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)

In anaplastic large cell lymphoma, the ALK gene at 2p23 is known to be fused to NPM, TPM3, TPM4, TFG, ATIC, CLTC, MSN, and ALO17. All of these translocations result in the expression of chimeric ALK transcripts that are translated into fusion proteins with tyrosine kinase activity and oncogenic properties. We report a case showing a restricted cytoplasmic staining pattern of ALK and a novel chromosomal abnormality, t(2;22)(p23;q11.2), demonstrated by fluorescence in situ hybridization analysis. The result of 5' RACE analysis showed that the ALK gene was fused in-frame to a portion of the non-muscle myosin heavy chain gene, MYH9. Nucleotide sequence of the MYH9-ALK chimeric cDNA revealed that the ALK breakpoint was different from all those previously reported. It is localized in the same exonic sequence as MSN-ALK, but 6 bp downstream, resulting in an in-frame fusion of the two partner proteins. In contrast to the previously reported ALK fusion proteins, MYH9-ALK may lack a functional oligomerization domain. However, biochemical analysis showed that the new fusion protein is tyrosine phosphorylated in vivo but seems to lack tyrosine kinase activity in vitro. If further investigations confirm this latter result, the in vivo tyrosine phosphorylation of MYH9-ALK protein could involve mechanisms different from those described in the other ALK hybrid proteins.
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PMID:Non-muscle myosin heavy chain (MYH9): a new partner fused to ALK in anaplastic large cell lymphoma. 1280 Jan 56

Anaplastic large cell lymphomas (ALCLs) represent a heterogeneous group of malignant lymphoproliferative diseases. Most of the cases are of T-cell line with a loss of cell surface receptors but with a production of cytotoxic cytoplasmatic granules--immunohistochemically (IHC) positive perforin, granzyme B, and TIA-1. The diagnostics of ALCL is based on morphological findings and results of IHC, which further stratify ALCLs to basic immunophenotypes according to ALK (anaplastic lymphoma kinase) protein expression--ALCL CD30+ ALK+ and ALCL CD30+ ALK+. The morphological investigations are supplemented by karyotyping and/or by a demonstration of breakpoint at 2p23 harboring ALK gene (FISH), and by molecular detection of chimeric genes characteristic of ALK+ lymphomas (NPM-ALK, ATIC-ALK, TPM3-ALK, TFG-ALK, and some even rarer rearrangements). Molecular diagnostics is important in monitoring minimal residual disease. As some of the characteristic molecular changes were demonstrated in healthy individuals and in Hodgkin's disease by quantitative PCR, the validation of these findings demands further studies. ALK protein positive ALCLs affect patients in age categories up to the third decade, whereas ALK protein negative cases occur in older patients with an average age of 60 years. Both subgroups of lymphomas are aggressive but ALK+ lymphomas react well to systemic treatment, and have a more favorable prognosis. Primary skin ALCLs belong to a group of T-cell lymphoproliferative diseases of the skin and have, in the majority of cases, a favorable course without generalization.
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PMID:[Anaplastic large-cell lymphoma: review]. 1463 6

Majority of anaplastic large-cell lymphomas (ALCLs) are associated with the t(2;5)(p23;q35) translocation, fusing the NPM (nucleophosmin) and ALK (anaplastic lymphoma kinase) genes (NPM-ALK). Recent studies demonstrated that ALK may also be involved in variant translocations, namely, t(1;2)(q25;p23), t(2;3)(p23;q21), t(2;17)(p23;q23) and inv(2)(p23q35), which create the TPM3-ALK, TFG-ALK5, CLTC-ALK, and ATIC-ALK fusion genes, respectively. Although overexpression of NPM-ALK has previously been shown to transform fibroblasts, the transforming potential of variant X-ALK proteins has not been precisely investigated. We stably transfected the cDNAs coding for NPM-ALK, TPM3-ALK, TFG-ALK, CLTC-ALK or ATIC-ALK into nonmalignant NIH3T3 cells. All X-ALK variants are tyrosine phosphorylated and their subcellular distribution was in agreement with that observed in tumors. Moreover, our results show that the in vitro transforming capacity of NIH3T3-transfected cells are in relation to the level of X-ALK fusion proteins excepted for TPM3-ALK for which there is an inverse correlation. The differences between the five X-ALK variants with regard to proliferation rate, colony formation in soft agar, invasion, migration through the endothelial barrier and tumorigenicity seem to be due to differential activation of various signaling pathways such as PI3-kinase/AKT. These findings may have clinical implications in the pathogenesis and prognosis of ALK-positive ALCLs.
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PMID:Differential effects of X-ALK fusion proteins on proliferation, transformation, and invasion properties of NIH3T3 cells. 1520 56

