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:2.7.10.2 (focal adhesion kinase)
44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The c-kit receptor tyrosine kinase (KIT) is constitutively activated by naturally occurring mutations in either the juxtamembrane domain or the kinase domain. Although the juxtamembrane domain mutations led to ligand-independent KIT dimerization, the kinase domain mutations (Asp814 --> Val or Tyr) did not. In an effort to determine if the kinase domain mutant could transfer oncogenic signaling without receptor dimerization, we have constructed the truncated types of c-kitWild and c-kitTyr814 cDNAs (c-kitDel-Wild and c-kitDel-Tyr814 cDNAs, respectively), in which ligand-binding and ligand-induced dimerization domains were deleted. When c-kitDel-Wild and c-kitDel-Tyr814 genes were introduced into a murine interleukin-3 (IL-3)-dependent cell line Ba/F3, KITDel-Tyr814 was constitutively phosphorylated on tyrosine and activated, whereas KITDel-Wild was not. In addition, Ba/F3 cells expressing KITDel-Tyr814 (Ba/F3(Del-Tyr814)) grew in suspension culture without the addition of exogenous growth factor, whereas Ba/F3 cells expressing KITDel-Wild (Ba/F3(Del-Wild)) required IL-3 for growth. The factor-independent growth of Ba/F3(Del-Tyr814) cells was virtually abrogated by coexpression of KITW42 that is a dominant-negative form of KIT, but not by that of KITWild, suggesting that KITDel-Tyr814 may not function as a monomer but may require receptor dimerization for inducing factor-independent growth. Furthermore, KITDel-Tyr814 was found to be coimmunoprecipitated with KITWild or KITW42 by an ACK2 monoclonal antibody directed against the extracellular domain of KIT. Moreover, KITW42 was constitutively associated with a chimeric FMS/KITTyr814 receptor containing the ligand-binding and receptor dimerization domain of c-fms receptor (FMS) fused to the transmembrane and cytoplasmic domain of KITTyr814, but not with a chimeric FMS/KITWild receptor even after stimulation with FMS-ligand. These results suggest that constitutively activating mutation of c-kit at the Asp814 codon may cause a conformation change that leads to receptor self-association not in the extracellular domain and that the receptor self-association of the Asp814 mutant may be important for activation of downstream effectors that are required for factor-independent growth and tumorigenicity.
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PMID:Activating mutation in the catalytic domain of c-kit elicits hematopoietic transformation by receptor self-association not at the ligand-induced dimerization site. 994 75

To screen the receptor genes in renal cell carcinoma (RCC) associated with angiogenesis, we performed differential hybridization of the cDNA library of membrane-type protein tyrosine kinases (mPTKs). Three thousand plaques of a mPTKs-enriched cDNA library were screened with mPTKs mixture probes produced from hypervascular RCC tissues and RCC cell lines. Six different cDNA fragments of the PTK genes were isolated, and the sequence analysis showed that these represented cDNAs for TIE1, KDR, FMS, FGFR-4, JAK1 and HCK. Of these genes, the expression of TIE1, KDR, and FGFR-4 was studied in RCC tissue and cell lines by Northern blot analysis. We also investigated the expression of vascular endothelial growth factor (VEGF), placenta growth factor (PlGF) and their receptor FLT-1. In all the hypervascular RCC tissues, the amounts of mRNAs for KDR and FLT-1 were increased compared to adjacent normal tissues. The TIE1 and FGFR-4 genes were also overexpressed in most of the hypervascular RCC tissues, while no mRNA of KDR, FLT-1, or TIE1 could be detected in any of the four human RCC cell lines. The amounts of the VEGF and PlGF mRNAs were increased in hypervascular RCC tissues, while VEGF mRNA was detected in the four cell lines but PlGF mRNA was not. FGFR-4 mRNA was expressed in three of the four cell lines. These results suggest that KDR, FLT-1, PlGF and TIE1 mRNAs are present in the mesenchymal cells of RCC, while VEGF and FGFR-4 genes are expressed in RCC cells themselves in vivo.
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PMID:Identification of receptor genes in renal cell carcinoma associated with angiogenesis by differential hybridization technique. 1020 73

