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 high-affinity receptors for human granulocyte-macrophage colony-stimulating factor (GM-CSF), interleukin-3 (IL-3), and IL-5 are heterodimeric complexes consisting of cytokine-specific alpha subunits and a common signal-transducing beta subunit (hbetac). We have previously demonstrated the oncogenic potential of this group of receptors by identifying constitutively activating point mutations in the extracellular and transmembrane domains of hbetac. We report here a comprehensive screen of the entire hbetac molecule that has led to the identification of additional constitutive point mutations by virtue of their ability to confer factor independence on murine FDC-P1 cells. These mutations were clustered exclusively in a central region of hbetac that encompasses the extracellular membrane-proximal domain, transmembrane domain, and membrane-proximal region of the cytoplasmic domain. Interestingly, most hbetac mutants exhibited cell type-specific constitutive activity, with only two transmembrane domain mutants able to confer factor independence on both murine FDC-P1 and BAF-B03 cells. Examination of the biochemical properties of these mutants in FDC-P1 cells indicated that MAP kinase (ERK1/2), STAT, and JAK2 signaling molecules were constitutively activated. In contrast, only some of the mutant beta subunits were constitutively tyrosine phosphorylated. Taken together, these results highlight key regions involved in hbetac activation, dissociate hbetac tyrosine phosphorylation from MAP kinase and STAT activation, and suggest the involvement of distinct mechanisms by which proliferative signals can be generated by hbetac.
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PMID:Saturation mutagenesis of the beta subunit of the human granulocyte-macrophage colony-stimulating factor receptor shows clustering of constitutive mutations, activation of ERK MAP kinase and STAT pathways, and differential beta subunit tyrosine phosphorylation. 973 Oct 57

Recent reports have demonstrated fusion of the TEL gene on 12p13 to the JAK2 gene on 9p24 in human leukemias. Three variants have been identified that fuse the TEL pointed (PNT) domain to (i) the JAK2 JH1-kinase domain, (ii) part of and (iii) all of the JH2 pseudokinase domain. We report that all of the human TEL/JAK2 variants, and a human/mouse chimeric hTEL/mJAK2(JH1) fusion gene, transform the interleukin-3 (IL-3)-dependent murine hematopoietic cell line Ba/F3 to IL-3-independent growth. Transformation requires both the TEL PNT domain and JAK2 kinase activity. Furthermore, all TEL/JAK2 variants strongly activated STAT 5 by phosphotyrosine Western blots and by electrophoretic mobility shift assays (EMSA). Mice (n = 40) transplanted with bone marrow infected with the MSCV retrovirus containing either the hTEL/mJAK2(JH1) fusion or its human counterpart developed a fatal mixed myeloproliferative and T-cell lymphoproliferative disorder with a latency of 2-10 weeks. In contrast, mice transplanted with a TEL/JAK2 mutant lacking the TEL PNT domain (n = 10) or a kinase-inactive TEL/JAK2(JH1) mutant (n = 10) did not develop the disease. We conclude that all human TEL/JAK2 fusion variants are oncoproteins in vitro that strongly activate STAT 5, and cause lethal myelo- and lymphoproliferative syndromes in murine bone marrow transplant models of leukemia.
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PMID:Transformation of hematopoietic cell lines to growth-factor independence and induction of a fatal myelo- and lymphoproliferative disease in mice by retrovirally transduced TEL/JAK2 fusion genes. 973 11

Multiple counterregulatory mechanisms have been identified in B-cell precursors that operate to regulate cell survival and growth, thereby ensuring the orderly development and differentiation of B-cells. Inappropriate apoptosis may underlie the pathogenesis of immunodeficiencies, as well as pathogenesis and drug/radiation resistance of human leukemias and lymphomas, which makes control of apoptosis an important potential target for therapeutic interventions. Therefore, identification of the molecular regulators of apoptosis is an area of intense investigation. Bruton's tyrosine kinase (BTK) is the first tyrosine kinase to be identified as a dual-function regulator of apoptosis, which promotes radiation-induced apoptosis but inhibits Fas-activated apoptosis in B-cells. BTK functions in a pro-apoptotic manner when B-cells are exposed to reactive oxygen intermediates, at least in part, by down-regulating the anti-apoptotic activity of STAT-3 transcription factor. In contrast, BTK associates with the death receptor Fas and impairs its interaction with Fas-associated protein with death domain (FADD), which is essential for the recruitment and activation of FLICE by Fas during the apoptotic signal, thereby preventing the assembly of a pro-apoptotic death inducing signaling complex (DISC) after Fas-ligation. The identification of BTK as a dual-function regulator of apoptosis will significantly increase our understanding of both the biological processes involved in programmed cell death and the diseases associated with dysregulation of apoptosis. New agents with BTK-modulatory activity may have clinical potential in the treatment of B-cell malignancies (in particular acute lymphoblastic leukemia, the most common form of childhood cancer), as well as B-cell immunodeficiencies.
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PMID:Bruton's tyrosine kinase (BTK) as a dual-function regulator of apoptosis. 975 Oct 72

