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)

To identify mechanisms by which GH receptors (GHR) mediate downstream events representative of growth and metabolic responses to GH, stimulation by GH of c-fos and egr-1 expression and glucose transport activity were examined in Chinese hamster ovary (CHO) cells expressing mutated GHR. In CHO cells expressing wild-type GHR(GHR(1-638)), GH stimulated the expression of c-fos and egr-1, and stimulated 2-deoxyglucose uptake, responses also mediated by endogenous GHR in 3T3-F442A cells. Deletion of the proline-rich box 1 of GHR (GHR(deltaP)) abrogated all of these responses to GH, indicating that box 1, a site of association of GHR with the tyrosine kinase JAK2, is crucial for these GH-stimulated responses. As the C-terminal half of the cytoplasmic domain of GHR is required for GH-stimulated calcium flux and for stimulation of spi-2.1 transcription, GHR lacking this sequence (GHR(1-454)) were examined. Not only did GHR(1-454) mediate stimulation of c-fos and egr-1 expression and 2-deoxyglucose uptake, but they also mediated GH-stimulated transcriptional activation via Elk-1, a transcription factor associated with the c-fos Serum Response Element. Thus, the C-terminal half of the cytoplasmic domain of GHR is not required for GH-stimulated c-fos transcription, suggesting that increased calcium is not required for GH-stimulated c-fos expression. In CHO cells lacking all but five N-terminal residues of the cytoplasmic domain (GHR(1-294)), GH did not induce c-fos or egr-1 expression or stimulate 2-deoxyglucose uptake. Further, in 3T3-F442A fibroblasts with endogenous GHR, GH-stimulated c-fos expression and 2-deoxyglucose uptake were reduced by the tyrosine kinase inhibitors herbimycin A, staurosporine, and P11. Herbimycin A and staurosporine inhibit JAK2 and tyrosyl phosphorylation of all proteins stimulated by GH, whereas P11 inhibits the GH-dependent tyrosyl phosphorylation of only some proteins, including extracellular signal regulated kinases ERK1 and -2, but not JAK2. Taken together, these results implicate association of GHR with JAK2 and GH-stimulated tyrosyl phosphorylation of an additional cellular protein in GH-stimulated glucose transport and c-fos and egr-1 expression. These studies also indicate that, in contrast to spi-2.1, the N-terminal half of the cytoplasmic domain of GHR is sufficient to mediate stimulation of c-fos and egr-1 expression and Elk-1 activation, supporting multiple mechanisms for GH signaling to the nucleus.
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PMID:Regulation of glucose transport and c-fos and egr-1 expression in cells with mutated or endogenous growth hormone receptors. 952 72

In GN4 rat liver epithelial cells, angiotensin II (Ang II) produces intracellular calcium and protein kinase C (PKC) signals and stimulates ERK and JNK activity. JNK activation appears to be mediated by a calcium-dependent tyrosine kinase (CADTK). To define the ERK pathway, we established GN4 cells expressing an inhibitory Ras(N17). Induction of Ras(N17) blocked EGF- but not Ang II- or phorbol ester (TPA)-dependent ERK activation. In control cells, Ang II and TPA produced minimal increases in Ras-GTP level and Raf kinase activity. PKC depletion by chronic TPA exposure abolished TPA-dependent ERK activation but failed to diminish the effect of Ang II. In PKC-depleted cells, Ang II increased Ras-GTP level and activated Raf and ERK in a Ras-dependent manner. In PKC depleted cells, Ang II stimulated Shc and Cbl tyrosine phosphorylation, suggesting that without PKC, Ang II activates another tyrosine kinase. PKC-depletion did not alter Ang II-dependent tyrosine phosphorylation or activity of p125(FAK), CADTK, Fyn or Src, but PKC depletion or incubation with GF109203X resulted in Ang II-dependent EGF receptor tyrosine phosphorylation. In PKC-depleted cells, EGF receptor-specific tyrosine kinase inhibitors blocked Ang II-dependent EGF receptor and Cbl tyrosine phosphorylation, and ERK activation. In summary, Ang II can activate ERK via two pathways; the latent EGF receptor, Ras-dependent pathway is equipotent to the Ras-independent pathway, but is masked by PKC action. The prominence of this G-protein coupled receptor to EGF receptor pathway may vary between cell types depending upon modifiers such as PKC.
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PMID:Angiotensin II stimulates ERK via two pathways in epithelial cells: protein kinase C suppresses a G-protein coupled receptor-EGF receptor transactivation pathway. 956 40

