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:2.7.11.1 (protein kinase)
81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Interleukin-2 (IL-2) activates the receptor-associated Janus family tyrosine kinases, Jak1 and Jak3, which in turn phosphorylate and activate specific STAT proteins (signal transducers and activators of transcription), such as STAT5. Activation of Jak and STAT proteins by IL-2 is transient and the mechanism for the subsequent down-regulation of their activity is largely unknown. We report here that IL-2-induced DNA-binding activity and tyrosine phosphorylation of STAT5 are stabilized by a proteasome inhibitor MG132; however, no detectable ubiquitination of the STAT proteins is observed. This sustained STAT5 activation can be blocked by protein kinase inhibitors, which is consistent with the ability of the proteasome inhibitor to stabilize IL-2-induced tyrosine phosphorylation of Jak1 and Jak3. These results suggest that proteasome-mediated protein degradation modulates protein-tyrosine phosphatase activity that negatively regulates the Jak-STAT signaling pathways.
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PMID:Involvement of proteasomes in regulating Jak-STAT pathways upon interleukin-2 stimulation. 916 19

Thrombopoietin (Tpo) is a cytokine which stimulates megakaryocyte maturation. We found that Tpo is constitutively and ubiquitously expressed in all tissues examined, including bone marrow stromal cells, even in thrombocytopenia, thrombosis and steady-state condition in mice. Thus, platelet level in circulation is not regulated by Tpo gene expression. Furthermore, when the purified megakaryocytes were cocultured with the stromal cells, most of the megakaryocytes adhered to the stromal cells and remained unchanged, while free megakaryocytes induced proplatelet formation. Thus the stromal cells in bone marrow secrete Tpo and stimulate megakaryocytopoiesis, but the interaction of megakaryocytes with the stromal cells may suppress platelet formation. Study on signal transduction through Mp1 revealed that Tpo induces activation of JAK2 and Tyk2, which in turn activate STAT1, STAT3 and STAT5. Further, Tpo stimulates transcription factors GATA-1 and NF-E2, which induce differentiation markers, GPIIb/IIIa and Pm-1. In addition, Shc, Vav, Ras, Raf-1, MAPKK, MAPK and Pim-1 are also activated. Thus, Tpo activates a lineage-specific cascade as well as a specific JAK-STAT cascade and a common signaling cascade.
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PMID:Regulation of megakaryocytopoiesis by thrombopoietin and stromal cells. 920 16

We have previously established that stromal/osteoblastic cells collectively express receptors for all members of the cytokine subfamily that share the gp130 signal transducer and that different receptor repertoires may be expressed at different stages of differentiation of this lineage. We have now used human (MG-63) and murine (MC3T3-E1) osteoblastic cell lines as well as primary murine calvaria cells to test the hypothesis that these receptors mediate effects of the cytokines on the biology of osteoblasts. We report that as in other cell types, all of the osteoblastic cell models responded to interleukin-6 (IL-6)-type cytokines with activation of both the JAK/STAT (Janus kinase/signal transducer and activator of transcription) and the mitogen-activated protein kinase (MAPK) pathways. In addition, IL-6-type cytokines stimulated alkaline phosphatase activity and osteocalcin expression and inhibited (MG-63), stimulated (MC3T3-E1), or had no effect (calvaria cells) on the rate of cell proliferation. The ability of a given cell type to respond to a particular member of this family of cytokines was strictly dependent on the presence of the corresponding ligand-binding subunit (alpha) of the cytokine receptor, and the magnitude of all the effects was closely correlated with the concentration of this subunit. The relative contribution of the JAK/STAT and MAPK pathways to the biological effects of the cytokines was evaluated using kinase inhibitors. Cytokine-mediated modulation of cell proliferation as well as stimulation of alkaline phosphatase activity were abrogated by tyrosine kinase inhibitors as well as a threonine/serine kinase inhibitor, but were only minimally affected by a specific inhibitor of MAPK phosphorylation. These results demonstrate that IL-6-type cytokines, besides their osteoclastogenic properties, promote differentiation of committed osteoblastic cells toward a more mature phenotype and that this action is mediated primarily via the activation of the JAK/STAT pathway.
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PMID:Activation of the Janus kinase/STAT (signal transducer and activator of transcription) signal transduction pathway by interleukin-6-type cytokines promotes osteoblast differentiation. 927 51

