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)

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal tumors in the human digestive tract, but their molecular etiology and cellular origin are unknown. Sequencing of c-kit complementary DNA, which encodes a proto-oncogenic receptor tyrosine kinase (KIT), from five GISTs revealed mutations in the region between the transmembrane and tyrosine kinase domains. All of the corresponding mutant KIT proteins were constitutively activated without the KIT ligand, stem cell factor (SCF). Stable transfection of the mutant c-kit complementary DNAs induced malignant transformation of Ba/F3 murine lymphoid cells, suggesting that the mutations contribute to tumor development. GISTs may originate from the interstitial cells of Cajal (ICCs) because the development of ICCs is dependent on the SCF-KIT interaction and because, like GISTs, these cells express both KIT and CD34.
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PMID:Gain-of-function mutations of c-kit in human gastrointestinal stromal tumors. 943 54

Gastrointestinal stromal/smooth muscle tumors (GISTs) are uncommon neoplasms for which current criteria for the diagnosis of malignancy (location, size, and mitotic index) do not always reliably predict patient outcome. Recently, mutation of KIT oncogene exon 11 has been observed in some of these tumors, but the relationship between mutation and clinical outcome has not yet been determined. DNA was obtained from the formalin-fixed, paraffin-embedded tissue of 35 gastric GISTs. A segment of exon 11 was amplified by PCR and sequenced on an ABI 377 sequencer. The relationship between the presence or absence of mutation, tumor size, and mitotic index was investigated using correlation analysis, and the relationship between mutation and outcome was investigated using Kaplan-Meier plots, the Cox-Mantel statistic, and the Cox regression model. Exon 11 deletion mutations were identified in 10 cases, and point mutations were identified in an additional 3 cases; 22 cases demonstrated no KIT mutations. KIT mutation was associated with decreased survival (p = 0.001), with fewer than 30% of patients surviving more than 3 years, compared with over 65% survival for patients whose tumors did not bear the mutation. KIT mutation did not correlate with either the mitotic index or the tumor size. In conclusion, KIT mutation is associated with poor prognosis in patients with gastrointestinal stromal tumors. Whether the KIT mutation will prove to be an independent prognostic factor awaits the completion of larger studies.
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PMID:KIT mutation portends poor prognosis in gastrointestinal stromal/smooth muscle tumors. 988 63

The proto-oncogene c-KIT encodes a growth factor receptor, KIT, with ligand-dependent tyrosine kinase activity that is expressed by several cell types including mast cells. c-KIT juxtamembrane coding region mutations causing constitutive activation of KIT are capable of transforming cell lines and have been identified in a human mast cell line and in situ in human gastrointestinal stromal tumors, but have not been demonstrated in situ in neoplastic mast cells from any species. To determine whether c-KIT juxtamembrane mutations occur in the development of mast cell neoplasms, we examined canine mastocytomas, which are among the most common tumors of dogs and which often behave in a malignant fashion, unlike human solitary mastocytomas. Sequencing of c-KIT cDNA generated from tumor tissues removed from seven dogs revealed that three of the tumors contained a total of four mutations in an intracellular juxtamembrane coding region that is completely conserved among vertebrates. In addition, two mutations were found in three mast cell lines derived from two additional dogs. One mutation from one line matched that found in situ in one of the tumors. The second was found in two lines derived from one dog at different times, indicating that the mutation was present in situ in the animal. All five mutations cause high spontaneous tyrosine phosphorylation of KIT. Our study provides in situ evidence that activating c-KIT juxtamembrane mutations are present in, and may therefore contribute to, the pathogenesis of mast cell neoplasia. Our data also suggest an inhibitory role for the KIT juxtamembrane region in controlling the receptor kinase activity.
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PMID:Clustering of activating mutations in c-KIT's juxtamembrane coding region in canine mast cell neoplasms. 998 91

Gastrointestinal stromal tumors (GISTs) are the most common mesenchymal neoplasms arising in the gastrointestinal tract. GISTs express the KIT receptor tyrosine kinase, and many cases have activating mutations in the KIT juxtamembrane region. We now report an analysis of KIT cDNA and genomic sequences in eight GISTs that lack juxtamembrane region mutations. Six cases contained heterozygous exon 9 mutations in which six nucleotides, encoding Ala-Tyr, were duplicated. The other two cases contained homozygous exon 13 missense mutations, resulting in substitution of Glu for Lys(642), that were associated with constitutive KIT tyrosine phosphorylation. Sequence analysis of DNAs from nonneoplastic companion tissues revealed that both the exon 9 and exon 13 mutations were somatic. These are the first descriptions, in any tumor, of mutations in KIT exons encoding the C-terminal end of the extracellular domain and the first part of the split kinase domain. These findings indicate that KIT may be activated by mutations in at least three domains-extracellular, juxtamembrane, and kinase-in GISTs.
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PMID:KIT extracellular and kinase domain mutations in gastrointestinal stromal tumors. 1070 94

