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)

Congenital insensitivity to pain with anhidrosis (CIPA), also referred to as hereditary sensory and autonomic neuropathy type IV (HSAN-IV), is an autosomal recessive hereditary disorder characterized by recurrent episodic fever, anhidrosis (inability to sweat), absence of reaction to noxious stimuli, self-mutilating behavior, and mental retardation. The TRKA (NTRK1) gene located on chromosome 1 (1q21-q22), consists of 17 exons and spans at least 23 kb. TRKA encodes the receptor tyrosine kinase (RTK) for nerve growth factor (NGF) and is the gene responsible for CIPA. Defects in NGF signal transduction at the TRKA receptor lead to failure to support survival of sympathetic ganglion neurons and nociceptive sensory neurons derived from the neural crest. Thirty-seven different TRKA mutations, identified in patients in various countries, including nine frameshift, seven nonsense, seven splice, and 14 missense mutations, are distributed in an extracellular domain involved in NGF binding, as well as in the intracellular signal-transduction domain. Extensive analysis of CIPA mutations and associated intragenic polymorphisms should facilitate detection of CIPA mutations and aid in the diagnosis and genetic counseling of this painless but severe genetic disorder with devastating complications. In addition, naturally occurring TRKA missense mutations with loss of function provide considerable insight into the structure-function relationship in the RTK family. Further, molecular pathology of CIPA would provide unique opportunities to explore critical roles of the autonomic sympathetic nervous system as well as peripheral sensory nervous system that transmit noxious stimuli in humans.
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PMID:Molecular basis of congenital insensitivity to pain with anhidrosis (CIPA): mutations and polymorphisms in TRKA (NTRK1) gene encoding the receptor tyrosine kinase for nerve growth factor. 1174 40

Reports on the association of papillary thyroid carcinoma with paraganglionic or desmoid tumors have appeared infrequently. The former setting usually affects middle-aged females; the latter is typical of familial adenomatous polyposis. We report the case of a 69-yr-old man in whom two abdominal masses had been instrumentally detected following an access of abdominal pain. Save for a moderate hypertension, he was asymptomatic and an impalpable thyroid nodule was detected by ultrasonography. A high urinary noradrenaline output and cytology of the masses raised the suspicion of pheochromocytoma. At laparotomy, an adrenal pheochromocytoma and a paracaval paraganglioma were excised. Subsequently, hemithyroidectomy was performed, and histopathology revealed papillary microcarcinoma. A nodule of desmoid tumor was also removed from the abdominal wall. An analysis of RET, APC, and TP53 gene mutations, and of RET and NTRK1 gene rearrangements, yielded negative results. No in vitro transforming activity was detected in the tumor DNA when assayed in transfection experiments. The lack of a consistent family history also made unlikely the possibility of identifying the putative germline defect by linkage analyses. Should this unusual aggregation of tumors represent a new entity, a number of genetic alterations have now been excluded.
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PMID:Concurrent Pheochromocytoma, Paraganglioma, Papillary Thyroid Carcinoma, and Desmoid Tumor: A Case Report with Analyses at the Molecular Level. 1211 65

The thyroid TRK-T3 oncogene, produced by a chromosomal translocation, is a chimeric, constitutively activated version of the NTRK1/NGF receptor and it is able to transform NIH3T3 cells and differentiate PC12 cells. TRK-T3 oncoprotein triggers multiple signal transduction pathways. Among others, TRK-T3 binds and phosphorylates the Shc and SNT1/FRS2 adaptor proteins both involved in coupling the receptor tyrosine kinase to the mitogen-activated protein kinase pathway by recruiting Grb2/SOS. We were interested in defining the role of Shc in the oncogenesis by TRK-T3. The mutation of TRK-T3 tyrosine 291, docking site for both Shc and FRS2, abrogates the oncogene biological activity. To directly explore the role of Shc we used the ShcY317F mutant, which carries the mutation of a tyrosine residue involved in Grb2 recruitment. We demonstrated that the ShcY317F mutant exerts an inhibitory effect on TRK-T3 transforming activity. Such effect can be modulated by the amount of ShcY317F protein and affects the viability of cells expressing TRK-T3 by means of a mechanism involving apoptosis. Our results indicate a definitive role of the adaptor protein Shc in TRK-T3 transforming activity.
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PMID:Biological activity of the thyroid TRK-T3 oncogene requires signalling through Shc. 2722 98

