Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UNIPROT:P06889 (Mol)
 630,302 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Genetic studies have implicated the cytosolic juxtamembrane region of the Kit receptor tyrosine kinase as an autoinhibitory regulatory domain. Mutations in the juxtamembrane domain are associated with cancers, such as gastrointestinal stromal tumors and mastocytosis, and result in constitutive activation of Kit. Here we elucidate the biochemical mechanism of this regulation. A synthetic peptide encompassing the juxtamembrane region demonstrates cooperative thermal denaturation, suggesting that it folds as an autonomous domain. The juxtamembrane peptide directly interacted with the N-terminal ATP-binding lobe of the kinase domain. A mutation in the juxtamembrane region corresponding to an oncogenic form of Kit or a tyrosine-phosphorylated form of the juxtamembrane peptide disrupted the stability of this domain and its interaction with the N-terminal kinase lobe. Kinetic analysis of the Kit kinase harboring oncogenic mutations in the juxtamembrane region displayed faster activation times than the wild-type kinase. Addition of exogenous wild-type juxtamembrane peptide to active forms of Kit inhibited its kinase activity in trans, whereas the mutant peptide and a phosphorylated form of the wild-type peptide were less effective inhibitors. Lastly, expression of the Kit juxtamembrane peptide in cells which harbor an oncogenic form of Kit inhibited cell growth in a Kit-specific manner. Together, these results show the Kit kinase is autoinhibited through an intramolecular interaction with the juxtamembrane domain, and tyrosine phosphorylation and oncogenic mutations relieved the regulatory function of the juxtamembrane domain.
Mol Cell Biol 2003 May
PMID:Autoinhibition of the kit receptor tyrosine kinase by the cytosolic juxtamembrane region. 1269 9

Gastrointestinal stromal tumors (GISTs), defined by the presence of constitutively activated KIT, are the most common gastrointestinal mesenchymal malignancies. This observation has been successfully exploited in clinical trials of Gleevec (also known as imatinib mesylate, STI-571) for patients with unresectable and/or metastatic GISTs. The biological mechanisms of Gleevec as well as its downstream molecular effects are generally unknown. We used a DNA microarray-based approach to identify gene expression patterns and signaling pathways that were altered in response to Gleevec in GIST cells. We identified a total of 148 genes or expressed sequence tags (of 10,367) that were differentially regulated; 7 known genes displayed a durable response after treatment. The significantly down-regulated genes were SPRY4A, FZD8, PDE2A, RTP801, FLJ20898, and ARHGEF2. The only up-regulated gene was MAFbx. On a functional level, we demonstrated that imatinib inhibited phosphorylation of KIT, AKT, and extracellular signal-regulated kinase 1/2 without affecting the total level of these proteins and that differential expression of these response genes involved activation of mitogen-activated protein kinase-dependent and -independent pathways. In an attempt to correlate these in vitro findings to clinical data, we examined GIST needle biopsy specimens taken from patients before and after Gleevec administration according to the CSTI571-B2222 Phase II trial and demonstrated that expression levels of the two gene transcripts evaluated correlated well with clinical response. This study emphasizes the potential value of an in vitro cell model to investigate GIST response to imatinib in vivo, for the purpose of identifying important genetic markers of clinical response, mechanisms of drug action, and possible therapeutic targets.
Mol Cancer Ther 2003 Aug
PMID:Response markers and the molecular mechanisms of action of Gleevec in gastrointestinal stromal tumors. 2207 11

