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 BCR/ABL oncogene in chronic myelogenous leukemia produces an activated tyrosine kinase fusion protein (p210). Like other tyrosine kinase oncogenes, BCR/ABL can abrogate the interleukin-3 (IL-3) dependence of lymphoid cell lines. To investigate the ability of BCR/ABL to generate growth factor independence in myeloid cells, the IL-3 dependent myeloid cell line NFS/N1.H7 (H7) was transfected with the p210BCR/ABL-containing plasmid, pGD210. Stable clones A54 and A74 were capable of IL-3 independent growth and tumor formation in syngeneic mice. Relief of growth factor dependence was not mediated by autocrine release of IL-3. The baseline proliferation rate of the BCR/ABL transformed cells was greater than that of the parental H7 cells maximally stimulated by IL-3. Abundant constitutive expression of c-myc, c-jun, and c-fos was observed in the p210BCR/ABL transfectants even in low serum conditions. In contrast, c-myc expression in H7 cells was dependent upon IL-3 stimulation, and neither c-jun nor c-fos was highly expressed following IL-3 stimulation in H7 cells. Thus, BCR/ABL transformation and relief of IL-3 dependence involve not only pathways that can substitute for IL-3 induced growth via tyrosine kinase mediated signals, but also pathways that recruit constitutive c-jun and c-fos expression.
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PMID:BCR/ABL confers growth factor independence upon a murine myeloid cell line. 137 13

The expression of 10 protooncogenes has been quantitatively studied in liver of male rats L10 age of 1, 10.5, 22 and 37 months. It was shown that a number of specific mRNA transcripts and, therefore, the levels of expression of protooncogenes C-MYC, C-FOS, N-MYC, HA-RAS, KI-RAS, SIS, ABL, YES, MOS and MET in rat liver were constant during life span. These data are in accordance with resistance of the rat strain L10 to spontaneous hepatocarcinogenesis.
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PMID:[Proto-oncogene expression in the liver of male rats of different age]. 171 16

The expression and function of several proto-oncogenes were examined in a human acute T cell leukemia line, JURKAT, during phorbol ester-induced terminal differentiation. Treating JURKAT cells with the phorbol ester tetradecanoyl phorbol acetate (TPA) inhibited their proliferation and induced expression of the gene for the interleukin 2 receptor alpha chain (IL2R-alpha), consistent with previous reports. In unstimulated proliferating JURKAT cells, high levels of C-MYC, N-RAS, and BCL2 mRNAs were found that diminished rapidly following TPA-induced cessation of growth. In contrast, accumulation of mRNAs for the C-FOS, C-JUN, and EGR-1 genes increased markedly in TPA-treated cells and preceded the induction of IL2R-alpha mRNA. Expression of C-MYB, C-RAF-1, C-LCK, C-FYN, and C-FGR proto-oncogenes was relatively unchanged. To explore directly the function of two of these protooncogenes in regulating the growth of JURKAT T cells, we stably transferred C-MYC and BCL2 expression plasmids into these cells. Despite sustained expression of C-MYC, BCL2, or the combination of these protooncogenes, TPA continued to inhibit JURKAT cell growth and to induce IL2R expression. Thus, although C-MYC and BCL2 proto-oncogene expression correlated with proliferation in TPA-treated JURKAT cells, continuous over-expression of even the combination of these oncogenes was insufficient for abrogating the effects of TPA in these leukemic T cells. Because human lymphoid malignancies frequently contain chromosomal translocations that deregulate the expression of C-MYC and BCL2, our findings could have relevance for attempts to induce terminal differentiation of leukemic cells by in vitro exposure of patients' bone marrow cells to phorbol esters.
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PMID:Phorbol ester-mediated inhibition of growth and regulation of proto-oncogene expression in the human T cell leukemia line JURKAT. 201 1