Interleukin (IL)-3, IL-5 and granulocyte-macrophage colony-stimulating factor (GM-CSF) regulate proliferation, differentiation and apoptosis of target cells. Receptors for these cytokines consist of a cytokine-specific alpha subunit and a common shared beta c subunit. Tyrosine phosphorylation of the beta c is thought to play a critical role in mediating signal transduction events. We have examined the effect of mutation of beta c tyrosines on the activation of multiple signal transduction pathways. Activation of protein kinase B (PKB) required JAK2 and was inhibited by dominant-negative phosphatidylinositol 3-kinase (P13K). Overexpression of JAK2 was sufficient to activate both protein kinase B (PKB) and extracellular regulated kinase-1 (ERK1). Tyrosine 577 and 612 were found to be critical for the activation of PKB and ERK1, but not activation of STAT transcription factors. Activation of both PKB and ERK have been implicated in the regulation of proliferation and apoptosis. We generated GM-CSFR stable cell lines expressing receptor mutants to evaluate their effect on these processes. Activation of both PKB and ERK was perturbed, while STAT activation remained unaffected. Tyrosines 577 and 612 were necessary for optimal proliferation, however, mutation of these tyrosine residues did not affect GM-CSF mediated rescue from apoptosis. These data demonstrate that while phosphorylation of beta c tyrosine residues 577 and 612 are important for optimal cell proliferation, rescue from apoptosis can be mediated by alternative signalling routes apparently independent of PKB or ERK activation.
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PMID:Regulation and function of protein kinase B and MAP kinase activation by the IL-5/GM-CSF/IL-3 receptor. 1036 54

To identify the novel substrate of c-kit which is important for hematopoietic stem cell self-renewal or differentiation, CD34-low/negative, Sca-1-positive, c-kit-positive, and lineage marker-negative (CD34(low/-)Sca-1(+)c-kit(+)Lin(-)) cells were sorted by a fluorescence-activated cell sorter from mouse bone marrow cells and a yeast two-hybrid cDNA library was constructed. By screening with c-kit as bait, we cloned a novel cDNA, designed STAP-1, encoding an adaptor protein with a Pleckstrin homology domain, the Src homology 2 (SH2) domain, and a number of tyrosine phosphorylation sites. RT-PCR analysis revealed that STAP-1 expression is restricted in the bone marrow cell fraction expressing c-kit. The highest expression was observed in the CD34(low/-)Sca-1(+)c-kit(+)Lin(-) stem cell-enriched fraction. The murine myeloid cell line, M1, expressed a high level of STAP-1. However, the expression was strongly repressed in response to leukemia inhibitory factor (LIF) which induced monocytic differentiation of M1 cells, suggesting that STAP-1 is associated with the undifferentiated cell type. A two-hybrid assay indicated that STAP-1 bound not only to c-kit but also to c-fms but not to JAK2 or Pyk2. In 293 cells, STAP-1 was tyrosine-phosphorylated by activated c-kit. An in vitro binding assay suggested that the STAP-1 SH2 domain interacted with several tyrosine-phosphorylated proteins including c-kit and STAT5. These suggest that STAP-1 functions as an adaptor molecule downstream of c-kit in hematopoietic stem cells.
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PMID:Molecular cloning of murine STAP-1, the stem-cell-specific adaptor protein containing PH and SH2 domains. 1067 68

The tyrosine kinase inhibitor STI571 inhibits BCR/ABL and induces hematologic remission in most patients with chronic myeloid leukemia. In addition to BCR/ABL, STI571 also inhibits v-Abl, TEL/ABL, the native platelet-derived growth factor (PDGF)beta receptor, and c-KIT, but it does not inhibit SRC family kinases, c-FMS, FLT3, the epidermal growth factor receptor, or multiple other tyrosine kinases. ARG is a widely expressed tyrosine kinase that shares substantial sequence identity with c-ABL in the kinase domain and cooperates with ABL to regulate neurulation in the developing mouse embryo. As described here, ARG has recently been implicated in the pathogenesis of leukemia as a fusion partner of TEL. A TEL/ARG fusion was constructed to determine whether ARG can be inhibited by STI571. When expressed in the factor-dependent murine hematopoietic cell line Ba/F3, the TEL/ARG protein was heavily phosphorylated on tyrosine, increased tyrosine phosphorylation of multiple cellular proteins, and induced factor-independent proliferation. The effects of STI571 on Ba/F3 cells transformed with BCR/ABL, TEL/ABL, TEL/PDGFbetaR, or TEL/ARG were then compared. STI571 inhibited tyrosine phosphorylation and cell growth of Ba/F3 cells expressing BCR/ABL, TEL/ABL, TEL/PDGFbetaR, and TEL/ARG with an IC(50) of approximately 0.5 microM in each case, but it had no effect on untransformed Ba/F3 cells growing in IL-3 or on Ba/F3 cells transformed by TEL/JAK2. Culture of TEL/ARG-transfected Ba/F3 cells with IL-3 completely prevented STI571-induced apoptosis in these cells, similar to what has been observed with BCR/ABL- or TEL/ABL-transformed cells. These results indicate that ARG is a target of the small molecule, tyrosine kinase inhibitor STI571.
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PMID:ARG tyrosine kinase activity is inhibited by STI571. 1129 Jun 9