Activation of tyrosine kinase receptors is associated with human tumors. Tumorigenic versions of several RTKs, such as Ret, Kit and Met carry activating mutations at highly conserved residues of the tyrosine kinase domain. We have investigated the effect of some of these mutations on the NTRK1/NGF receptor, for which no naturally occurring activating point mutations have been so far detected. We introduced the following mutations in NTRK1 tyrosine kinase domain: (i) D668N equivalent to Met D1246N associated to HPRC; (ii) D668V modelled on Kit D816V found in mastocytosis; (iii) M688T corresponding to Ret M918T associated to the cancer syndrome MEN2B. The Met-like mutation rendered the NTRK1 receptor more responsive to ligand, as observed for the corresponding mutation in Met. On the contrary the Kit-like D668V resulted as neutral mutation. Surprisingly, the MEN2B-like M688T completely abrogated NTRK1 receptor activity, resulting as a loss of function mutation. Our results show that the mutations tested, although involving conserved amino acids in highly homologous regions, exert distinct effects in different receptors, and suggest a very peculiar auto-inhibitory mechanism for NTRK1.
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PMID:Gain of function mutations of RTK conserved residues display differential effects on NTRK1 kinase activity. 1244 96

The TRK-T3 oncoprotein, isolated from a human papillary thyroid tumor, arises from the fusion between the N-terminal domain of the TFG gene and the tyrosine kinase domain of the NTRK1 receptor. The 68 kDa TRK-T3 oncoprotein displays a constitutive tyrosine kinase activity resulting in its capability to transform NIH3T3 cells. The TFG portion of TRK-T3 contains a coiled-coil domain, which mediates protein oligomerization essential for the oncogene constitutive activation, and several consensus sites for protein interaction. In this study, we investigate the role of TFG sequences outside the coiled-coil domain on TRK-T3 activation, We constructed four mutants carrying different deletions of TFG sequences and expressed them in mammalian cells. By performing biochemical and biological assays we demonstrated that all the deleted regions are required for TRK-T3 activation, as they are involved in different mechanisms such as protein processing, formation of stable and/or functional complexes, and possible interaction with other proteins. By constructing site-specific mutants, we demonstrated a crucial role for a PB1 domain and a considerable contribution of an SH2-binding motif in TRK-T3 oncogenic activation. This work establishes an important role for TFG sequences outside the coiled-coil domain in the activation of the thyroid TRK-T3 oncogene.
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PMID:Role of TFG sequences outside the coiled-coil domain in TRK-T3 oncogenic activation. 1258 59

RET and NTRK1 are receptor tyrosine kinase (RTK) proteins which play a role in the development and maturation of specific component of the nervous system. Their alterations have been associated to several human diseases, including some forms of cancer and developmental abnormalities. These features have contributed to the concept that one gene can be responsible for more than one disease. Moreover, both genes encoding for the two RTKs show genetic alterations that belong to either "gain of function" or "loss of function" class of mutations. In fact, receptor rearrangements or point mutations convert RET and NTRK1 in dominantly acting transforming genes leading to thyroid tumors, whereas inactivating mutations, associated with Hirschsprung's disease (HSCR) and congenital insensitivity to pain with anhidrosis (CIPA), impair RET and NTRK1 functions, respectively. In this review we have summarized the main features of the two receptors, their physiological and pathological roles. In addition, we attempted to identify the correlations between the different genetic alterations and the related pathogenetic mechanisms.
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PMID:RET and NTRK1 proto-oncogenes in human diseases. 1265 44

Patients with congenital insensitivity to pain and anhidrosis (CIPA), caused by mutations in the NTRK1 gene, can be difficult to diagnose because of their variable presentation, the lack of simple diagnostic tests, and the paucity of cases reported in North America. We describe a 1-year-old infant who had tooth loss and palmar hyperkeratosis as the primary manifestations of CIPA. He was initially evaluated by a pediatric dentist and epidermal dysplasia syndromes were considered, but insensitivity to pain was suspected after a skeletal survey revealed an unrecognized skull fracture. Nerve conduction studies were normal, as was his response to subdermal histamine injection. Sequence analysis of his NTRK1 gene revealed 2 mutations: 1 mutation is novel, while the other has been described previously in a patient of northern European descent. An antibody directed against NTRK1 revealed persistent expression in keratinocytes, consistent with the mutations in this patient. Skin biopsy specimens revealed a lack of epidermal and sweat gland innervation. Immunohistochemistry of skin biopsy specimens, together with routine nerve conduction studies, can provide quick and reliable confirmation if CIPA is clinically suspected.
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PMID:An infant with primary tooth loss and palmar hyperkeratosis: a novel mutation in the NTRK1 gene causing congenital insensitivity to pain with anhidrosis. 1294 19

