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)

Using a polymerase chain reaction-mediated approach we have characterized cDNAs from human and mouse origin representing a novel type of receptor protein tyrosine kinase (RTK). The deduced amino acid sequence (855 amino acids) of the longest open reading frame has a unique extracellular region encompassing a factor VIII-like domain, not previously described for RTKs. The most closely related RTKs are members of the neurotrophin receptors (TRK), which showed 47-49% homology with the kinase domain of the new RTK. Therefore, the new gene has been called TKT (Tyrosine-Kinase related to TRK). TKT orthologs from man and mouse were 98% similar. In both species a major transcript of 10 kb was found to be expressed at high levels in heart and lung. Low levels of this mRNA-species were detected in human brain, placenta, liver, skeletal muscle, kidney and in mouse brain and testis. Analysing human/mouse somatic cell hybrids we demonstrated that TKT segregates with human chromosome 1.
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PMID:Structure, expression and chromosomal mapping of TKT from man and mouse: a new subclass of receptor tyrosine kinases with a factor VIII-like domain. 824 48

There is considerable interest in the role of the TRK family of neuotrophin receptors in regulating growth and differentiation in normal and neoplastic nerve cells. A neuroblastoma is a common pediatric tumor derived from the neural crest, and the majority of favorable neuroblastomas express a high level of TRK-A mRNA. However, little is known about the expression or function of TRK-B in these tumors. TRK-B encodes a tyrosine kinase that binds to brain-derived neuotrophic factor (BDNF), as well as neurotrophin-3 (NT-3) and NT-4/5. We have studied the N-myc-amplified human neuroblastoma cell line, SMS-KCN, which expresses both TRK-B and BDNF. Exogenous BDNF induces tyrosine phosphorylation of TRK-B as well as phosphorylation of phospholipase C-gamma 1, the extracellular signal-regulated kinases 1 and 2, and phosphatidylinositol-3 kinase. BDNF also induces expression of the immediate-early genes c-FOS and NGFI-A but not NGFI-B or NGFI-C. In addition, BDNF appears to promote cell survival and neurite outgrowth. SMS-KCN cells also express TRK-A, which is phosphorylated in response to nerve growth factor. However, the downstream TRK-A signaling is apparently defective. Finally, we determined that in a series of 74 primary neuroblastomas, 36% express TRK-B mRNA, 68% express BDNF mRNA, and 31% express both. Truncated TRK-B appears to be preferentially expressed in more-differentiated tumors (ganglioneuromas and ganglioneuroblastomas), whereas full-length TRK-B is expressed almost exclusively in immature neuroblastomas with N-myc amplification. Our findings suggest that in TRK-B-expressing human neuroblastomas, BDNF promotes survival and induces neurite outgrowth in an autocrine or paracrine manner. The BDNF/TRK-B pathway may be particularly important for growth and differentiation of neuroblastomas with N-myc amplification.
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PMID:Expression and function of TRK-B and BDNF in human neuroblastomas. 826 43

TRK oncogenes are created by chromosomal rearrangements linking the tyrosine-kinase domain of the NTRK1 gene (encoding one of the receptors for the nerve growth factor) to foreign activating sequences. TRK oncogenes are frequently detected in human papillary thyroid carcinoma, as result of rearrangements involving at least three different activating genes. We have found that the rearrangements creating all the TRK oncogenes so far characterized fall within a 2.9-kb XbaI/SmaI restriction fragment of the NTRK1 gene. Here we report the nucleotide sequence and the exon organization of this fragment.
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PMID:Characterization of the NTRK1 genomic region involved in chromosomal rearrangements generating TRK oncogenes. 828 44

The expression and cellular localization of NGF receptors in the developing rat retina were investigated immunocytochemically and biochemically. In in vitro preparations of retinal neurons from neonatal rats the functional NGF receptor p140trkA was immunocytochemically detected on retrogradely labeled retinal ganglion cells (RGCs). In transverse retinal sections p140trk-immunopositive cells were localized exclusively at the level of the RGC layer. Affinity labeling with 125I-NGF, chemical cross-linking, and immunoprecipitation with anti-NGF antibodies revealed the presence of three complexes which migrate on SDS-PAGE at approximately 90, 95, and 150 kDa. The bands at 90 and 95 kDa correspond to the so-called low affinity NGF receptor p75NGFR. Western blotting experiments using anti-TRK antibodies revealed that the slowest migrating band (150 kDa), which is not immunoprecipitated by monoclonal antibodies to p75NGFR, corresponds to p140trkA. The presence of the functional NGF receptor on RGCs provides the molecular explanation for the reported sensitivity of these cells to the biological action of NGF.
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PMID:Developing rat retinal ganglion cells express the functional NGF receptor p140trkA. 836 54

We have isolated a murine cDNA, nep, which encodes a novel receptor-like protein tyrosine kinase. The kinase region of NEP protein bears 50% amino acid sequence identity to the neurotrophin receptors (TRKs). While the intracytoplasmic portion of NEP also contains a short kinase insert region and C-terminal tail reminiscent of the TRK proteins, the putative extracellular domain of NEP is unrelated to any known proteins. The nep gene is strongly expressed within proliferating neuroepithelia of mouse embryos, commencing at the early somite stage (embryonic day 8.0) and persisting in the proliferative ventricular zones of the brain and spinal cord, suggesting that one function of NEP kinase is to signal proliferation of neuroepithelial cells in response to an as yet unknown ligand. The nep gene is also expressed in embryonic sensory ganglia, striated muscle and epidermis, as well as in several adult tissues, including the ventricle linings and glia subpopulations in the brain.
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PMID:NEP: a novel receptor-like tyrosine kinase expressed in proliferating neuroepithelia. 839 69