Leridistim is a member of a novel family of engineered chimeric cytokines, myelopoietins, that contain agonists of both interleukin-3 (IL-3) receptors (IL-3R) and granulocyte colony-stimulating factor (G-CSF) receptors (G-CSFR). To more clearly understand Leridistim's function at the molecular level, binding to both IL-3R and G-CSFR and subsequent signaling characteristics have been delineated. The affinity of Leridistim for the human G-CSFR was found to be comparable to that of native G-CSF (IC(50) = 0.96 nM and 1.0 nM, respectively). Both Leridistim and G-CSF induced receptor tyrosine phosphorylation to a similar maximal level. Compared with native recombinant human IL-3 (rhIL-3), Leridistim was found to possess higher affinity for the IL-3R alpha chain (IL-3Ralpha) (IC(50) = 85 nM and 162 nM, respectively). However, the increase in Leridistim binding affinity to the functional, high-affinity heterodimeric IL-3Ralphabeta(c) receptor is lower than that observed with rhIL-3 (85 nM and 14 nM vs 162 nM and 3.5 nM, respectively). Leridistim induced tyrosine phosphorylation of beta(c) to a level comparable to native IL-3, and the level of JAK2 tyrosine phosphorylation in cells expressing both IL-3R and G-CSFR was comparable to that observed with IL-3 or G-CSF alone. The ability of Leridistim to interact with IL-3R and G-CSFR simultaneously was demonstrated using surface plasmon resonance analysis. These studies were extended to demonstrate that Leridistim exhibited a higher affinity for the IL-3R on cells that express both the IL-3Ralphabeta(c) and the G-CSFR (IC(50) = 2 nM) compared with cells that contain the IL-3Ralphabeta(c) alone (IC(50) = 14 nM). Leridistim binds to both IL-3R and G-CSFR simultaneously and has been shown to activate both receptors. The bivalent avidity may explain the unique biologic effects and unexpected potency of Leridistim in hematopoietic cells compared with rhIL-3 or G-CSF alone or in combination.
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PMID:Bivalent binding and signaling characteristics of Leridistim, a novel chimeric dual agonist of interleukin-3 and granulocyte colony-stimulating factor receptors. 1130 Nov 81

The granulocyte colony-stimulating factor receptor (G-CSFR) regulates the proliferation, differentiation and survival of neutrophilic progenitor cells. In these studies, we introduced mutant G-CSFRs with cytoplasmic domains truncated approximately every 30 amino acids from the C-terminus into interleukin-3 (IL-3)-dependent myeloid LGM-1 cells. The G-CSFR membrane proximal region containing the Box 2 homology sequence was determined to be critical for proliferative signaling, as well as for activation of Janus kinase (JAK2) and p44/42 mitogen-activated protein kinase (MAPK) following G-CSF stimulation. In the presence of increasing concentrations of JAK2 or p44/42 MAPK inhibitors, LGM-1 cells expressing the full-length G-CSFR exhibited a decreased capacity to proliferate in response to G-CSF. These results demonstrate that JAK2 and p44/42 MAPK activation is involved in proliferative signaling through the G-CSFR membrane proximal region containing the Box 2 homology sequence.
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PMID:Distinct region of the granulocyte colony-stimulating factor receptor mediates proliferative signaling through activation of Janus kinase 2 and p44/42 mitogen-activated protein kinase. 1181 52