Interleukin-5 (IL-5) regulates the production and function of B cells, eosinophils and basophils. In particular, IL-5 plays a critical role in the development of CD5-positive B (B-1) cells. The pleiotropic activity of IL-5 on target cells is directly dependent on the initial binding to IL-5 specific cell-surface receptor (IL-5R). The IL-5 signals are mediated through the high affinity IL-5R which is composed of two different polypeptide chains, alpha and beta. The alpha chain is a membrane-penetrated glycoprotein that specifically binds IL-5 and retains features common to the cytokine receptor superfamily. The beta chain by itself does not bind IL-5, but it can convert the low affinity IL-5R into the high affinity IL-5R and in indispensable for IL-5 signal transduction. The beta chain is shared among receptors for IL-5, IL-3 and GM-CSF and is called beta c. The cytoplasmic comains of both IL-5R alpha and beta c are essential for signal transduction. The membrane proximal proline-rich sequence of the cytoplasmic domain of IL-5R alpha was found to be essential for the IL-5-induced proliferative response, expression of nuclear proto-oncogenes such as c-jun, c-fos and c-myc, and activation of Bruton's tyrosine and JAK2 kinases. Furthermore, JAK2 activation correlates with proline residues in Pro-Pro-X-Pro motif in the cytoplasmic domain of IL-5R alpha. These results indicate that activation of JAK2 and its substrate is critical to coupling IL-5-induced tyrosine phosphorylation and ultimately mitogenesis. I will discuss about molecular mechanisms of IL-5 signaling and B cell defect in X-linked immunodeficient mice in relation to IL-5 signaling.
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PMID:[Structure and function of IL-5 receptor]. 747 55

Growth hormone (GH) plays a central role in regulating growth and intermediary metabolism in vertebrates, although the mechanisms by which GH initiates these actions are largely unknown. The GH receptor, a member of the cytokine receptor superfamily, does not demonstrate homology with any known tyrosine kinases. However, addition of GH to cells in vitro has been shown to stimulate tyrosine phosphorylation of various intracellular proteins including mitogen-activated protein kinases (MAP kinases) and the newly described Janus kinase, JAK2. Subsequent steps in GH-mediated signal transduction have not been delineated. In the present study, we have examined early events in GH action in vivo. Hypophysectomized juvenile male rats were treated with GH for 15, 30, or 60 min. Rat liver whole cell and nuclear extracts were prepared and analyzed via SDS-polyacrylamide gel electrophoresis and Western blotting techniques. GH rapidly stimulated the tyrosine phosphorylation of at least 8 nuclear proteins of 205, 91, 83, 80, 65, 53, 44, and 42 kDa, and caused the dephosphorylation of a single approximately 149-kDa protein. Using specific antibodies, we have identified three of these nuclear phosphoproteins as 42- and 44-kDa MAP kinases, and as STAT91, a 91-kDa component of the interferon-stimulated gene factor-3 protein complex. One consequence of the activation of STAT91 in the nucleus is the appearance of GH-stimulated DNA binding activity, as assessed by gel-mobility shift assay using an oligonucleotide containing a c-sis-inducible element from the c-fos promoter. These results show that nuclear protein tyrosine phosphorylation is a prominent early event in GH action in vivo and demonstrate a link between GH-stimulated signal transduction and target gene expression.
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PMID:Rapid changes in nuclear protein tyrosine phosphorylation after growth hormone treatment in vivo. Identification of phosphorylated mitogen-activated protein kinase and STAT91. 751 Jun 76

SHPTP2 is a ubiquitously expressed tyrosine-specific protein phosphatase that contains two amino-terminal Src homology 2 (SH2) domains responsible for its association with tyrosine-phosphorylated proteins. In this study, expression of dominant interfering mutants of SHPTP2 was found to inhibit insulin stimulation of c-fos reporter gene expression and activation of the 42-kDa (Erk2) and 44-kDa (Erk1) mitogen-activated protein kinases. Cotransfection of dominant interfering SHPTP2 mutants with v-Ras or Grb2 indicated that SHPTP2 regulated insulin signaling either upstream of or in parallel to Ras function. Furthermore, phosphotyrosine blotting and immunoprecipitation identified the 125-kDa focal adhesion kinase (pp125FAK) as a substrate for insulin-dependent tyrosine dephosphorylation. These data demonstrate that SHPTP2 functions as a positive regulator of insulin action and that insulin signaling results in the dephosphorylation of tyrosine-phosphorylated pp125FAK.
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PMID:Protein-tyrosine-phosphatase SHPTP2 is a required positive effector for insulin downstream signaling. 753 37

