Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.10.2 (focal adhesion kinase)
 44,029 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The vertebrate gene HCK encodes a protein-tyrosine kinase that is closely related to the product of the proto-oncogene SRC. HCK is expressed principally in monocytic and granulocytic hematopoietic cells, in coordination with differentiation of these cells. Here we report an initial description of the mechanisms by which expression of human HCK is controlled. Induction of the gene during differentiation was manifested by an increase in the steady-state levels of HCK RNA and protein product. The accumulation of RNA apparently resulted from modulation of transcription itself, since no change occurred in the stability of the transcripts. Transcription initiated at multiple sites, clustered c. 145 nucleotides upstream of the first intron of HCK. The sequence of 660 bp upstream of the major initiation site was determined, revealing candidate binding sites for Sp1 and AP-2 transcription factors, but neither TATA nor CAAT elements. Comparison to the same region of the mouse hck locus showed five small regions of similarity, only two of which were topographically analogous between the two sequences. It appears that expression of HCK is regulated primarily through control of transcription, but the mechanisms by which tissue-specific expression and increase of transcription during differentiation are achieved remain to be explored.
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PMID:Human protein-tyrosine kinase gene HCK: expression and structural analysis of the promoter region. 137 73

The lymphokine interleukin-3 (IL-3) promotes the growth and survival of immature hematopoietic cells. Previous studies have shown that IL-3 induces rapid increases in protein-tyrosine kinase (PTK) activity in IL-3--dependent cells. Unlike some other hematopoietic growth factor receptors (eg, c-fms and c-kit), however, the known subunits of the IL-3 receptor (IL-3R) lack intrinsic kinase activity. Recently, it was reported that the IL-2R (whose p75 beta-subunit shares sequence homology with a known murine IL-3R subunit and a common beta-subunit of the human IL-3R and granulocyte-macrophage colony-stimulating factor [GM-CSF] receptors) can physically associate with and regulate the activity of the SRC-family PTK, p56-LCK. Because most IL-3--dependent cells contain p53/56-LYN, but not p56-LCK, we explored the effects of IL-3 on the activities of LYN and other SRC-like PTKs in two human leukemic cell lines, AML-193 and TALL-101, which are phenotypically myeloid, and whose in vitro growth is dependent on IL-3. These cells expressed four of the eight known SRC-family proto-oncogenes: lyn, fyn, yes, and hck. When these factor-dependent leukemic cell lines were deprived of lymphokine to achieve cellular quiescence and then restimulated with IL-3, rapid increases (detectable within 1 minute and maximal by 10 minutes) were observed in the activity of the p53/56-LYN kinase, as assessed by in vitro kinase assays. In contrast, no alteration in the activities of other SRC-family PTKs present in these cells was detected after restimulation with IL-3 under the same conditions. This effect of IL-3 reflected an increase in the specific activity of the LYN kinase, because levels of the 53-Kd and 56-Kd LYN proteins were unaltered by IL-3 stimulation, as assessed by immunoblotting. Furthermore, the magnitude of these inducible increases in LYN kinase activity was dependent on the concentration of IL-3, and correlated with IL-3--induced proliferation. The IL-3--induced upregulation of LYN kinase activity may be mediated by the 120-Kd common subunit of the human IL-3 and GM-CSF receptors, because GM-CSF also stimulated marked increases in the activity of the LYN kinase, whereas granulocyte-CSF (G-CSF) did not, despite inducing cellular proliferation. These observations provide the first example of an IL-3--regulable PTK, and strongly suggest that the p53/56-LYN kinase participates in early IL-3--initiated signalling events, at least in some human leukemic cell lines.
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PMID:Interleukin-3 regulates the activity of the LYN protein-tyrosine kinase in myeloid-committed leukemic cell lines. 163 19