A103 is a melanocyte-associated monoclonal antibody that recognizes the Melan-A/MART-1 antigen in melanomas. The Melan-A/MART-1 antigen is also expressed in Leydig cells, adrenal tissue, and steroid-secreting tumors. A103 immunoreactivity in ovarian neoplasms, specifically sex cord stromal tumors (SCSTs), has not been well studied. Inhibin is known to be expressed in SCSTs but is also expressed in some carcinomas and other tumors. We sought to explore the usefulness of both antibodies in the diagnosis of ovarian neoplasms. Using conventional tissue sections and a tissue microarray, we studied the immunoreactivities of 131 ovarian tumors for A103 and inhibin: 30 SCSTs, including fibrothecoma, luteoma, hilus cell tumor, granulosa cell tumor, Sertoli-Leydig cell tumor, and sex cord tumor with annular tubules, and a control group of 96 surface epithelial tumors. A few other rare ovarian tumors including 1 small cell carcinoma, 1 adenocarcinoid tumor, 1 ovarian tumor of probable wolffian origin, 1 Krukenberg tumor, and 1 desmoplastic small round cell tumor were also studied. Inhibin staining was generally strong and diffuse in the majority of SCSTs (83%) and at least focally positive in the small cell carcinoma, ovarian tumor of probable wolffian origin, Krukenberg tumor, and desmoplastic small round cell tumor. Variable immunoreactivities were also present in 7 of 96 (7.3%) surface epithelial tumors. In comparison, A103 expression was usually weaker and more focal than that of inhibin and was present in a smaller proportion of SCSTs (37%) and negative in all the surface epithelial tumors. A103 was typically positive in the lipid-containing cells (both neoplastic and normal components) of these tumors (fibrothecomas, luteomas, Sertoli-Leydig cell tumors, hilus cell tumors, and granulosa cell tumors), and in some cases, moderate positivity was noted in these cells. Weak A103 positivity was identified in the single case of ovarian tumor of probable wolffian origin. A103 is relatively less sensitive than inhibin for recognizing SCSTs but does not appear to be expressed by ovarian surface epithelial tumors. It is therefore more specific than inhibin for SCSTs and is a useful marker for specifically identifying lipid-containing cells in tumors. Thus, adding A103 to a panel of markers including inhibin may be a valuable adjunct in the differential diagnoses of SCSTs and their distinction from other ovarian neoplasms.
Appl Immunohistochem Mol Morphol 2003 Sep
PMID:Melan-A (A103) and inhibin expression in ovarian neoplasms. 1296 51

Most gastrointestinal stromal tumors (GISTs) carry activating mutations of the KIT gene encoding the receptor tyrosine kinase KIT. In a previous study we were able to show an association between the lack of KIT mutations (wild-type GISTs) and the presence of a significant epithelioid tumor component. A very recent study described the occurrence of PDGFRalpha mutations in KIT wt GISTS. Therefore, we studied a panel of 87 GISTs for mutations in the hot spot regions of the PDGFRalpha gene with single strand conformation polymorphism analysis and sequencing and correlated the PDGFRalpha status with pathomorphological data. We detected 20 cases with exon 18 mutations but none with exon 12 mutations. The mutations were located in the second kinase domain of PDGFRalpha with 16 point mutations, and four larger deletions of 9 to 12 bp. All cases with mutations in the PDGFRalpha gene revealed wild-type KIT in common regions of mutation, ie, exons 9 and 11. Most interestingly, the occurrence of PDGFRalpha mutations was significantly associated with a higher frequency of epithelioid or mixed morphology (18 of 20 cases, P < 0.0001) and gastric location (all cases, P = 0.0008). Our data indicate that GISTs represent distinctive entities, differing in genetic, biological, and morphological features.
J Mol Diagn 2004 Aug
PMID:Association of platelet-derived growth factor receptor alpha mutations with gastric primary site and epithelioid or mixed cell morphology in gastrointestinal stromal tumors. 1526 95