STAT transcription factors are induced by a number of growth factors and cytokines. Within minutes of induction, the STAT proteins are phosphorylated on tyrosine and serine residues and translocated to the nucleus, where they bind to their DNA targets. The leukemia inhibitory factor (LIF) mediates pleiotropic and sometimes opposite effects both in vivo and in cultured cells. It is known, for example, to prevent differentiation of embryonic stem (ES) cells in vitro. To get insights into LIF-regulated signaling in ES cells, we have analyzed protein-binding and transcriptional properties of STAT recognition sites in ES cells cultivated in the presence and in the absence of LIF. We have detected a specific LIF-regulated DNA-binding activity implicating the STAT3 protein. We show that STAT3 phosphorylation is essential for this LIF-dependent DNA-binding activity. The possibility that ERK2 or a closely related protein kinase, whose activity is modulated in a LIF-dependent manner, contributes to this phosphorylation is discussed. Finally, we show that the multimerized STAT3-binding DNA element confers LIF responsiveness to a minimal thymidine kinase promoter. This, together with our observation that overexpression of STAT3 dominant-negative mutants abrogates this LIF responsiveness, clearly indicates that STAT3 is involved in LIF-regulated transcriptional events in ES cells. Finally, stable expression of such a dominant negative mutant of STAT3 induces morphological differentiation of ES cells despite continuous LIF supply. Our results suggest that STAT3 is a critical target of the LIF signaling pathway, which maintains pluripotent cell proliferation.
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PMID:Leukemia inhibitory factor-dependent transcriptional activation in embryonic stem cells. 929 77

Intracellular signaling events occurring downstream of receptor activation for the colony-stimulating factors GM-CSF and G-CSF and Steel factor the latter a member of the tyrosine kinase receptor family of hematopoietic growth factors, are discussed. Hematopoietic signaling pathways, including the Ras/Raf-1/MAP kinase cascade and the Jak-STAT pathway are defined and links existing between separate signaling pathways are discussed. Emphasis is given to exploring the relationships that exist between activation of receptor-associated proteins and signal transduction pathways, and the regulation of gene transcription, translation, and hematopoietic cell proliferation. A model system exploring the synergistic interaction between GM-CSF and Steel factor in the regulation of hematopoietic cell proliferation is presented.
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PMID:Advances in understanding the postreceptor mechanisms of action of GM-CSF, G-CSF, and Steel factor. 937 74

Cytokine receptors of the hematopoietic receptor superfamily lack intrinsic tyrosine kinase domains for the intracellular transmission of their signals. Instead all members of this family associate with Jak family nonreceptor tyrosine kinases. Upon ligand stimulation of the receptors, Jaks are activated to phosphorylate target substrates. These include STAT (signal transducers and activators of transcription) proteins, which after phosphorylation translocate to the nucleus and modulate gene expression. The exact role of the Jak-STAT pathway in conveying growth and differentiation signals remains unclear. Here we describe a deletion mutant of the thrombopoietin receptor (c-mpl) that has completely lost the capacity to activate Jaks and STATs but retains its ability to induce proliferation. This mutant still mediates TPO-induced phosphorylation of Shc, Vav, mitogen-activated protein kinase (MAPK) and Raf-1 as well as induction of c-fos and c-myc, although at somewhat reduced levels. Furthermore, we show that both wild-type and mutant receptors activate phosphatidylinositol (PI) 3-kinase upon thrombopoietin stimulation and that thrombopoietin-induced proliferation is inhibited in the presence of the PI 3-kinase inhibitor wortmannin. These results demonstrate that the Jak-STAT pathway is dispensable for the generation of mitogenic signals by a cytokine receptor.
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PMID:The thrombopoietin receptor can mediate proliferation without activation of the Jak-STAT pathway. 939 63