We have isolated cDNAs representing a previously unrecognized human gene that apparently encodes a protein-tyrosine kinase. We have designated the gene as HCK (hemopoietic cell kinase) because its expression is prominent in the lymphoid and myeloid lineages of hemopoiesis. Expression in granulocytic and monocytic leukemia cells increases after the cells have been induced to differentiate. The 57-kilodalton protein encoded by HCK resembles the product of the proto-oncogene c-src and is therefore likely to be a peripheral membrane protein. HCK is located on human chromosome 20 at bands q11-12, a region that is affected by interstitial deletions in some acute myeloid leukemias and myeloproliferative disorders. Our findings add to the diversity of protein-tyrosine kinases that may serve specialized functions in hemopoietic cells, and they raise the possibility that damage to HCK may contribute to the pathogenesis of some human leukemias.
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PMID:Identification of a human gene (HCK) that encodes a protein-tyrosine kinase and is expressed in hemopoietic cells. 349 23

The activation of src-related tyrosine kinases following IL-3 stimulation was examined in 32Dcl3 cells. Three src-related tyrosine kinases were activated following IL-3 stimulation: fyn, hck, and lyn. 32Dcl3 cells were transfected with retroviral vectors expressing each of these kinases and independent clones overexpressing each kinase were isolated. In cells overexpressing either fyn or hck, IL-3 stimulated a rapid increase in catalytic activity, which remained elevated longer compared with the kinetics observed in parental 32Dcl3 cells. An increase in the number of tyrosine-phosphorylated proteins in the presence and absence of IL-3 stimulation was observed in cells overexpressing fyn or hck. Transfection of 32Dcl3 cells with a retroviral vector encoding lyn also resulted in an elevated level of kinase activity, although the increase was not as dramatic as that observed with fyn or hck. Consistent with observations in parental 32Dcl3 cells, a high basal level of lyn kinase activity was observed in unstimulated lyn-transfected cells and IL-3 stimulation resulted in an approximate threefold increase in kinase activity. Overexpression of c-src in 32Dcl3 did not result in IL-3-stimulated activation of c-src, indicating specificity for fyn, hck, and lyn. While the overexpression of fyn, hck, or lyn in 32Dcl3 cells resulted in increased kinase activity and IL-3 stimulated tyrosine phosphorylation, it did not render the cells more sensitive to IL-3. These results suggests that in addition to the JAK2 tyrosine kinase, src-related kinases may play a significant role in signal transduction by cytokine receptors.
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PMID:Activation of src-related tyrosine kinases by IL-3. 763 26

To identify tyrosine kinases that may regulate regeneration of the mammalian intestinal epithelium, we amplified portions of the catalytic domains of protein kinases expressed in intestinal crypt cells, using the polymerase chain reaction technique with primers directed against two invariant amino acid sequence motifs found in all kinases. These fragments were cloned and a library of kinase catalytic domains was generated. Sequence analysis of unique clones resulted in the identification of the catalytic domains of several characterized tyrosine kinases, including lyn, hck, c-fgr, tec, JAK2, itk, and the putative receptor kinase ryk, and expression of these kinases has not previously been described in the intestine. We compared the levels of mRNA encoding these kinases in multiple tissues using RNase protection assays, and we localized the expression of hck, lyn, and JAK2 in the intestine using in situ hybridization. In addition, we identified two novel putative catalytic domain sequences. One of these, which we have named sik (src-related intestinal kinase), is expressed at high levels in the gastrointestinal tract and may play a specific role in signal transduction in epithelial tissues.
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PMID:Tyrosine kinase gene expression in the mouse small intestine. 820 50