Protooncogene c-kit encodes a receptor tyrosine kinase, KIT. Interstitial cells of Cajal (ICCs) that are important for the autonomous movement of the gastrointestinal tract essentially require the normal function of the KIT for their development. Therefore, germline loss-of-function mutations of the c-kit gene cause deficiency of ICCs that results in disturbed gastrointestinal movement. On the other hand, somatic gain-of-function mutations of the c-kit gene induce gastrointestinal stromal tumors (GIST) that are considered to originate from ICCs. Moreover, germline gain-of-function mutations of the c-kit gene are a cause of familial development of multiple GISTs.
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PMID:Effects of loss-of-function and gain-of-function mutations of c-kit on the gastrointestinal tract. 1077 23

C-kit proto-oncogene product (KIT, CD117) is a tyrosine kinase growth factor receptor for stem cell factor. This receptor is important for the development and maintenance of hematopoietic stem cells, mast cells, germ cells, melanocytes, and interstitial cells of Cajal and is constitutively expressed in them. Among mesenchymal tumors, KIT seems to be specific for the gastrointestinal stromal tumors, which consistently express this protein. Activating mutations in the tyrosine kinase or juxtamembrane domains of c-kit gene have been found in mastocytoma, seminoma, and gastrointestinal stromal tumors. Following up our initial observation of KIT expression in one angiosarcoma, we examined 50 angiosarcomas, 13 Kaposi sarcomas, 10 epithelioid hemangioendotheliomas, and 31 hemangiomas of different types for KIT expression using a polyclonal antiserum specific to KIT. Adult and fetal tissues and neovascular endothelia in 20 carcinomas were studied for comparison. More than half (56%) of the angiosarcomas representing different clinicopathologic and histologic subtypes and 2 of 13 Kaposi sarcoma were KIT positive. All epithelioid hemangioendotheliomas and hemangiomas were negative, with the exception of two infantile hemangiomas that showed KIT reactivity. The fetal capillary endothelia of lungs, placenta, and soft tissues were also KIT positive, although in soft tissues and placenta, KIT positivity was more prominent in the first trimester. However, endothelia of adult vessels and neovascular capillaries of carcinomas were negative. None of the four KIT-positive angiosarcomas and one KIT-positive Kaposi sarcomas that were studied showed mutations in the juxtamembrane or tyrosine kinase domains of the c-kit gene. These results indicate that KIT expression occurs in a subset of angiosarcomas, and the expression probably represents oncofetal expression (i.e., reversion of the tumor cell phenotype to that of fetal endothelial cells that may show KIT expression).
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PMID:KIT expression in angiosarcomas and fetal endothelial cells: lack of mutations of exon 11 and exon 17 of C-kit. 1082 25

Submucosal tumors of the gastrointestinal tract (GI tract) mainly consist of gastrointestinal mesenchymal tumors (GIMTs) that are distributed in the GI tract from the esophagus through the rectum. GIMTs include myogenic tumors, neurogenic tumors and gastrointestinal stromal tumors (GISTs). The term "GIST" is now preferentially used for the tumors that express CD34 and KIT. GIMTs are composed of spindle or epithelioid cells, and 20% to 30% show malignant behavior, including peritoneal dissemination and hematogenous metastasis. KIT expression and mutations in the c-kit gene are found only in GISTs, but not in myogenic or neurogenic tumors. Mutation in the c-kit gene is associated with aggressive features and poor prognosis, and malignant GISTs frequently have mutations in the c-kit gene. The clinicopathological features of GISTs with or without c-kit mutations are markedly different. Therefore, GIMTs may be divided into four major categories based on histochemical and genetic data: myogenic tumors; neurogenic tumors; GISTs with c-kit mutation; and GISTs without c-kit mutation. The origin of GISTs is not fully understood. However, phenotypical resemblance to the interstitial cells of Cajal (ICCs) and gain-of-function mutations in the c-kit gene may suggest origin from ICCs and/or multipotential mesenchymal cells that differentiate into ICCs.
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PMID:Biological and clinical review of stromal tumors in the gastrointestinal tract. 1100 53