Most gastrointestinal stromal tumors (GISTs) harbor oncogenic mutations in the KIT gene, and the majority of these mutations affect the juxtamembrane domain of the kinase encoded by exon 11. Screening GISTs for KIT gene mutations is important for translational research studies and for providing prognostic information on the likelihood of tumor response to treatment with the kinase inhibitor imatinib mesylate (Gleevec). In a series of GISTs analyzed in our laboratory by a combination of denaturing HPLC and direct DNA sequencing, we identified 19 cases with KIT exon 11 deletions that included from 1 to 14 bp of intron 10 sequence and resulted in loss of the normal splice acceptor site at the beginning of exon 11. Predicted use of the next potential splice-acceptor site was confirmed by cDNA sequencing in 4 cases. Thus, the resulting mutant isoform, deletion KPMYEVQWK 550-558, was the same in all 19 cases. Only two other examples of deletions across the intron 10-exon 11 boundary have been reported, yet among 722 GISTs analyzed in our laboratories these deletions were not uncommon, accounting for 3.9% of exon 11 mutations and 2.6% of all tumors. Loss of KIT intron 10 sequences may be under-recognized if the forward primer is too close to exon 11, or if cases are examined exclusively at the cDNA level. Laboratories that offer clinical screening for KIT mutations in GI stromal tumors should be aware of this class of mutations.
J Mol Diagn 2004 Nov
PMID:KIT gene deletions at the intron 10-exon 11 boundary in GI stromal tumors. 1550 76

Together with its ligand, stem cell factor, the receptor tyrosine kinase c-Kit is a key controlling receptor for a number of cell types, including hematopoietic stem cells, mast cells, melanocytes and germ cells. Gain-of-function mutations in c-Kit have been described in a number of human cancers, including testicular germinomas, acute myeloid leukemia and gastrointestinal stromal tumors. Stimulation of c-Kit by its ligand leads to dimerization of receptors, activation of its intrinsic tyrosine kinase activity and phosphorylation of key tyrosine residues within the receptor. These phosphorylated tyrosine residues serve as docking sites for a number of signal transduction molecules containing Src homology 2 domains, which will thereby be recruited to the receptor and activated many times through phosphorylation by the receptor. This review discusses our current knowledge of signal transduction molecules and signal transduction pathways activated by c-Kit and how their activation can be connected to the physiological outcome of c-Kit signaling.
Cell Mol Life Sci 2004 Oct
PMID:Signal transduction via the stem cell factor receptor/c-Kit. 1552 60

Signals through Kit receptor tyrosine kinase are essential for development of erythrocytes, melanocytes, germ cells, mast cells and interstitial cells of Cajal (ICCs). Mice and rats with a double gene dose of loss-of-function mutations of Kit show depletion of these cells. Although human homozygotes with loss-of-function mutations of Kit have not been reported, gain-of-function mutations of Kit result in development of tumors from mast cells, germ cells and ICCs in humans. The ICC tumors are called gastrointestinal stromal tumors (GISTs), and GISTs are a good target for the Kit inhibitor imatinib mesylate. The interrelationship between the type of Kit gain-of-function mutations and the therapeutic effect of imatinib mesylate has been well characterized in GISTs. Kit is interesting from both a biological and clinical view-point.
Cell Mol Life Sci 2004 Dec
PMID:Kit as a human oncogenic tyrosine kinase. 1558 54

Imatinib mesylate is a small molecule inhibitor of the c-Abl, platelet-derived growth factor (PDGF) receptor and c-Kit tyrosine kinases that is approved for the treatment of Philadelphia chromosome-positive chronic myeloid leukemia (CML) and gastrointestinal stromal tumors. Glioblastoma multiforme is a highly malignant primary brain tumor that is usually treated with surgery and/or radiotherapy. Previous studies implicate an autocrine loop caused by high expression of PDGF and its receptor, PDGFR, in the proliferation of some glioblastomas. Here, we demonstrate that pretreatment of a human glioblastoma cell line, RuSi RS1, with imatinib significantly enhanced the cytotoxic effect of ionizing radiation. This effect was not seen in human breast cancer (BT20) and colon cancer (WiDr) cell lines. Whereas c-Abl and c-Kit were expressed about equally in the three cell lines, RuSi RS1 cells showed significantly higher expression of PDGFR-beta protein in comparison to BT20 and WiDr. Imatinib treatment of RuSi RS1 cells decreased overall levels of cellular tyrosine phosphorylation and specifically inhibited phosphorylation of PDGFR-beta, while c-Abl was not prominently activated in these cells. These results suggest that imatinib may have clinical utility as a radiosensitizer in the treatment of human glioblastoma, possibly through disruption of an autocrine PDGF/PDGFR loop.
Blood Cells Mol Dis
PMID:Imatinib mesylate radiosensitizes human glioblastoma cells through inhibition of platelet-derived growth factor receptor. 1572 3