A subset of low-grade fibrosarcomas is composed of CD34-positive spindle cells. These include dermatofibrosarcoma, its morphologic variants, and its associated fibrosarcoma, solitary fibrous tumor, hemangiopericytoma and their malignant counterparts, and some cases of myxoinflammatory fibroblastic sarcoma. Dermatofibrosarcoma and related lesions are characterized by a t(17;22)(q22;q13) rearrangement resulting in fusion of the genes COL1A (17q21-22) and PDGFB1 (22q13). Solitary fibrous tumor displays varying cellularity and fibrosis and a peripheral hemangiopericytomatous pattern; most tumors formerly called hemangiopericytoma are now subsumed into the category of solitary fibrous tumor, although a few strictly defined examples are recognized; however, these are probably not composed of pericytes. Myofibroblastic malignancies are best identified by electron microscopy, with which varying degrees of differentiation, including the presence of fibronexus junctions, can be identified. Low-grade sarcomas showing myofibroblastic differentiation include myofibrosarcomas and inflammatory myofibroblastic tumors. Myofibrosarcomas are spindle cell neoplasms that occur in children or adults in the head and neck, trunk, and extremities as infiltrative neoplasms and that display a fascicular or fasciitis-like pattern with focal nuclear atypia and variable expression of myoid antigens. These sarcomas are prone to recurrence and a small number metastasize. Inflammatory myofibroblastic tumor (synonymous with inflammatory fibrosarcoma) is a neoplasm arising predominantly in childhood, and frequently in intraabdominal locations. It has spindle cells in fascicular, fasciitis-like and sclerosing patterns, with heavy chronic inflammation including abundant plasma cells. Many IMT have clonal chromosomal abnormalities involving 2p22-24, and fusion of the ALK gene with tropomyosin 3 (TPM3-ALK) or tropomyosin 4 (TPM4-ALK) is found in a subset.
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PMID:Low-grade sarcomas with CD34-positive fibroblasts and low-grade myofibroblastic sarcomas. 1576 78

Inflammatory myofibroblastic tumor is a rare spindle cell lesion of indeterminate malignant potential occurring in both pulmonary and extrapulmonary tissues. This report describes an unusual presentation of an unusual tumor at an unusual location: an intramural ileal case of inflammatory myofibroblastic tumor presenting with intussusception in a 29-year-old woman. We characterize this tumor through microscopic and ultrastructural analysis, extensive immunohistochemical analysis, ploidy analysis, and Epstein-Barr virus in situ hybridization, and we report the finding of an ALK/TPM3 fusion using fluorescence in situ hybridization.
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PMID:Inflammatory myofibroblastic tumor with ALK/TPM3 fusion presenting as ileocolic intussusception: an unusual presentation of an unusual neoplasm. 1636 Apr 23

Among different genetic factors involved in the pathogenesis of the papillary thyroid carcinoma (PTC), rearrangements of RET protooncogene (RET/PTC), as well as rearrangements of NTRK1 protooncogene are best known. The resulting hybrid oncogenes are found in PTCs with variable frequency, depending on the examined population. The relationship between these chromosomal aberrations and clinical outcome of PTCs remains still controversial. The study aimed at estimating the frequency of rearrangements of RET and/or NTRK1 protooncogenes in PTC in the Polish population, and at evaluating the possible relationships between the presence of RET and/or NTRK1 oncogenes and such parameters, as patient's age, gender, histopathological variant of tumor and clinical staging. Expression analysis of RET and NTRK1 was performed by duplex reverse transcription-polymerase chain reaction (duplex RT-PCR) and OneStep RT-PCR, respectively, in tumor tissues obtained from 33 patients with PTC. Rearrangements of the RET protooncogene (RET/PTC1, RET/PTC2 and RET/PTC3) were detected in 7 out of 33 PTC (21%), and rearrangements of NTRK1 [Trk-T1 and Trk(TPM3)] were detected in 4 out of 33 examined samples (12%). In none of the examined cases, did the RET and NTRK1 rearrangements occur in the same sample. No correlations were found between RET/PTC or Trk oncogenic sequences and patient's age, gender, the histopathological variant of PTC and the assignment to particular stage in clinical staging systems (TNM Staging, the University of Chicago clinical class, and Ohio State University Staging). Our study is the first one in which the frequency of NTRK1 rearrangements in PTC was reported for the Polish population. On the other hand, the frequency of RET rearrangements in PTC, as found by us, was similar to the previously reported results for the Polish population. Our results do not confirm the relationship between the structural aberrations in question and the clinical outcome of PTC.
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PMID:Molecular analysis of the RET and NTRK1 gene rearrangements in papillary thyroid carcinoma in the Polish population. 1648 15

The anaplastic lymphoma kinase (ALK) on 2p23 is a tyrosine kinase that forms chimeric fusions with numerous translocation partners. We describe a mass spectrometry-based approach for the identification of ALK fusion partners. This approach accurately identified the nucleophosmin (NPM)-ALK fusion protein in an anaplastic large cell lymphoma (ALCL)-derived cell line carrying the t(2;5)(p23;q35), and the TPM3-ALK in a clinical biopsy of inflammatory myofibroblastic tumor (IMT) carrying the t(1;2)(q21;p23). This study shows the ability of mass spectrometry to identify oncogenic chimeric proteins resulting from chromosomal rearrangements. This strategy can be adapted for the identification of known and unknown translocation partners of chimeric ALK fusion proteins involved in oncogenesis.
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PMID:Proteomic identification of oncogenic chromosomal translocation partners encoding chimeric anaplastic lymphoma kinase fusion proteins. 1665 37