Transmission of zucchini yellow mosaic virus (ZYMV) by aphids was examined by introducing mutations within the highly conserved proline-threonine-lysine (PTK) motif of the helper component proteinase (HC-Pro) using a cDNA full-length clone. Replacement of proline by alanine (ATK) in the PTK motif abolished transmission almost completely both from plants and from membranes. Substitution of the basic lysine by glutamic acid (PTE) did not reduce the rate of transmission compared with the wild-type. Replacement of threonine by valine (PVK) or serine (PSK) resulted in a rate of transmission that was lower than that of the wild-type. The rate was lower for PSK than for PVK. Western blot comparison did not permit attribution of HC-Pro functionality in transmission to its level in the host. The HC-Pro of strains that effected transmission (with the wild-type PTK motif, and with the mutated PTE and PVK motifs) could also bind in vitro to virions of ZYMV. HC-Pro with a PSK motif, which was less effective in assisting transmission, could bind only weakly to virions, while HC-Pro of the almost non-transmissible strains (with PAK and ATK motifs) did not bind at all. Interestingly, positive binding was recorded for transmission-defective ZYMV-Ct, which has a PTK motif but has glutamic acid instead of lysine in the lysine-leucine-serine-cysteine (KLSC) motif. These findings support the 'bridge hypothesis', and confirm the binding of the HC-Pro to the virion. The possible role of the PTK and KLSC motifs in binding to the virus and to the mouthparts of the aphid is discussed.
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PMID:Mutations in the HC-Pro gene of zucchini yellow mosaic potyvirus: effects on aphid transmission and binding to purified virions. 956 86

Kaposi's sarcoma (KS) spindle cell growth and spread have been reported to be modulated by various cytokines as well as the human immunodeficiency virus (HIV) gene product Tat. Recently, HIV-1 Tat has been shown to act like a cytokine and bind to the Flk-1/KDR receptor for the vascular endothelial growth factor A (VEGF-A), which is expressed by KS cells. We have characterized signal transduction pathways stimulated by HIV-1 Tat upon its binding to surface receptors on KS cells. We observed that stimulation in KS 38 spindle cells resulted in tyrosine phosphorylation and activation of the Flk-1/KDR receptor. We also report that HIV-1 Tat treatment enhanced the phosphorylation and association of proteins found in focal adhesions, such as the related adhesion focal tyrosine kinase RAFTK, paxillin, and p130(cas). Further characterization revealed the activation of mitogen-activated protein kinase, c-Jun amino-terminal kinase (JNK), and Src kinase. HIV-1 Tat contains a basic domain which can interact with growth factor tyrosine kinase receptors and a classical RGD sequence which may bind to and activate the surface integrin receptors for fibronectin and vitronectin. We observed that stimulation of KS cells with basic as well as RGD sequence-containing Tat peptides resulted in enhanced phosphorylation of RAFTK and activation of MAP kinase. These studies reveal that Tat stimulation activates a number of signal transduction pathways that are associated with cell growth and migration.
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PMID:Human immunodeficiency virus tat modulates the Flk-1/KDR receptor, mitogen-activated protein kinases, and components of focal adhesion in Kaposi's sarcoma cells. 962 Oct 77

Low plasma high density lipoprotein cholesterol (HDL-C) is a major risk factor for coronary heart disease (CHD) in adults. In the field of pediatrics, subjects with low plasma HDL-C are often found among obese or dyslipidemic children. However, it is not clear whether low HDL-C in children should be considered a risk factor for CHD. The purpose of this study was to evaluate the risk for CHD in children with low HDL-C by comparing their lipid and apolipoprotein levels and physicochemical characteristics of their HDL with those of age-matched children with normal HDL-C and CHD patients with low HDL-C. Plasma lipids and apolipoproteins were measured in 206 dyslipidemic children (dyslipidemic), 65 obese children (obese), 93 CHD patients with low HDL-C (< 40 mg/dl) and 128 children with normal HDL-C (controls). To evaluate the physicochemical characteristics of HDL, molar and fractional esterification rates of cholesterol in plasma (MER(plasma) and FER(plasma)) and HDL (MER(HDL) and FER(HDL)) were determined in 128 children with normal HDL-C, 71 dyslipidemic, 33 obese and 93 CHD who allowed second blood samples to be taken. Compared to controls, children with low HDL-C showed atherogenic profiles of lipid and apolipoprotein levels and physicochemical characteristics of HDL (lower apo A-I, lower ratio of apo A-I to apo B and higher FER(HDL)). Therefore, the differences in lipid and apolipoprotein profiles between children with low HDL-C and CHD patients with low HDL-C were examined next. The two groups of subjects based on the HDL-C level (Group I: < 30 mg/dl, Group II 30 < or = HDL-C < 40 mg/dl) were studied. Compared to CHD, Group I children showed less atherogenic apolipoprotein profiles (lower apo B and higher ratio of apo A-I to apo B). Similar findings were also found in Group II children, but the differences were less prominent than those in Group I children. FER(HDL) in children with low HDL-C were similar to those in CHD. These findings suggest that the physicochemical characteristics of HDL in children with low HDL-C are similar to those in CHD, but the abnormalities of apo B-containing lipoproteins are milder than those in CHD patients. Thus, if further changes in the nature of apo B-containing lipoproteins could be prevented, children with low HDL-C might not become high risk for CHD in later life.
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PMID:Comparison of children and coronary heart disease patients with low high density lipoprotein cholesterol levels. 962 75