Aberrant expression and activating mutations of the class III receptor tyrosine kinase Flt3 (Flk-2, STK-1) have been linked to poor prognosis in acute myeloid leukemia (AML). Inhibitors of Flt3 tyrosine kinase activity are, therefore, of interest as potential therapeutic compounds. We previously described bis(1H-2-indolyl)-1-methanones as a novel class of selective inhibitors for platelet-derived growth factor receptors (PDGFR). Several bis(1H-2-indolyl)-1-methanone derivatives, represented by the compounds D-64406 and D-65476, are also potent inhibitors of Flt3. They inhibit proliferation of TEL-Flt3-transfected BA/F3 cells with IC(50) values of 0.2-0.3 microM in the absence of IL-3 but >10 microM in the presence of IL-3. Ligand-stimulated autophosphorylation of Flt3 in EOL-1 cells and corresponding downstream activation of Akt/PKB are effectively inhibited by bis(1H-2-indolyl)-1-methanones whereas autophosphorylation of c-Kit/SCF receptor or c-Fms/CSF-1 receptor is less sensitive or insensitive, respectively. Flt3 kinase purified by different methods is potently inhibited in vitro, demonstrating a direct mechanism of inhibition. 32D cells, expressing a constitutively active Flt3 variant with internal tandem duplication are greatly sensitized to radiation-induced apoptosis in the presence of D-64406 or D-65476 in the absence but not in the presence of IL-3. Thus, bis(1H-2-indolyl)-1-methanones are potential candidates for the treatment of Flt3-driven leukemias.
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PMID:Bis(1H-2-indolyl)-1-methanones as inhibitors of the hematopoietic tyrosine kinase Flt3. 1214 94

Angiogenesis is a key process in a variety of human diseases, including cancer. The ability to target selectively the tumor vasculature is potentially useful for the diagnosis and treatment of cancer. Still, little information is available regarding markers that are restricted to the ECs of tumor vessels. cDNA array technology allows simultaneous analysis of relative expression levels of a broad spectrum of genes in 2 related cell populations. We used this technology with the aim of identifying markers specific for TECs. TECs were isolated by CD31-mediated immunomagnetic separation from tumors induced by s.c. injection of NF9006 breast carcinoma cells into syngeneic mice. NECs were isolated from lactating mammary glands. The endothelial nature of isolated cells was confirmed by RT-PCR using CD31-specific primers and by uptake of DiI-Ac-LDL. Macrophage contamination in the EC isolations could be reasonably ruled out by assessing the expression of the macrophage marker c-fms. (32)P-labeled cDNA probes generated by reverse transcription from total RNA were hybridized to mouse-specific gene arrays. Several genes consistently showed differential expression between TECs and NECs. However, expression of only 1 of these genes, IGFBP-3, was restricted exclusively to ECs. Semiquantitative RT-PCR revealed 22- to 33-fold differential expression of IGFBP-3 in the TEC fraction. IGFBP-3 was overexpressed by a factor of 5 in an additional mouse model of breast carcinoma induced by 4T1.2 tumor cells. These results indicate that IGFBP-3 is a potential novel marker of angiogenesis. Elucidation of its role in tumor neovascularization may open the possibility of IGFBP-3 as a therapeutic target for antiangiogenesis.
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PMID:Insulin-like growth factor binding protein-3 is overexpressed in endothelial cells of mouse breast tumor vessels. 1249 64

As a c-fms-interacting protein, we cloned a novel adaptor molecule, signal-transducing adaptor protein-2 (STAP-2), which contains pleckstrin homology- and Src homology 2-like (PH and SRC) domains and a proline-rich region. STAP-2 is structurally related to STAP-1/BRDG1 (BCR downstream signaling-1), which we had cloned previously from hematopoietic stem cells. STAP-2 is a murine homologue of a recently identified adaptor molecule, BKS, a substrate of BRK tyrosine kinase. STAP-2 was tyrosine-phosphorylated and translocated to the plasma membrane in response to epidermal growth factor when overexpressed in fibroblastic cells. To define the function of STAP-2, we generated mice lacking the STAP-2 gene. STAP-2 mRNA was strongly induced in the liver in response to lipopolysaccharide and in isolated hepatocytes in response to interleukin-6. In the STAP-2(-/-) hepatocytes, the interleukin-6-induced expression of acute-phase (AP) genes and the tyrosine-phosphorylation level of STAT3 were reduced specifically at the late phase (6-24 h) of the response. These data indicate that STAP-2 plays a regulatory role in the AP response in systemic inflammation. STAP-2 contains a YXXQ motif in the C-terminal region that is a potential STAT3-binding site. Overexpression of wild-type STAP-2, but not of mutants lacking this motif, enhanced the AP response element reporter activity and an AP protein production. These data suggest that STAP-2 is a new class of adaptor molecule that modulates STAT3 activity through its YXXQ motif.
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PMID:STAP-2/BKS, an adaptor/docking protein, modulates STAT3 activation in acute-phase response through its YXXQ motif. 1254 Aug 42


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