Endometrial stromal tumors are rare uterine neoplasms including benign stromal nodules, low-grade endometrial stromal sarcomas (ESS), and undifferentiated endometrial sarcomas (UES), the latter representing the most aggressive form. Morphological characteristics and cytogenetic abnormalities are heterogeneous, making diagnosis difficult. Recently, a gene fusion on chromosome 7 that includes two zinc-finger genes (JAZF1 and JJAZ1) has been discovered in these tumors. Hitherto only 31 cases, described by three different research groups, have shown JAZF1/JJAZ1 fusion in approximately 50% of all analyzed low-grade ESSs whereas it is less frequent in UESs. In this study we analyzed 20 ESS and 2 UES cases using two-step reverse transcriptase-polymerase chain reaction optimized for formalin-fixed, paraffin-embedded tissue. In our subset of samples, the JAZF1/JJAZ1 fusion transcript occurred in 80% of analyzed ESS cases and in none of two UES cases. In comparison to published data, our results identified the JAZF1/JJAZ1 gene fusion more frequently in endometrial stromal tumors than hitherto presumed. This cytogenetic abnormality was not present in normal endometria, leiomyomas, or leiomyosarcomas or in lung, gastric, or hepatic carcinomas, indicating its specificity for endometrial stromal tumors. In combination with other established methods, accurate reverse transcriptase-polymerase chain reaction analysis of JAZF1/JJAZ1 gene fusion may be useful in diagnosing difficult or unusual ESS/UES cases.
J Mol Diagn 2005 Aug
PMID:JAZF1/JJAZ1 gene fusion in endometrial stromal sarcomas: molecular analysis by reverse transcriptase-polymerase chain reaction optimized for paraffin-embedded tissue. 1604 11

CD117 (KIT) is a type III receptor tyrosine kinase operating in cell signal transduction in several cell types. Normally KIT is activated (phosphorylated) by binding of its ligand, the stem cell factor. This leads to a phosphorylation cascade ultimately activating various transcription factors in different cell types. Such activation regulates apoptosis, cell differentiation, proliferation, chemotaxis, and cell adhesion. KIT-dependent cell types include mast cells, some hematopoietic stem cells, germ cells, melanocytes, and Cajal cells of the gastrointestinal tract, and neoplasms of these cells are examples of KIT-positive tumors. Other KIT-positive normal cells include epithelial cells in skin adnexa, breast, and subsets of cerebellar neurons. KIT positivity has been variably reported in sarcomas such as angiosarcoma, Ewing sarcoma, synovial sarcoma, leiomyosarcoma, and MFH; results of the last three are controversial. The variations in published data may result from incomplete specificity of some polyclonal antibodies, possibly contributed by too high dilutions. Also, KIT is expressed in pulmonary and other small cell carcinomas, adenoid cystic carcinoma, renal chromophobe carcinoma, thymic, and some ovarian and few breast carcinomas. A good KIT antibody reacts with known KIT positive cells, and smooth muscle cells and fibroblasts are negative. KIT deficiency due to hereditary nonsense/missense mutations leads to disruption of KIT-dependent functions such as erythropoiesis, skin pigmentation, fertility, and gastrointestinal motility. Conversely, pathologic activation of KIT through gain-of-function mutations leads to neoplasia of KIT-dependent and KIT-positive cell types at least in three different systems: mast cells/myeloid cells--mastocytosis/acute myeloid leukemia, germ cells--seminoma, and Cajal cells--gastrointestinal stromal tumors (GISTs). KIT tyrosine kinase inhibitors such as imatinib mesylate are the generally accepted treatment of metastatic GISTs, and their availability has prompted an active search for other treatment targets among KIT-positive tumors such as myeloid leukemias and small cell carcinoma of the lung, with variable and often nonconvincing results.
Appl Immunohistochem Mol Morphol 2005 Sep
PMID:KIT (CD117): a review on expression in normal and neoplastic tissues, and mutations and their clinicopathologic correlation. 1608 45


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