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: UNIPROT:P10721 (c-kit)
6,575 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Suppressor of cytokine signaling 1 (SOCS1) is a negative regulator of c-Kit and interleukin-3 (IL-3) receptor signaling. We examined the role of SOCS1 in regulating IL-3-induced cell growth of primary bone marrow-derived mast cells (BMMCs) from SOCS1-/- mice. Instead of showing increased proliferation, SOCS1-deficient BMMCs responded poorly to IL-3 and stem cell factor. SOCS1-/- BMMCs showed increased apoptosis and defective cell cycle entry. We show that the growth retardation of SOCS1-/- BMMCs was due to a cell intrinsic defect. Protein tyrosine phosphorylation following IL-3 stimulation was markedly diminished in SOCS1-/- BMMCs. Intriguingly, JAK2 and STAT5 proteins were selectively diminished in SOCS1-/- BMMCs, which also showed lower molecular mass products of p85 and Vav suggesting proteolytic degradation. Incubation of the SOCS1-/- BMMC lysate with STAT5, p85, and Vav immunoprecipitated from SOCS1+/+ cells directly demonstrated the dysregulated proteolytic activity in SOCS1-/- BMMCs. The proteolytic activity in SOCS1-/- BMMCs was selectively inhibited by phenylmethylsulfonyl fluoride and soybean trypsin inhibitor, suggesting that the protease regulated by SOCS1 is a tryptase. The dysregulated tryptase in SOCS1-/- BMMCs is unlikely to be mMCP6 or mMCP7, because the enzyme activity was not inhibited by Polybrene but was inhibited by normal mouse plasma. SOCS1+/+ BMMC lysate inhibited the proteolytic activity present in SOCS1-/- BMMC lysate, indicating that SOCS1-/- BMMCs lack an endogenous protease inhibitor. These results show that SOCS1 is required for the expression and/or stability of an endogenous protease inhibitor, which protects mast cells from their own proteolytic enzymes.
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PMID:Suppressor of cytokine signaling 1 regulates an endogenous inhibitor of a mast cell protease. 1291 17

The hematopoietic class III receptor tyrosine kinase (RTK) Flt3 (Flk2, STK1) has recently received much attention as a potential drug target. Activation of Flt3 by different types of mutations plays an important role for proliferation, resistance to apoptosis, and prevention of differentiation of leukemic blasts in acute myeloid leukemia (AML). At least one type of such mutations - an internal tandem duplication in the Flt3 juxtamembrane domain (Flt3-ITD) - has been associated with an unfavorable prognosis. Signal transduction of Flt3 involves activation of several conserved pathways, including the RAS/MAP-Kinase and the phosphoinositide-3-kinase/Akt signaling cascades. Transforming versions of Flt3 exhibit altered signaling, for example a very pronounced activation of STAT5, ultimately resulting in alternate profiles of gene expression and cell transformation. Selective inhibitors of Flt3 tyrosine kinase activity have the potential to suppress aberrant Flt3 signaling. Although highly homologous to other class III RTKs, Flt3 is resistant to the phenylaminopyrimidine STI571 (Gleevec, Imatinib), a potent inhibitor of other RTKs in the family, such as the PDGFbeta-receptor or c-Kit. STI571 binding to Flt3 is prevented by the phenylalanine 691 side-chain in the ATP binding center and mutating this site to threonine renders the corresponding Flt3 mutant sensitive to STI571. Compounds of several other structural families, including the quinoxaline AG1296, the bis(1H-2-indolyl)-1-methanone D-65476, the indolinones SU5416 and SU11248, the indolocarbazoles PKC412 and CEP-701, and the piperazonyl quinazoline CT53518, are potent inhibitors of Flt3 kinase. They exhibit different selectivity profiles, both with respect to other kinases and among wildtype Flt3 and its activated versions. These compounds hold promise as novel drugs against AML and as probes for understanding activation mechanisms and signaling pathways in the class III RTK family.
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PMID:Flt3 receptor tyrosine kinase as a drug target in leukemia. 1518 May 25