Gastrointestinal stromal tumors (GISTs), the most common mesenchymal tumors of the gastrointestinal tract, typically express the KIT protein. Activating mutations in the juxtamembrane domain (exon 11) of the c-kit gene have been shown in a subset of GISTs. These mutations lead into ligand-independent activation of the tyrosine kinase of c-kit, and have a transforming effect in vitro. Several groups have studied the clinical implication of the c-kit mutation status of exon 11 in GISTs and a possible relationship between c-kit mutations and malignant behavior has been established. Recently, a 1530ins6 mutation in exon 9 and missense mutations, 1945A>G in exon 13 of the c-kit gene were reported. The frequency and clinical importance of these findings are unknown. In this study we evaluated 200 GISTs for the presence of mutations in exons 9 and 13 of c-kit. Six cases revealed 1530ins6 mutation in exon 9 and two cases 1945A>G mutation in exon 13. All tumors with mutations in exon 9 and 13 lacked mutations in exon 11 of c-kit. None of the analyzed tumors had more than one type of c-kit mutation. All but one of the eight tumors with mutations in exon 9 or 13 of the c-kit gene were histologically and clinically malignant. All four of six cases with exon 9 mutation of which location of primary tumor was known, were small intestinal, suggesting that this type of mutation could preferentially occur in small intestinal tumors. Exon 9 and 13 mutations seem to be rare, and they cover only a small portion (8%) of the balance of GISTs that do not have mutations in exon 11 of c-kit. This finding indicates that other genetic alterations may activate c-kit in GISTs, or that KIT is not activated by mutations in all cases.
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PMID:Mutations in exons 9 and 13 of KIT gene are rare events in gastrointestinal stromal tumors. A study of 200 cases. 1102 12

Gastrointestinal stromal tumors (GISTs), mesenchymal tumors largely specific for the gastrointestinal tract, have been well defined in the stomach and small intestine, but have not been extensively documented or contrasted with true smooth muscle tumors in the colon. This study was undertaken to determine the clinicopathologic features of GISTs of the colon, excluding the rectum, and to compare them with leiomyosarcomas (LMSs) of the same location. A total of 37 colonic GISTs and seven LMSs from the files of the Armed Forces Institute of Pathology and the Haartman Institute of the University of Helsinki were analyzed. The GISTs occurred predominantly in adults older than 50 years of age (median, 67 yrs), and most were histologically malignant; four small benign tumors (< or = 1 cm) were incidentally detected, and 10 others had minimal mitotic activity (five or fewer mitoses per 50 high-power fields). The colonic GISTs were typically transmural tumors with frequent intraluminal and outward bulging components. Histologically, they usually showed a spindle cell pattern (92%), whereas 8% were epithelioid. Most tumors (19 of 25) were positive for CD117 (KIT) and for CD34 (16 of 27); six tumors coexpressed alpha-smooth muscle actin and CD117; none showed desmin or S-100 protein. C-kit mutations in exon 11 were seen in 5 (36%) of 14 colonic GISTs. None of the patients with incidental small tumors had a recurrence, whereas 2 of 10 patients with tumors larger than 1 cm but minimal mitotic activity died of the disease with liver metastasis. Nearly all patients whose tumor was larger than 1 cm and showed more than five mitoses per 50 high-power fields died of disease; half had evidence of metastasis. LMSs were typically intraluminally bulging, polypoid masses that showed a histologic likeness to differentiated smooth muscle cells. They occurred in five men and two women with a median age of 61 years. Most LMSs were high-grade histologically and showed smooth muscle actin, desmin, or both. All were negative for CD34 and CD117 and lacked c-kit mutations. Five of the seven patients died of disease, and two had a long-term survival, despite high mitotic activity. These results show that KIT-positive GISTs are more common than LMSs of the colon, and these tumor groups have clinicopathologic differences that warrant their separation.
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PMID:Gastrointestinal stromal tumors and leiomyosarcomas in the colon: a clinicopathologic, immunohistochemical, and molecular genetic study of 44 cases. 1102 95

The proto-oncogene KIT encodes the receptor tyrosine kinase KIT. Gain-of-function mutations in the juxtamembrane domain of KIT have been reported in human gastrointestinal stromal tumors. In a family with multiple gastrointestinal stromal tumors and diffuse hyperplasia of myenteric plexus layer, we have identified another mutation of KIT, a single base mutation, resulting in the substitution of Glu for Lys(642) in the kinase I domain, and studied its biological effect in a cellular system. The mouse homologue of the human KIT mutant was generated by site-directed mutagenesis and stably transfected into the interleukin-3-dependent Ba/F3 murine cell line. The oncogenic potential of the mutated KIT was assessed in vitro by a proliferation assay and in vivo by transplantation into nude mice. Transfected Ba/F3 cells grew autonomously in absence of growth factors and formed tumors in nude mice. Substitution of Glu for Lys(642) is an oncogenic mutation in the tyrosine kinase domain of KIT. As germline heterozygous mutation, it causes a diffuse hyperplasia of myenteric interstitial cells of Cajal during embryonic development and occurrence of multiple gastrointestinal stromal tumors at adulthood.
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PMID:Germline-activating mutation in the kinase domain of KIT gene in familial gastrointestinal stromal tumors. 1107 17


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