Tyrosine phosphorylation pathways are essential components of the process of macrophage activation and the resultant production of inflammatory mediators such as tumor necrosis factor (TNF) and nitric oxide (NO). Several lines of evidence suggest that members of the src family of protein tyrosine kinases play important roles in macrophage activation by gram-negative bacterial lipopolysaccharide (LPS) or the cytokine interferon-gamma (IFN-gamma), but targeted disruption of three members of the src family (hck, fgr, and lyn) in mice failed to demonstrate a requirement for these particular kinases in macrophage activation. We report that the pyrazolopyrimidine PP1, a src family-selective tyrosine kinase inhibitor, potently inhibits the production of TNF and inducible nitric oxide synthase (iNOS) in RAW 264.7 murine macrophages stimulated with LPS, rlFN-gamma, or LPS + rIFN-gamma. Furthermore, the tested concentrations of PP1 inhibit LPS- and rlFN-gamma-mediated tyrosine phosphorylation of the hck tyrosine kinase and its putative substrate, vav, but fail to block rlFN-gamma-mediated JAK2 tyrosine phosphorylation. These findings provide additional support for a model of macrophage activation involving one or more src-related kinases. Selective inhibitors of this signaling pathway should be studied in animal models of sepsis.
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PMID:The src family-selective tyrosine kinase inhibitor PP1 blocks LPS and IFN-gamma-mediated TNF and iNOS production in murine macrophages. 1056 9

Protein tyrosine kinase (PTK) activity is abundant in microglia, but the PTKs that participate in their activation have not been identified. For these studies, we used three paradigms to characterize PTK expression during microglial activation: resting and activated microglia were bulk fractionated from the adult brain, cultured newborn microglia were treated with lipopolysaccharide (LPS) to model the transition from activated toward phagocytic microglia, and PTK expression was examined in activated microglia in situ after facial nerve axotomy. Two PCR-based strategies were used to show that 21 different PTK genes are expressed by rat brain microglia: 5 receptor PTKs, 10 nonreceptor PTKs, and 6 members of the src family. Seven of the 21 PTKs were examined in greater detail. Five PTK mRNAs (fgr, hck, fak, jak-2, and flk-1) increased expression across all three models of activation. We conclude that they represent key components in the cascades that participate in microglial activation. In contrast, expression of fes and fms correlated with stimuli that affect microglial proliferation. Four of the PTKs (hck, fgr, fes, and fms) are believed to be myeloid cell specific and were not expressed by cultured astrocytes. HCK and FAK protein were also not expressed in lysates of immature astrocytes and oligodendrocytes. Because of their putative specificity, these kinases represent potential targets for inhibitors of microglial activation. Because reactive microglia can exacerbate the severity of neurological diseases, the identification of specific kinases that participate in microglial activation represents an important advance toward the development of new therapeutics.
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PMID:Differential expression of protein tyrosine kinase genes during microglial activation. 1223 40

In cell suspensions subjected to high-shear rotatory motion, human PMN (polymorphonuclear cells) adhered to E-selectin-expressing CHO (Chinese-hamster ovary) cells (CHO-E), and formed homotypic aggregates when challenged by E-selectin-IgG fusion protein, by a mechanism that involved beta2 integrins. Both heterotypic and homotypic PMN adhesion was accompanied by tyrosine phosphorylation of a 110 kDa protein (P110). This event was prevented by blocking anti-(beta2 integrin) antibodies and by inhibitors of Src-family kinases, suggesting that it was part of an 'outside-in' signalling that was initiated by integrin engagement. Interestingly, Src-family kinase inhibitors prevented beta2-integrin-mediated (i) homotypic PMN adhesion triggered by E-selectin-IgG, (ii) heterotypic CHO-E/PMN adhesion in mixed-cell suspensions, and (iii) firm adhesion of PMN to CHO-E monolayers under physiological flow. Similarly to PMN treated with Src-family kinase inhibitors, PMN from hck-/-fgr-/- and hck-/-fgr-/-lyn-/- mice showed significant impairment of beta2-integrin-mediated adhesion to CHO-E. Moreover, the expression of beta2 integrin activation epitopes at the sites of cell-cell contact in CHO-E/PMN conjugates was abolished by Src-family kinase inhibitors. One component of P110 was identified as the FAK (focal adhesion kinase) Pyk2 (proline-rich tyrosine kinase 2), which was phosphorylated in a beta2 integrin- and Src-family-kinase-dependent manner. Thus, Src-family kinases, and perhaps Pyk2, mediate a signal necessary for beta2 integrin function in PMN tethered by E-selectin.
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PMID:Src-family kinases mediate an outside-in signal necessary for beta2 integrins to achieve full activation and sustain firm adhesion of polymorphonuclear leucocytes tethered on E-selectin. 1643 32