A large number of continuous human leukemia cell lines have been established over the last three decades. Clearly, leukemia cell lines have become important research tools. Here, we have summarized the immunological, molecular and standard cytogenetic features of a panel of well characterized B cell precursor (BCP)-leukemia cell lines which were derived from patients with acute lymphoblastic/undifferentiated leukemia (ALL/AUL) or chronic myeloid leukemia (CML) in blast crisis. Following the recently proposed immunological EGIL classification, we assigned our panel of 27 BCP-cell lines to one of the following categories: B-I pro-B cell line; B-II common-B cell line; and B-III pre-B cell line. All cell lines express general B-lineage associated surface markers (HLA-DR, CD22, CD79a) being negative for surface immunoglobulin (Ig); the differences between the subgroups reside in expression of CD10 and cytoplasmic Ig. Several BCP-cell lines show the myelomonocytic cell-associated markers CD13 and/or CD33. These immunologically 'biphenotypic' BCP-cell lines are generally TdT+ CD10+ CD13+ CD19+ CD22+ CD34+ and carry the Philadelphia (Ph) translocation. The BCP-cell lines display surface receptors for interferon-gamma (CD119), interleukin-7 (CD127) and FLT-3 ligand (CD135). All BCP-cell lines examined have complex numerical and structural chromosomal alterations including translocations commonly seen in BCP-ALL such as t(4;11), t(9;22), t(11;19), t(12;21), and t(17;19) involving the fusion genes MLL-AF4, BCR-ABL, ENL-MLL, TEL/ETV6-AML1 and E2A-HLF, respectively. Besides the expected rearrangement of the Ig heavy chain receptor gene, several cell lines also have rearrangements of the T cell receptor genes beta, gamma or delta. While some BCP-cell lines express (aberrantly) myeloperoxidase at the mRNA level, most lines are negative in the immunological or cytochemical staining. Several large series documented the difficulty in establishing such BCP cell lines with success rates in the range of 10-20% (on average 15%). Still, since the establishment of the first bonafide BCP-cell line in 1974 (cell line REH), some 150 cell lines have been established of which, however, only a small percentage have been sufficiently well characterized and described. A higher success rate for immortalizing any given leukemia cell might depend on a closer emulation of the physiological in vivo microenvironment. The possibility to grow in vitro leukemia cells at will would represent ideal experimental systems permitting basic research and patient-specific investigations. In summary, the use of well-characterized BCP-cell lines provide unprecedented opportunities for studying a multitude of biological aspects related to normal and neoplastic B-lymphocytes.
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PMID:Establishment and characterization of human B cell precursor-leukemia cell lines. 968 Jan 6

Xiphophorus fish have been the subject of intensive genetic research for more than 60 yr, primarily because of the availability of a number of interspecific hybrids that are malignant melanoma models with apparently simple oncogene and tumor suppressor gene determinants. The gene map of Xiphophorus is one of the most extensive among nonhuman vertebrates, with about 100 genes assigned to at least 20 independently assorting linkage groups (LGs), as well as more than 250 anonymous DNA sequence markers, providing coverage for most of the genome for genetic mapping studies. This characteristic has resulted in the mapping of a tumor suppressor locus, DIFF, which is one of two genetic determinants of melanoma formation in the best-studied hybrid melanoma, the Gordon-Kosswig melanoma model. The other gene responsible for melanoma formation in this model is a sex-linked tyrosine kinase gene related to EGFR and called Xiphophorus melanoma receptor kinase (Xmrk). The cellular oncogene homologues of the non-receptor tyrosine kinase family orthologous toyes and fyn have also been found to be overexpressed in malignant melanomas of Xiphophorus and may be involved in tumor progression. We report here the map location of a Xiphophorus yes gene, YES1, in LG VI, closest to the EGFR gene and the assignment of a fyn gene homologue to newly designated LG XV, linked to the gene for cytosolic alpha-galactosidase. We also confirmed that an EGFR-related sequence (EGFRL1) that we previously assigned to Xiphophorus LG VI by cross-hybridization to a viral erbB probe was the EGFR orthologue. Our results suggest that the presence of expressed duplicates of members of the tyrosine kinase gene family in teleost fishes may increase the potential number of targets in oncogenic cascades in fish tumor models.
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PMID:Mapping of tyrosine kinase gene family members in a Xiphophorus melanoma model. 968 40