The accumulation and organization of extracellular matrix (ECM) components play critical roles in development, maintenance, and pathogenesis of most organ systems. These processes are regulated by the precisely orchestrated expression of ECM components, their receptors, and matrix proteases. The collagen gel culture system has been extensively used as a model to examine ECM remodeling similar to that which occurs during development and wound healing. Growth factors, including transforming growth factor-beta, platelet-derived growth factor, insulin-like growth factor, and angiotensin II, have been shown to stimulate collagen gel contraction. The present studies were undertaken to begin to examine the mechanisms through which angiotensin II stimulates collagen remodeling and gel contraction. These studies indicate that angiotensin II stimulates collagen gel contraction by isolated heart fibroblasts in a dose-dependent manner and that this response is inhibited by the AT1 receptor antagonist Losartan. Furthermore, stimulation of collagen gel contraction by angiotensin II is also blocked by the src-related tyrosine kinase inhibitors genistein and herbimycin, indicating that activation of tyrosine kinases plays critical roles in this process. Stimulation of gel contraction by angiotensin II also involves the activation of JAK2, a member of the JAK/STAT pathways of transcriptional activation. Immunoprecipitation of surface-labeled fibroblasts indicate that cell surface levels of collagen-binding integrins also increase in response to angiotensin II treatment. Determining the underlying mechanisms regulating ECM remodeling is essential to understanding the role of ECM organization in development and disease.
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PMID:Angiotensin II-stimulated collagen gel contraction by heart fibroblasts: role of the AT1 receptor and tyrosine kinase activity. 976 19

Platelet-derived growth factor (PDGF) and ciliary neurotrophic factor (CNTF) have pleiotropic actions on many cell types. In the presence of these factors, oligodendroglia respond by enhanced survival when deprived of trophic factors or in the presence of the cytotoxic cytokine, tumor necrosis factor-alpha (TNF-alpha). To determine whether these two oligodendroglial survival factors converge in their signaling cascades, we examined their JAK/STAT pathways in enriched oligodendrocyte (OL) progenitors and in the progenitor OL cell line, central glia-4 (CG-4). Cytokine pathways such as JAK/STAT have been characterized extensively in hematopoietic cells; however, it is increasingly evident that the same cytokines that play a role in hematopoiesis also play a role during development and injury of the central nervous system. This is the first study that clearly defines the presence and activation of JAK/STAT proteins in OL progenitors and compares the signal transduction pathway of two well-known oligodendroglial survival factors. In this study, we report that PDGF- and CNTF-induced OL progenitors responded with a rapid tyrosine phosphorylation of JAK1, JAK2, STAT1alpha/beta, and STAT3. We feel that these identified JAK/STAT signaling molecules play a large role in the cellular response to these factors. Because both PDGF and CNTF enhance OL progenitor survival, these JAK/STATs may play a role in regulating this important cellular process.
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PMID:Oligodendroglial survival factors, PDGF-AA and CNTF, activate similar JAK/STAT signaling pathways. 978 78

GH binding to its receptor, which belongs to the cytokine receptor superfamily, activates Janus kinase (JAK) 2 tyrosine kinase, thereby activating a number of intracellular key proteins such as STAT (signal transducers and activators of transcription) proteins and mitogen-activated protein (MAP) kinases, which finally lead to GH's biological actions including gene expression. In contrast to receptor tyrosine kinases, the signalling pathways leading to MAP kinase activation by GH are poorly understood but appear to involve Grb2 and Shc. We now show that GH stimulated tyrosine phosphorylation of epidermal growth factor receptor (EGFR) and its association with Grb2, and concomitantly stimulated MAP kinase activity in liver, a major target tissue. Expression of EGFR and its mutants into CHO-GH receptor (GHR) cells revealed that GH-induced full activation of MAP kinase and c-fos expression required tyrosine phosphorylation sites of EGFR but not its intrinsic tyrosine kinase activity. Moreover, by also using dominant negative JAK2 and in vitro kinase assay, we demonstrated that tyrosine 1068 of EGFR was evidently one of the major phosphorylation and Grb2 binding sites stimulated by GH via JAK2. These data suggest that the role of EGFR in GH signalling is to be phosphorylated by JAK2, thereby providing docking sites for Grb2 and activating MAP kinases and gene expression. This novel cross talk pathway may provide the first example of the hormone and cytokine receptor superfamily transducing signals via associated nonreceptor tyrosine kinase by phosphorylating growth factor receptor and utilizing it as a docking protein independent of its receptor tyrosine kinase activity.
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PMID:Growth hormone-induced tyrosine phosphorylation of EGF receptor as an essential element leading to MAP kinase activation and gene expression. 979 Feb 26