We herein describe a 4-year-old boy who after being treated for pneumonia showed an abnormal shadow at the hilus of the right lung on chest X-rays with continued inflammatory findings in his laboratory data. CT and MR investigations suggested the existence of a neoplasm at that site. An open biopsy was thus performed for a definite diagnosis. The histological findings and the expression of TPM3-ALK fusion gene confirmed a diagnosis of an inflammatory myofibroblastic tumor. A right upper and middle lobectomy including the tumor was thus performed for a complete resection. In addition to the histological diagnosis, the detection of the tumor specific fusion gene provided objective evidence in making a diagnosis.
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PMID:A case of an inflammatory myofibroblastic tumor in the lung which expressed TPM3-ALK gene fusion. 1706 37

Cytogenetic discoveries of balanced translocations in soft tissue tumors have opened the way to molecular genetic definition of these translocations as gene fusions from the late 1980s. Many sarcomas are known to have such fusions, and the demonstration of the fusion transcripts in tumor tissue is of great value in specific diagnosis of synovial sarcoma (SYT-SSX), Ewing sarcoma (EWS-Fli1), clear cell sarcoma (EWS-ATF1), myxoid liposarcoma (FUS-CHOP), and other sarcomas. These translocations are believed to be disease-specific and pathogenetic forces, despite occasional observations to the contrary. Demonstration of SYT-SSX and EWS-ATF1 fusion assists in the diagnosis of synovial and clear cell sarcomas in unusual locations, such as the gastrointestinal tract, where these tumors occur with low frequency. Demonstration of sarcoma translocations and their fusion by different assays is well established; use of in situ hybridization is limited by availability of specific probes. In two exceptional instances, the same translocation and gene fusion occurs in two unrelated diseases: ETV6-NTRK fusion in infantile fibrosarcoma and secretory carcinoma of the breast, and ALK-TPM3 fusion in inflammatory myofibroblastic tumor and large cell anaplastic lymphoma. Thus, the target cell of the genetic change is an important factor to define the resulting disease. Activating mutations in two related receptor tyrosine kinases (RTKs), KIT, and platelet-derived growth factor receptor alpha (PDGFRA) is central to the pathogenesis of gastrointestinal stromal tumors (GISTs), and countering the mutational activation by specific tyrosine kinase inhibitors, such as Imatinib mesylate, is now standard treatment for metastatic GISTs. KIT exon 11 mutations (in frame deletions, point mutations, and duplications) occur in GISTs of all locations, whereas a characteristic exon 9 insertion-duplication AY502-503 is nearly specific for intestinal vs gastric tumors. In contrast, PDGFRA mutations are nearly specific for gastric GISTs, especially those with epithelioid morphology. Mutation type influences therapy responsiveness, but fortunately very few GISTs carry primarily Imatinib-resistant mutations. Secondary drug resistance acquired during Imatinib treatment based on new, Imatinib-resistant mutations is a major problem limiting treatment success. Loss of NF2 tumor suppressor gene in a biallelic fashion is believed to be central in the pathogenesis of neurofibromatosis 2 (NF2) associated and sporadic schwannomas and meningiomas. The mechanism includes nonsense or missense mutation in NF2 gene, and loss of the other NF2 allele as a part of losses in chromosome 22q. Schwannoma types may differ in their pathogenesis: gastrointestinal schwannomas lack NF2 changes suggesting a different pathogenesis. Intraneural and sclerosing perineuriomas display similar NF2 gene alterations as seen in meningioma, indicating a similar pathogenesis and molecular homology. Specific viral sequences of human herpesvirus 8 (HHV8) are diagnostic markers for Kaposi sarcoma (KS), and are absent in angiosarcoma. Despite discovery on simian virus SV40 sequences in mesothelioma as a possible pathogenetic factor, recent studies suggest that the presence of these sequences may be artifactual and based on common presence of some SV40 sequences as PCR contaminants.
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PMID:From morphological to molecular diagnosis of soft tissue tumors. 1716 60

Translocations of the anaplastic lymphoma kinase (ALK) gene result in the production of a number of oncogenic ALK fusion proteins implicated in tumour development. We have previously shown that X-ALK fusion proteins have differential effects on the proliferation, transformation, and invasion properties of NIH3T3 cells in vitro. In the present study, we have investigated the metastatic potential of various X-ALK expressing cell lines using an experimental lung metastasis assay. We have shown that TPM3-ALK expression bestows higher metastatic capacities than other X-ALK fusion proteins and in addition, that TPM3-ALK fusion protein expression specifically induces changes in cell morphology and cytoskeleton organisation. Co-immunoprecipitation studies demonstrate a specific interaction between TPM3-ALK and endogenous tropomyosin. Together the specific actions of TPM3-ALK on the cytoskeleton organisation offer an interesting hypothesis with respect to the higher cell motility and metastatic potential of this fusion protein.
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PMID:TPM3-ALK expression induces changes in cytoskeleton organisation and confers higher metastatic capacities than other ALK fusion proteins. 1727 53


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