Partial PTK6 (also known as Brk) cDNA was initially isolated by reverse transcription-PCR of normal human melanocyte mRNAs and the full-length cDNA encodes a non-receptor protein tyrosine kinase with an SH3 domain, an SH2 domain, and a kinase catalytic domain. We have cloned the human PTK6 gene by screening human genomic lambda libraries using the full-length PTK6 cDNA as probe. The human PTK6 gene consists of 8 exons encompassing 8.8 kb and all the splicing junctions followed the conserved GT/AG rule. Coding sequence of the PTK6 gene was identical to that of the cDNA cloned from T-47D, human breast tumor cell line. Although the amino acid sequence of the PTK6 polypeptide showed the strongest homology to those of the Src family members of protein tyrosine kinases, exon-intron boundaries of the PTK6 gene were quite different from those of the Src family genes, which are evolutionarily conserved. The 813-bp 5'-flanking sequence of the PTK6 gene upstream of a luciferase reporter gene conferred significant promoter activity, at approximately 60% level of the SV40 promoter, in transient expression assays into MCF-7, human breast tumor cell line. PTK6 mRNA was expressed at very high level in colon and at high levels in small intestine and prostate, and at low levels in some tested fetal tissues. These results suggest that PTK6 constitutes an evolutionarily distinct family of non-receptor protein tyrosine kinases and may function as an intracellular signal transducer in specific tissues.
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PMID:Exon-intron structure of the human PTK6 gene demonstrates that PTK6 constitutes a distinct family of non-receptor tyrosine kinase. 974 26

Bruton's tyrosine kinase (Btk) is a non-receptor protein tyrosine kinase (PTK) that is expressed in all haemopoietic lineages except mature T cells and plasma cells. Despite the broad range of expression. mutations that inactivate this molecule affect primarily the development of the B-cell lineage. As a PTK, Btk could potentially be involved directly or indirectly in the processes that relate to the malignant transformation of all the cell lineages where this molecule is expressed. Previous studies have failed to demonstrate mutations in patients with B-cell origin acute lymphoblastic leukaemia (ALL). We have utilized a recently developed method that enables the rapid and convenient detection of mutations at the cDNA level, namely, the non-isotopic RNase cleavage assay (NIRCA) to analyse Btk sequences from 27 patients with different types of acute myeloid leukaemia (AML). The only alteration that we observed was a polymorphism at position 2031. This polymorphism has already been seen in previous studies. Furthermore, using the same methodology, we identified the Btk mutations in six XLA (X-linked agammaglobulinaemia) patients. Our results, although they do not exclude the involvement of Btk mutations in the development or progression of some type of AML, nevertheless suggest that such mutations do not constitute a major co-factor in the development of myeloid malignancies.
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PMID:Absence of Bruton's tyrosine kinase (Btk) mutations in patients with acute myeloid leukaemia. 975 52

The receptors for the I1-3/IL-5/GM-CSF cytokine family are composed of a heterodimeric complex of a cytokine-specific alpha chain and a common beta chain (betac). Binding of IL-3/IL-5/GM-CSF to their respective receptors rapidly induces activation of multiple intracellular signalling pathways, including the Ras-Raf-ERK, the JAK/STAT, the phosphatidylinositol 3-kinase PKB, and the JNK/SAPK and p38 signalling pathways. This review focuses on recent advancements in understanding how these different signalling pathways are activated by IL-3/IL-5/GM-CSF receptors, and how the individual pathways contribute to the pleiotropic effects of IL-3/IL-5/GM-CSF on their target cells, including proliferation, differentiation, survival, and effector functions.
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PMID:Regulation of proliferation, differentiation and survival by the IL-3/IL-5/GM-CSF receptor family. 979 43


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