To investigate the role of constitutively active internal tandem duplication (ITD) mutants of the Fms-like tyrosine kinase 3 (Flt3) receptor in leukemogenesis, we introduced the Flt3-ITD, W51, into human cord blood CD34+ cells and evaluated their phenotype in diverse hematopoietic assays. W51 expression resulted in a strong proliferative advantage and enhanced erythropoiesis as determined by immunophenotyping, colony assays, and molecular analyses. In MS-5 stromal cocultures, numerous early cobblestone areas (CAs) were generated within 10 to 14 days. Such W51-associated early CAs disappeared by 4 weeks, yet retained self-renewal properties as demonstrated by generation of secondary and tertiary CAs upon replating. This phenotype appears related to the expression of W51 since it was abolished by exposure to the FLT3 inhibitor, AG1295, but not to the c-kit inhibitor PD16. Wild-type Flt3-overexpressing CD34+ cells exposed to high levels of its physiologic ligand did not produce early CAs, highlighting differences in intracellular signaling between wild-type Flt3 and W51. W51-associated signal transducer and activator of transcription 5 (Stat5) activation plays a major role in this phenotype, although additional downstream targets of W51 may be relevant. Flt3-ITD+ acute myeloid leukemia (AML) blasts from patients invariably generated early AG1295-sensitive CAs in MS-5 cocultures, further validating the phenotype observed in transduced CD34+ cells.
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PMID:Enforced expression of an Flt3 internal tandem duplication in human CD34+ cells confers properties of self-renewal and enhanced erythropoiesis. 1524 79

Activation of the interleukin-2 receptor (IL-2R) induces signalling cascades promoting T cell proliferation. However, signal transduction pathways triggered in IL-2R-expressing solid tumours are unknown. This report shows that human papillomavirus (HPV)-associated cervical cancer cells express an IL-2R composed of beta and gamma chains (IL-2Rbetagamma), and that IL-2-mediated activation increases the phosphorylation of JAK3 and STAT5, stimulating cell proliferation. Interestingly, endogenous IL-2 is not produced by these cells, suggesting the activation of IL-2Rbetagamma by an alternative mechanism. Accordingly, we found that Stem Cell Factor (SCF)-activated c-Kit induces phosphorylation of the IL-2Rbeta chain in the absence of IL-2. Moreover, inhibition of IL-2Rbeta phosphorylation by blocking c-Kit tyrosine kinase activity abolishes both, IL-2 and SCF-mediated proliferation. Thus, these results demonstrate that IL-2 triggers a JAK3/STAT5 cascade in HPV-associated cervical cancer cells expressing IL-2Rbetagamma, and that this receptor can be alternatively activated by SCF-activated c-Kit in the absence of IL-2.
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PMID:Interleukin-2 (IL-2) receptor-betagamma signalling is activated by c-Kit in the absence of IL-2, or by exogenous IL-2 via JAK3/STAT5 in human papillomavirus-associated cervical cancer. 1533 23

SLP-76-related adaptor protein MIST (also called Clnk) is expressed in a variety of cytokine-dependent hematopoietic cell lines of myeloid and lymphoid origin as well as some cytokine-independent mast cell lines. To understand the molecular mechanisms underlying the MIST gene expression, we have characterized the 5'-flanking region of the mouse MIST gene. We have identified an enhancer region (-773 to -709), which is active in P815 mast cells expressing the endogenous MIST gene, but not in EL-4 T cells lacking MIST expression. Outside of this enhancer region, one STAT element present in the MIST promoter (-44 to -36) was found to bind STAT5A when IC-2 mast cells were stimulated with IL-3. Mutation of this STAT element did not affect basal MIST promoter activity in P815 mast cells, but was required for STAT5-mediated activation of the MIST promoter. Furthermore, endogenous MIST gene expression was induced in mast cells by a constitutively activated form of STAT5A, but not by an active mutant of c-Kit receptor. These findings suggest that STAT5 is involved in cytokine-mediated up-regulation of MIST gene expression, probably in collaboration with other lineage-specific transcription factors that promote basal MIST expression in mast cells.
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PMID:Transcriptional regulation of SLP-76 family hematopoietic cell adaptor MIST/Clnk by STAT5. 1535 27