Growth hormone (GH) treatment of cells promotes activation of JAK2, a GH receptor (GHR)-associated tyrosine kinase. We now explore JAK2 regions required for GHR-induced signaling. Wild-type (WT) JAK2 and JAK2 molecules with deletions of the amino terminus (JAK2ATD), carboxyl terminus (JAK2CTD), or kinase-like domain (JAK2PKD) were each transiently coexpressed in COS-7 cells with the rabbit GHR. The following responses were assayed: GH-induced transactivation of a luciferase reporter governed by a c-fos enhancer element; GH-induced shift in the molecular mass of a cotransfected epitope-tagged extracellular signal-regulated kinase molecule; and GH-induced antiphosphotyrosine immunoprecipitability of the transfected JAK2 form. In each assay, WTJAK2 and JAK2PKD allowed GH-induced signaling, whereas JAK2ATD and JAK2CTD did not. Anti-GHR serum coimmunoprecipitated WTJAK2, JAK2PKD, and JAK2CTD, but not JAK2ATD. Finally, a chimera in which the JAK2 kinase domain replaced the GHR cytoplasmic domain signaled GH-induced transactivation. We conclude: 1) kinase-like domain deletion eliminates neither physical nor functional interaction between JAK2 and the GHR; 2) kinase domain deletion eliminates functional but not physical coupling of JAK2 to the GHR; 3) interaction with the GHR appears dependent on the NH2-terminal one-fifth of JAK2; and 4) a GH-responsive signaling unit can include as little as the GHR external and transmembrane domains and the JAK2 kinase domain.
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PMID:Regions of the JAK2 tyrosine kinase required for coupling to the growth hormone receptor. 754 Jan 78

Ferritin, the major intracellular iron storage protein of eucaryotic cells, is regulated during inflammation and malignancy. We previously reported that transcription of the H subunit of ferritin (ferritin H) is negatively regulated by the adenovirus E1A oncogene in mouse NIH 3T3 fibroblasts (Y. Tsuji, E. Kwak, T. Saika, S. V. Torti, and F. M. Torti, J. Biol. Chem. 268:7270-7275, 1993). To elucidate the mechanism of transcriptional repression of the ferritin H gene by E1A, a series of deletions in the 5' flanking region of the mouse ferritin H gene were constructed, fused to the chloramphenicol acetyltransferase (CAT) gene, and transiently cotransfected into NIH 3T3 cells with an E1A expression plasmid. The results indicate that the E1A-responsive region is located approximately 4.1 kb 5' to the transcription initiation site of the ferritin H gene. Further analyses revealed that a 37-bp region, termed FER-1, is the target of E1A-mediated repression. This region also serves as an enhancer, augmenting ferritin H transcription independently of position and orientation. FER-1 was dissected into two component elements, i.e., a 22-bp dyad symmetry element and a 7-bp AP1-like sequence. Insertion of these DNA sequences into a ferritin H-CAT chimeric gene lacking an E1A-responsive region indicated that (i) the 22-bp dyad symmetry sequence by itself has no enhancer activity, (ii) the AP1-like sequence has moderate enhancer activity which is repressed by E1A, and (iii) the combination of the dyad symmetry element and the AP1-like sequence is required for maximal enhancer activity and repression by E1A. Gel retardation assays and cotransfection experiments with c-fos and c-jun expression vectors suggested that members of the Fos and Jun families bind to the AP1-like element of FER-1 and contribute to its regulation. In addition, gel retardation assays showed that E1A reduces the ability of nuclear proteins to bind to the AP1-like sequence without affecting the levels of nuclear factors that recognize the 22-bp dyad symmetry element. Taken together, these results demonstrate that FER-1 serves as both an enhancer of ferritin H transcription and a target for E1A-mediated repression.
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PMID:FER-1, an enhancer of the ferritin H gene and a target of E1A-mediated transcriptional repression. 765 32

