasia type 2A (MEN2A). 786 65

The c-ret proto-oncogene encodes a receptor tyrosine kinase that plays important roles in human disease and in normal mammalian development. Mutations in the human RET gene are associated with multiple endocrine neoplasia syndromes and Hirschsprung's disease in humans, while targeted mutagenesis of murine c-ret resulted in severe developmental abnormalities affecting the excretory and peripheral nervous systems. To examine the evolutionary conservation of the ret protein sequence and its developmental expression pattern, we isolated and sequenced cDNA clones of chicken c-ret and examined its expression in chick embryos and adult tissues. The cytoplasmic domains of chicken and human ret were relatively well conserved (91% similar), but the extracellular domains were more divergent (68% similar), although the conservation of cysteine residues in this region suggests a conserved secondary structure. As in mouse and human, chicken c-ret encodes two protein isoforms. The number and sizes of the transcripts were similar to those in human and mouse cells, and during chick embryogenesis, c-ret mRNA was observed in many of the same sites as in the mouse, including the Wolffian duct and ureteric bud, the enteric, dorsal root, sympathetic and facioacoustic ganglia, and the ventral spinal cord. Evolutionary differences in expression were observed in the trigeminal ganglion, the ventral roots of the spinal cord, the mesenchymal cells of the branchial arches and the adult testes. The results are discussed with regard to the role of the ret receptor in normal development and disease.
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PMID:Isolation and characterization of a chicken homolog of the c-ret proto-oncogene. 786 41

The RET proto-oncogene encodes a tyrosine-kinase receptor specifically expressed in tissues of neuroectodermal origin. Recently specific point mutations of RET have been demonstrated to be responsible for the Multiple Endocrine Neoplasia type 2A and 2B and Familial Medullary Thyroid Carcinoma syndromes, characterized by the occurrence of medullary thyroid carcinomas. Here we report that a human medullary thyroid carcinoma cell line, the TT cell line, harbours a MEN2A-type mutation, specifically a cysteine to triptophan substitution at the level of the RET codon 634. This mutation is heterozygous and both normal and mutated alleles are expressed. We suggest that the TT cell line could be a useful cell system to investigate the role played by the RET oncogene in the transformation and differentiation of human thyroid C-cells.
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PMID:Point mutation of the RET proto-oncogene in the TT human medullary thyroid carcinoma cell line. 786 88

Constitutional mutations of the RET proto-oncogene have been identified in multiple endocrine neoplasia type 2A (MEN 2A), type 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC) families. We sequenced RET exons 10 and 11 in 86 unrelated patients with an inherited predisposition to MTC (excluding MEN 2B). Germ-line mutations were identified in 93% of the MEN 2A families and 67% of the FMTC families tested. All were missense mutations affecting one of three cysteines in the extracellular domain of the RET tyrosine kinase receptor. The prevalence of phaeochromocytoma and hyperparathyroidism was significantly higher in families with a mutation of cysteine 634. These data confirm the preferential localisation of MEN 2A and FMTC associated mutations and the strong correlation between clinical manifestations and the position of RET mutation. Although direct sequencing of RET exons 10 and 11 allows the identification of a constitutional mutation in a large proportion of MEN 2A and FMTC families, our data sustain the existence of other MTC predisposing mutations elsewhere in RET coding or regulating region.
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PMID:RET proto-oncogene mutations in French MEN 2A and FMTC families. 787 9

Mutations of the RET proto-oncogene are the underlying cause of some cases of Hirschsprung disease (HSCR) and the inherited cancer syndromes multiple endocrine neoplasia types 2A (MEN 2A) and 2B (MEN 2B) and familial medullary thyroid carcinoma (FMTC). In HSCR these mutations are dispersed throughout the gene, while in MEN 2A and FMTC, they are tightly clustered in five cysteine codons of the RET extracellular domain. HSCR and MEN 2 are usually distinct but occasional families have been reported with both diseases. In each of five families with HSCR with or without MEN 2A or FMTC, we have identified a nucleotide substitution in one of the five cysteine codons previously associated with MEN 2A or FMTC. In one family, which had HSCR as its only phenotype, we detected a Cys-->Trp mutation at codon 609 which had not been previously observed. In three families, both HSCR and MEN 2A were associated with a single Cys-->Arg mutation at either codon 618 or 620 of RET. In the fifth family, FMTC and HSCR were present but we could not determine whether HSCR arose from mutation of the RET locus. We suggest that specific mutations in cysteine codons 618 and 620 result in MEN 2A or FMTC, but can also predispose to HSCR with low penetrance.
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PMID:Diverse phenotypes associated with exon 10 mutations of the RET proto-oncogene. 788 14

Distinct point mutations in the RET proto-oncogene are the cause of the inherited multiple endocrine neoplasia type 2 syndromes (MEN 2), and the congenital gut disorder Hirschsprung disease. The site and type of these mutations suggests that they have differing effects on the activity of the receptor tyrosine kinase encoded by RET. The normal function of the RET receptor tyrosine kinase has yet to be determined. However, this has been investigated by the inactivation of the RET gene in transgenic mice. The developmental abnormalities apparent in these mice, together with the observation that the major tissues affected in MEN 2 and Hirschsprung disease have a common origin in the embryonal neural crest, suggest that RET encodes a receptor for a developmental regulator involved in the genesis of a variety of neural crest derivatives, and in the organogenesis of the kidney.
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PMID:Mutations of the RET proto-oncogene in the multiple endocrine neoplasia type 2 syndromes and Hirschsprung disease. 788 91


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