IL-5 is produced mainly by activated Th2 and mast cells. High level of IL-5 mRNA expression is detected in c-kit- cells in the lung, spleen, stomach and small intestine in RAG2-/- mice, suggesting the IL-5 production by non-T/non-mast/non-eosinophils. The IL-5R consists of two distinct membrane proteins, IL-5Ralpha and betac. The binding of IL-5 occurs through the IL-5Ralpha, and the betac forms a high-affinity IL-5R in combination with the IL-5Ralpha and transduces signals into nuclei. Activation of Btk and Jak2 kinases, rapid tyrosine phosphorylation of betac, adaptor proteins and transcription factors STAT5; and inductions of transcription of several nuclear proto-oncogenes are essential for the IL-5 signal transduction. Transgenic mice expressing the IL-5 gene exhibit elevated levels of serum IgM, IgA and IgE, increase in numbers of B-1 cells and eosinophils, and show persistent eosinophilia. Functional analysis of the IL-5Ralpha-/- and IL-5-/- mice revealed that IL-5 plays critical roles in the homeostatic proliferation, cell survival and activation of mature B-1 cells and regulates IgA production in the mucosal tissues in response to LPS. We also found that IL-5 can induce mu to gamma1 class-switch recombination in activated B-2 cells by activating AID and Blimp-1. Taking together, IL-5 plays important roles in terminal differentiation of B-lineage cells. In humans, IL-5 preferentially acts on eosinophil precursors and mature eosinophils to prolong maturation, survival and activation. Humanized anti-IL-5 mAb treatment for asthmatic patients was shown to reduce 100% for blood eosinophils but does not deplete airway or bone marrow eosinophils. No significant changes in airway hyper-responsiveness and peak flow recordings between the anti-IL-5 and placebo-treated groups were reported. At this moment, the role of IL-5 and eosinophil in allergic inflammation remains uncertain.
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PMID:[Role of interleukin-5 in immune regulation and inflammation]. 1550 Jan 44

Activating mutations of c-KIT lead to ligand-independent growth. Internal tandem duplications (ITDs) of exon 11, which encodes the juxtamembrane domain (JMD), are constitutively activating mutations found in 7% of gastrointestinal stromal tumors (GISTs) but have not been described in childhood acute myeloid leukemia (AML). DNA and cDNA from 60 children with AML were screened by polymerase chain reaction (PCR) for mutations of the JMD. A complex ITD (kit cITD) involving exon 11 and exon 12 was identified with a relative frequency of 7% (4/60). The human kit cITDs were inserted into the murine c-Kit backbone and expressed in Ba/F3 cells. KIT cITD induced factorindependent growth and apoptosis resistance, and exhibited constitutive autophosphorylation. KIT cITD constitutively activated the PI3K/AKT pathway and phosphorylated STAT1, STAT3, STAT5, and SHP-2. Imatinib (IM) or rapamycin (Rap) led to complete inhibition of growth, with IC50 values at nanomolar levels. IM and Rap synergistically inhibited growth and surmounted KIT cITD-induced apoptosis resistance. IM but not LY294002 inhibited phosphorylation of STAT3 and STAT5, suggesting aberrant cross talk between PI3K- and STAT-activating pathways. The findings presented may have immediate therapeutic impact for a subgroup of childhood AML-expressing c-KIT mutations.
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PMID:Newly identified c-KIT receptor tyrosine kinase ITD in childhood AML induces ligand-independent growth and is responsive to a synergistic effect of imatinib and rapamycin. 1684 Jul 25