Papillary thyroid carcinoma (PTC) is associated with RET and NTRK1 rearrangements and BRAF mutations. A series of 60 PTCs collected in a single center from Italian patients were histologically re-examined and subclassified as well differentiated or tall cell variant. The sample collection was analysed for the presence of all the reported PTC-associated genetic alterations through DNA or cDNA amplification, followed by automated sequencing. The analysis of exons 11 and 15 of BRAF gene revealed the T1796A (V599E) mutation in 32% of cases, and this alteration is significantly associated with PTC tall cell variant. Oncogenic rearrangements of RET and NTRK1 receptors were found in 33 and 5% of cases, respectively. No Ras mutations were detected. Overall, genetic alterations were detected in two-thirds of samples, and in no single case more than one mutational event was found simultaneously. Gene expression profiling of a subset of 31 tumors performed using cDNA microarray chips showed no strong differences in global gene expression among the different cases. However, a supervised analysis of the obtained data identified a subset of genes differentially expressed in tumors carrying BRAF mutation or RTK rearrangement.
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PMID:Alternative mutations of BRAF, RET and NTRK1 are associated with similar but distinct gene expression patterns in papillary thyroid cancer. 1527 15

Hereditary sensory neuropathies (HSNs) are a group of genetically determined peripheral neuropathies with prominent disturbance of the peripheral sensory neurons. They are characterized by sensory loss, insensitivity to pain, a variable degree of muscle weakness and wasting, as well as autonomic features. Frequent complications are foot ulcerations and infections that may lead to osteomyelitis, followed by necrosis and amputations. Consequently, the hereditary sensory neuropathies have also been termed ulceromutilating neuropathies. On the other hand, in the presence of additional motor weakness, they have been subclassified among the group of Charcot-Marie-Tooth (CMT) disorders. Sporadic and familial cases with different modes of inheritance are known to affect both children and adults. The most prevalent forms of the autosomal dominantly inherited hereditary sensory neuropathies are HSN I and CMT 2b. HSN I is associated with mutations in the SPTLC1 gene, whereas mutations in the RAB7 gene have been identified in CMT 2b. However, at least one more hitherto unknown gene responsible for autosomal-dominant hereditary sensory neuropathies must exist. Autosomal-recessive hereditary sensory neuropathies types III and IV, and probably also type V, result from mutations in the IKBKAP and NTRK1 genes. Very recently, the gene in HSN II (HSN2) has been identified. A spontaneous autosomal-recessive mutation in the Cct4 gene has been reported in the Sprague-Dawley rat strain with early onset sensory neuropathy. Although no curative treatment is available so far, and current therapy is limited to symptom relief, these molecular genetic advances in knowledge about the hereditary sensory neuropathies can be translated into clinical practice by improving diagnosis and genetic counseling. They will also be the basis for functional studies in the future.
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PMID:Hereditary sensory neuropathies. 1531 94

SHP-1 is a cytoplasmic SH2 domain containing protein-tyrosine phosphatase (PTP) involved in the negative regulation of multiple signaling pathways in hematopoietic, nervous, and epithelial cells. The thyroid TRK-T3 oncogene consists of the NTRK1 tyrosine kinase domain fused in-frame with sequences of the TFG (TRK-fused gene), encoding a protein of unknown function. TFG contains a coiled-coil domain responsible for TRK-T3 oligomerization. In addition, recent analysis of the sequences outside of the coiled-coil domain suggested possible interactions with other proteins. Based on the presence of a putative SHP-1 SH2-binding site within the TFG sequences, we have investigated the role of the SHP-1 phosphatase in TRK-T3 oncoprotein signaling. In this study we show that SHP-1 interacts with and down-regulates TRK-T3. We provide evidence that SHP-1 SH2 and catalytic domains, respectively, associate with the TFG- and NTRK1-derived portions of TRK-T3. Our data contribute to the definition of cellular mechanisms involved in thyroid tumorigenesis. Moreover, it reveals TFG as a novel protein able to modulate SHP-1 activity.
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PMID:Analysis of SHP-1-mediated down-regulation of the TRK-T3 oncoprotein identifies Trk-fused gene (TFG) as a novel SHP-1-interacting protein. 1555 41


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