GH and its related peptide PRL are known to stimulate proliferation and insulin biosynthesis in pancreatic beta-cells, and assumed to be involved in their functional maturation. We investigated signal transduction of GH and PRL in insulin-secreting cells using the differentiated rat insulinoma cell line, INS-1. In these cells, both hormones stimulated proliferation and DNA synthesis, increased viability, cellular metabolism and insulin content. GH induced cytosolic Ca2+ ([Ca2+]i) rises, which appear to be due to Ca2+-influx through voltage-gated Ca2+-channels. GH also promoted tyrosine phosphorylation of several proteins in INS-1 cells, one of which was identified as JAK2 tyrosine kinase. Moreover, GH caused changes in DNA binding of nuclear proteins to some interferon-gamma-activated sites. Verapamil inhibited neither DNA synthesis nor JAK2 phosphorylation stimulated by GH, whereas a tyrosine kinase inhibitor, lavendustin A, blocked the mitogenic effect. Involvement of cAMP is also suggested because Rp-cAMPS, a competitive inhibitor of protein kinase A, abolished both [Ca2+]i rises and DNA synthesis stimulated by GH. The effects of GH and PRL on [Ca2+]i, JAK2 phosphorylation and DNA binding of the STATs were virtually identical in INS-1 cells. Since both hormones failed to activate MAP kinase in these cells, it is strongly suggested that activation of the JAK-STAT pathway is the major signalling event for the mitogenic effects of GH and PRL in beta-cells. It remains to be clarified whether the [Ca2+]i rise mediates other effects of these hormones.
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PMID:GH signalling in pancreatic beta-cells. 979 Feb 27

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

Cytokine pathways are essential for the differentiation and function of lymphoid cells. The major T-cell growth factor is IL-2, which is produced by subsets of T lymphocytes in response to antigenic stimulation. The IL-2 receptor is expressed by T cells after antigenic stimulation, and when engaged by IL-2 induces proliferation, differentiation, and protection from apoptosis. Rare patients with severe combined immune deficiency (SCID) have been found to have mature T lymphocytes that do not produce IL-2, although no genetic abnormality has yet been defined for these patients. The fact that these patients and IL-2 knockout mice have the ability to generate mature T lymphocytes indicates that IL-2 is the major growth factor for mature T lymphocytes but not for immature thymocytes. X-linked SCID, the most common form of SCID, has a phenotype of thymic hypoplasia, peripheral T lymphopenia, the presence of B lymphocytes that do not undergo normal class switching, and usually the absence of natural killer (NK) cells. X-SCID is caused by mutations of a receptor subunit, which was originally described as the IL-2Rgamma. The phenotypic differences between X-SCID and IL-2-deficient SCID suggests that the IL-2Rgamma chain might be a component of other receptors needed for thymic development, B cell class-switching, and NK development. The IL-2Rgamma is now known to be a shared subunit between the IL-2, IL-4, IL-7, IL-9, and IL-15 receptors, which explains the complex X-SCID phenotype. Because of this shared usage, the IL-2Rgamma is known as the common gamma chain (gamma c). Each ligand induces dimerization of gamma c with the ligand-specific receptor subunit, eg, the IL-2Rbeta, resulting in signal transduction through the JAK-STAT (signal transducers and activators of transcription) pathway. The JAK3 tyrosine kinase is constitutively associated with the gamma c and is necessary for signaling through the gamma c-containing receptors. Deficiency of JAK3 gives rise to a SCID phenotype that closely resembles that of X-SCID, but is autosomally recessive in inheritance. It is likely that other specific immune deficiencies of the cytokine pathways exist, eg, IL-7Ralpha-deficient SCID. T cells with wild-type gamma c and JAK3 proteins have a profound selective advantage over cells that contain mutant proteins. The selective advantage allows these patients to be treated by bone marrow transplantation (BMT) without ablative chemotherapy, and is the reason that these forms of SCID are potential targets for early gene therapy efforts.
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PMID:X-linked SCID and other defects of cytokine pathways. 980 Dec 59

Interleukin (IL)-4 signaling proceeds via cytoplasmic activation of the Janus kinases JAK1 and JAK3 and the signal transducer and activator of transcription STAT6. We show that the IL-4 receptor, like other cytokine receptor systems utilizing the common receptor gamma-chain (gammac), is also connected to a signaling pathway that involves STAT5. Both STAT5a and STAT5b become tyrosine-phosphorylated and acquire specific DNA-binding properties in response to IL-4 receptor stimulation in the murine pro-B cell line Ba/F3. In preactivated human T cells, STAT5 became activated in an IL-4-dependent fashion as assayed by IL-4-induced STAT5 translocation from the cytoplasm to the cell nucleus and by binding to cognate DNA. Moreover, stimulation of preactivated human T cells by IL-4 led to specific transcriptional up-regulation of STAT5 target genes. IL-4 receptor-mediated STAT5 activation is dependent on the presence of gammac and JAK3 within the receptor complex. In COS-7 cells, the JAK/STAT pathway leading from the IL-4 receptor to STAT5-dependent regulation of a reporter gene relied largely on coexpression of JAK3. In Ba/F3 cells, studies on signal transduction evoked by directed specific receptor homo- or heterodimerization revealed that STAT5 activation can be triggered exclusively by IL-4R heterodimers containing gammac.
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PMID:The interleukin-4 receptor activates STAT5 by a mechanism that relies upon common gamma-chain. 981 29


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