In acute myeloid leukemia (AML), autocrine or paracrine activation of receptor tyrosine kinases such as c-kit and FLT3 contributes to proliferation and apoptosis resistance of leukemic blasts. This provided the rationale for a multicenter clinical trial in patients with refractory AML with SU5416, a small molecule kinase inhibitor which blocks phosphorylation of c-kit, FLT3, VEGFR-1, VEGFR-2 (KDR) and VEGFR-3. The levels of VEGF mRNA expression were investigated in peripheral blood leukemic blasts taken from AML patients before and during treatment with SU5416. Rapid down regulation of VEGF was observed in AML blasts from 72% (13 of 18) of patients analysed. Patients initially expressing high VEGF-levels had a stronger downregulation and a higher clinical response rate (mean 865-fold, n = 10, P = 0,01) than patients initially expressing low VEGF-levels (mean four-fold, n = 8). These results suggest that abnormal high VEGF expression is downregulated by SU5416 treatment, and furthermore that decreases in VEGF mRNA levels may provide an early marker of therapeutic response with anti-angiogenic therapy. Additionally, protein expression of STAT5 and AKT was assessed by western blotting in these patient samples, as well as in the leukemia cell line, M-07e, treated in vitro with SU5416 as a model system. In the AML patient samples, parallel downregulation of both STAT5 and AKT was observed in several cases (STAT5 in four of 15; AKT in three of six examined patients). These effects were confirmed with the cell line M-07e after incubation with SU5416 in vitro using concentrations that are achievable in patients. In summary, our data show suppression of the expression of VEGF and key signal transduction intermediates in AML blasts during treatment with SU5416.
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PMID:Downregulation of VEGF-A, STAT5 and AKT in acute myeloid leukemia blasts of patients treated with SU5416. 1716 5

Defining how cancer-associated mutations perturb signaling networks in stem/progenitor populations that are integral to tumor formation and maintenance is a fundamental problem with biologic and clinical implications. Point mutations in RAS genes contribute to many cancers, including myeloid malignancies. We investigated the effects of an oncogenic Kras(G12D) allele on phosphorylated signaling molecules in primary c-kit(+) lin(-/low) hematopoietic stem/progenitor cells. Comparison of wild-type and Kras(G12D) c-kit(+) lin(-/low) cells shows that K-Ras(G12D) expression causes hyperproliferation in vivo and results in abnormal levels of phosphorylated STAT5, ERK, and S6 under basal and stimulated conditions. Whereas Kras(G12D) cells demonstrate hyperactive signaling after exposure to granulocyte-macrophage colony-stimulating factor, we unexpectedly observe a paradoxical attenuation of ERK and S6 phosphorylation in response to stem cell factor. These studies provide direct biochemical evidence that cancer stem/progenitor cells remodel signaling networks in response to oncogenic stress and demonstrate that multi-parameter flow cytometry can be used to monitor the effects of targeted therapeutics in vivo. This strategy has broad implications for defining the architecture of signaling networks in primary cancer cells and for implementing stem cell-targeted interventions.
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PMID:K-RasG12D expression induces hyperproliferation and aberrant signaling in primary hematopoietic stem/progenitor cells. 1719 89

Aggressive systemic mastocytosis (ASM) is a very rare form of mast cell neoplasm that does not benefit from conventional chemotherapy. The majority of adult mast cell neoplasms and gastrointestinal stromal tumors (GISTs) have mutations in the proto-oncogene c-kit, which encodes the KIT receptor tyrosine kinase. The c-kit gene mutations are generally confined to the tyrosine kinase II domain in mast cell neoplasms, but are often observed at the juxtamembrane domain in GISTs. We found a case of ASM with a juxtamembrane-type mutation, Val559Ile, and in this report the mutation was characterized through transfection of the mutated c-kit cDNA into human embryonic kidney cells. Phosphorylation of KIT and its possible downstream signaling molecules were examined in the presence or absence of imatinib, a selective tyrosine kinase inhibitor. Ligand-independent autophosphorylation was observed in the mutant KIT with Val559Ile as well as that with Val559Asp, as found in GISTs. Imatinib, at a concentration of 10 microM, inhibited autophosphorylation of the mutant KIT with Val559Asp, but not that with the Val559Ile. Phosphorylation of MAPK and STAT5 was also inhibited by imatinib at the same concentration, in cells expressing Val559Asp but not in those expressing Val559Ile. These results suggest that different mutations, even at the same codon, in juxtamembrane domain of the c-kit gene show different inhibitory effects of imatinib, and that patients with GISTs or mast cell neoplasms possessing this Val559Ile mutation are resistant to imatinib therapy.
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PMID:Juxtamembrane-type c-kit gene mutation found in aggressive systemic mastocytosis induces imatinib-resistant constitutive KIT activation. 1748 96


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