The chemotactic peptide formyl-methionyl-leucyl-phenilalanine (fMLP) triggers intracellular protein tyrosine phosphorylation leading to neutrophil activation. Deficiency of the Src family kinases Hck and Fgr have previously been found to regulate fMLP-induced degranulation. In this study, we further investigate fMLP signaling in hck-/-fgr-/- neutrophils and find that they fail to activate a respiratory burst and display reduced F-actin polymerization in response to fMLP. Additionally, albeit migration of both hck-/-fgr-/-mouse neutrophils and human neutrophils incubated with the Src family kinase inhibitor 4-amino-5-(4-chlorophenyl)-7-(t-butyl)pyrazolo[3,4-d]pyrimidine (PP2) through 3-microm pore size Transwells was normal, deficiency, or inhibition, of Src kinases resulted in a failure of neutrophils to migrate through 1-microm pore size Transwells. Among MAPKs, phosphorylation of ERK1/2 was not different, phosphorylation of p38 was only partially affected, and phosphorylation of JNK was markedly decreased in fMLP-stimulated hck-/-fgr-/- neutrophils and in human neutrophils incubated with PP2. An increase in intracellular Ca(2+) concentration and phosphorylation of Akt/PKB occurred normally in fMLP-stimulated hck-/-fgr-/- neutrophils, indicating that activation of both phosphoinositide-specific phospholipase C and PI3K is independent of Hck and Fgr. In contrast, phosphorylation of the Rho/Rac guanine nucleotide exchange factor Vav1 and the Rac target p21-activated kinases were markedly reduced in both hck-/-fgr-/- neutrophils and human neutrophils incubated with a PP2. Consistent with these findings, PP2 inhibited Rac2 activation in human neutrophils. We suggest that Hck and Fgr act within a signaling pathway triggered by fMLP receptors that involves Vav1 and p21-activated kinases, leading to respiratory burst and F-actin polymerization.
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PMID:The Src family kinases Hck and Fgr regulate neutrophil responses to N-formyl-methionyl-leucyl-phenylalanine. 1733 87

Prolactin-induced Protein (PIP), an aspartyl protease unessential for normal mammalian cell function, is required for the proliferation and invasion of some breast cancer (BCa) cell types. Because PIP expression is particularly high in the Luminal A BCa subtype, we investigated the roles of PIP in the related T47D BCa cell line. Nucleic acid and antibody arrays were employed to screen effects of PIP silencing on global gene expression and activation of receptor tyrosine kinases (RTKs), respectively. Expression of PIP-stimulated genes, as defined in the T47D cell culture model, was well correlated with the expression of PIP itself across a cohort of 557 mRNA profiles of diverse BCa tumors, and bioinformatics analysis revealed cJUN and cMYC as major nodes in the PIP-dependent gene network. Among 71 RTKs tested, PIP silencing resulted in decreased phosphorylation of focal adhesion kinase (FAK), ephrin B3 (EphB3), FYN, and hemopoietic cell kinase (HCK). Ablation of PIP also abrogated serum-induced activation of the downstream serine/threonine kinases AKT, ERK1/2, and JNK1. Consistent with these results, PIP-depleted cells exhibited defects in adhesion to fibronectin, cytoskeletal stress fiber assembly and protein secretion. In addition, PIP silencing abrogated the mitogenic response of T47D BCa cells to estradiol (E2). The dependence of BCa cell proliferation was unrelated, however, to estrogen signaling because: 1) PIP silencing did not affect the transcriptional response of estrogen target genes to hormone treatment, and 2) PIP was required for the proliferation of tamoxifen-resistant BCa cells. Pharmacological inhibition of PIP may therefore serve the bases for both augmentation of existing therapies for hormone-dependent tumors and the development of novel therapeutic approaches for hormone-resistant BCa.
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PMID:Prolactin-induced protein (PIP) regulates proliferation of luminal A type breast cancer cells in an estrogen-independent manner. 2375 96


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