The TRK-T1 oncogene, isolated from a human thyroid carcinoma, represents a rearranged form of the high affinity nerve growth factor (NGF) receptor encoded by the NTRK1 gene; it is created by an intrachromosomal rearrangement fusing the NTRK1 tyrosine kinase domain to the 5' portion of the TPR gene. We have investigated the effect of the TRK-T1 oncogene in PC12 cells, a model system for studying neuronal differentiation and the mechanism of action of NGF. Here, we report that, in PC12 cells, the TRK-T1 oncogene has a differentiating effect that resembles that of NGF and requires the phosphorylation of the oncoprotein. Our results are consistent with the hypothesis that TRK-T1, as well as the original TRK oncogene, induces PC12 differentiation by mimicking the action of NGF bound to its receptor.
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PMID:Expression of TRK-T1 oncogene induces differentiation of PC12 cells. 839 95

We have recently reported that about 50% of papillary thyroid carcinomas harbor an activated TRK or RET oncogene. Two retroviral vectors containing the activated TRK or RET/PTC oncogene have been used to infect a differentiated rat thyroid epithelial cell line, namely the PC Clone 3 cell line. Upon infection with the TRK virus, the PC Clone 3 cells lost only the ability to trap iodide and to express the thyroperoxidase gene. Conversely, when infected with the PTC virus, the PC Clone 3 cells completely lost all of their differentiated functions. However, both the PC-TRK and PC-PTC cell lines were unable to grow in soft agar, and they were not tumorigenic when injected into nude mice. A completely undifferentiated and malignant phenotype was obtained by the cooperation between the TRK or RET and the viral Ha-ras or Ki-ras oncogenes.
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PMID:The TRK and RET tyrosine kinase oncogenes cooperate with ras in the neoplastic transformation of a rat thyroid epithelial cell line. 849 86

Cancer from exposure to chemicals is known for more than two centuries. Today, approximately 40 compounds have been identified as unequivocally carcinogenic in humans, more than 300 have been shown to be carcinogenic in animal experimentation. Accordingly, an old system subdivides carcinogens as human carcinogens (A1), animal carcinogens (A2, and compounds being suspective of exerting carcinogenic activity. There exist no threshoulds of effect for notorious carcinogens. In order to improve the protection of those exposed to carcinogens in the working area, a special type of tolerance values has been introduced (technical guidance values, TRK). Contrary to MAK-values, these TRKs take into account a certain residual cancer risk which in most cases can not be quantified. The amount of acceptable residual risks is a matter of political consensus which has to be organized between the societal groups involved. For the purpose of quantitative comparisons, "unit risks" have been introduced; the problematics of this category is discussed to some extend.
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PMID:[Strategies for evaluating carcinogenic substances]. 857 7

The pharmacokinetics and ototoxicity of the new platinum analogue TRK-710 (3, 9, 15 mg/kg x 3 days) were compared with those of cisplatin (1, 3, 5 mg/kg x 3). The perilymphatic concentration of TRK-710 was one seventh of that of cisplatin even 1 h after the administration. The N1 threshold of the compound action potential was elevated dose-dependently in both groups with a similar degree of hearing impairment. Morphological observation using phase contrast microscopy and scanning electron microscopy revealed the damage of the outer hair cells to almost the same degree mainly in the basal and second turns. Despite its usefulness against cisplatin-resistant tumors and a lesser degree of nephrotoxicity and myelosuppression, TRK-710 should be clinically used with caution similar to cisplatin.
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PMID:Ototoxicity of the new platinum anticancer agent TRK-710 in comparison with cisplatin. 858 76

Neurotrophic factors, particularly the neurotrophins nerve growth factor (NGF) and brain-derived neurotrophic factor (BDNF) and related molecules are proposed for the experimental treatment of neurode-generative disease. Earlier observations had suggested down-regulation of the neurotrophin receptor response with chronic stimulation. We therefore tested for effects of acute and chronic NGF treatment in vivo on the tyrosine phosphorylation response of Trk-type neurotrophin receptors in adult and aged rats. Rats were treated for 1 week with daily injections of NGF directly into the striatum. Surprisingly, this chronic neurotrophin treatment induced long-lasting tyrosine phosphorylation of Trk type receptors beyond the last injection. A similar result was obtained with 1 week of daily injections of BDNF into the hippocampus. Persistent TRK tyrosine phosphorylation was also observed after single neurotrophin injections. With 1 microgram of NGF injected, Trk-type receptors were maximally stimulated from immediately after the injection until 3 days after the treatment. Maintaining Trk tyrosine phosphorylation required maintained energy levels in the tissue. Incubation of microslices of brain tissue from NGF-injected animals in glucose-free buffer completely abolished all Trk tyrosine phosphorylation signals. Recovery of tissue in presence of glucose restored the signals in microslices derived from NGF-injected animals, in absence of acute NGF treatment. This result, together with dose-response comparisons after 2-h and 2-day survival times suggest that Trk protein remains tyrosine phosphorylated due to trophic protein which is only slowly being cleared out of the tissue during several days after the injection. Experiments with aged rats indicated similar extent and duration of Trk receptor activation after NGF administration in young adult and in aged brain.
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PMID:Intraparenchymal NGF injections in adult and aged rats induce long-lasting Trk tyrosine phosphorylation. 863 59


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