Treatment of quiescent Swiss 3T3 cells with 20 microM ([(3,4,5-trihydroxyphenyl)methylene]propanedinitrile) (tyrphostin) caused a 76% reduction in the tyrosine phosphorylation of the M(r) 110,000-130,000 band induced by bombesin. This was accompanied by a 48% reduction in the tyrosine phosphorylation of the cytosolic tyrosine kinase p125 focal adhesion kinase. Preincubation with 20 microM tyrphostin did not inhibit either protein kinase A activation by forskolin or protein kinase C (PKC) activation by phorbol 12,13-dibutyrate in intact Swiss 3T3 cells. Similarly, 20 microM tyrphostin neither interfered with binding of bombesin to its receptor nor prevented bombesin-stimulated Ca2+ mobilization or PKC activation. Thus tyrphostin selectively inhibits tyrosine phosphorylation induced by bombesin in intact Swiss 3T3 cells. Consequently, we examined the contribution of this tyrosine phosphorylation pathway to the subsequent induction of c-fos and stimulation of mitogenesis by bombesin. Tyrphostin prevented both c-fos mRNA expression and DNA synthesis induced by bombesin. The incorporation of [3H] thymidine was inhibited by tyrphostin in a dose-dependent manner (IC50 = 20 microM), and this effect was not reversed even at high concentrations of bombesin. These results provide evidence that tyrosine phosphorylation is a mitogenic signal for bombesin.
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PMID:Tyrphostin inhibits bombesin stimulation of tyrosine phosphorylation, c-fos expression, and DNA synthesis in Swiss 3T3 cells. 768 55

Using the 3T3-F442A preadipocyte line as a model of GH-dependent differentiation, early changes in the DNA-binding affinity of transcription factors in response to GH addition were investigated. Addition of 50 ng/ml human GH to cells in chemically defined medium led to a rapid increase in binding activity of activator protein 1 (AP-1) and CCAAT enhancer-binding protein (C/EBP), which was significant at 30 min and reached maximal induction by 2 h (3-fold for AP-1, 2.5-fold for C/EBP). Induction in AP-1 DNA binding correlates with a concomitant GH trans-activation of c-jun and c-fos genes described previously. Using specific antibodies in electrophoretic mobility shift assays and Western blots, it was shown that the increase in activity of C/EBP is the result of an increase in synthesis of two alternatively translated forms of C/EBP beta: 40-C/EBP beta and 23-C/EBP beta. This increase in protein was not accompanied by alteration in mRNA level and could be blocked by a Janus kinase 2 tyrosine kinase inhibitor and a C kinase inhibitor at concentrations shown to inhibit GH-dependent activation of microtubule-associated protein (MAP) kinases. Concomitant with the translationally activated increase in C/EBP beta, a GH-dependent increase was observed in C/EBP delta transcription. This was accompanied by an increase in mRNA for C/EBP delta, which was superinduced by cycloheximide and, unlike the increase in C/EBP beta protein, was not observed with insulin. Thus GH exerts its effects on C/EBP isoforms at two levels: transcriptional activation of C/EBP delta and translational activation of C/EBP beta. It is proposed that GH-dependent phosphorylation results in the efficient translation of 40-C/EBP beta and 23-C/EBP beta (the mouse homolog of the inhibitor liver-enriched inhibitory protein), and that together with the induction of C/EBP delta, these may be involved in initiating the adipocyte differentiation program.
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PMID:Early responses of trans-activating factors to growth hormone in preadipocytes: differential regulation of CCAAT enhancer-binding protein-beta (C/EBP beta) and C/EBP delta. 776 Aug 44


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