The binding of insulin to its receptor initiates multiple signal transduction pathways regulating such diverse processes as proliferation, differentiation, glucose transport, and glycogen metabolism. The STAT-family of transcription factors has been demonstrated to play a critical role in gene induction by a variety of hemopoietic cytokines and hormones. Furthermore, constitutive activation of STATs is observed in transformed cells. Here we describe activation of a transcriptional complex binding to a consensus STAT-transcriptional element in response to insulin challenge. This complex is induced rapidly after tyrosine autophosphorylation of the insulin receptor, and is sustained for several hours. Supershift analysis of the insulin-induced complex reveals that it specifically contains the transcription factor Stat3. DAN binding of this complex is inhibited by pre-incubation with tyrosine, but not serine/threonine protein kinase inhibitors, whereas transcriptional activation is inhibited by both. Utilising a dominant negative mutant of p21ras we demonstrate that both insulin-induced Stat3 DNA-binding and also transactivation do not require p21ras. Furthermore, although previous studies have suggested a role for MAP kinases (ERKs) and PI-3K in STAT activation, utilising the specific MEK inhibitor PD098059 and the PI-3K inhibitor wortmannin, we demonstrate that activation of ERKs or PI-3K are not required for insulin induced Stat3 phosphorylation or transactivation.
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PMID:Insulin activates Stat3 independently of p21ras-ERK and PI-3K signal transduction. 939 41

Signal transduction through the interferongamma (IFNgamma) receptor involves the formation of a ligand-dependent multimolecular association of receptor chains (alpha and beta), Janus tyrosine kinases (Jak1 and Jak2), and the transcription factor (signal transducers and activators of transcription 1alpha (STAT1alpha)) in addition to activation of mitogen-activated protein kinases (MAPK). Interactions between components of the Jak/STAT cascade and the p21(ras)/Raf-1/MAPK cascade are unexplored. Treatment of HeLa cells with IFNgamma resulted in the rapid and transient activation of Raf-1 and MAPK. Parallel activation of cells resulted in essentially no enhancement of p21(ras) activation despite marked enhancement after treatment with epidermal growth factor. In HeLa (E1C3) and fibrosarcoma (U4A) cell lines, both of which are deficient in Jak1 kinase, Raf-1 activation by IFNgamma was absent. Reconstitution of Raf-1 activity was observed only with kinase active Jak1 in both cell lines. In COS cells, transient expression of wild type or kinase-inactive Jak1 coimmunoprecipitated with Raf-1, but activation of Raf-1 activity was only observed in cells expressing kinase-active Jak1. These observations suggest that a kinase-active Jak1 is required for IFNgamma activation of Raf-1 that is p21(ras)-independent.
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PMID:Interferon gamma activation of Raf-1 is Jak1-dependent and p21ras-independent. 944 16

Eosinophils are potent effector cells contributing to allergic inflammation and asthma. The differentiation, recruitment, and effector functions of eosinophils are greatly affected by interleukin (IL)-5. In the eosinophil, signal transduction pathways including Jak-STAT and Ras-Raf-MAP kinase are stimulated by IL-5 and enzymatic activation of tyrosine kinases Jak-2 and Lyn has been demonstrated. The participation of adapter proteins in the responses of the Ras-Raf-MAP kinase pathway has been documented in many cytokine family receptors but the expression and activation of these proteins have not been demonstrated in eosinophils. In these studies, we have found three isoforms of the adapter protein, Shc, to be expressed in eosinophils. One of these isoforms, p52 Shc, was tyrosine phosphorylated following IL-5 treatment of eosinophils. A second adapter protein, Grb2, coimmunoprecipitated with Shc following IL-5 stimulation of eosinophils. Furthermore, p52 Shc was increasingly associated with a cell fraction resistant to detergent solubilization, following IL-5 administration. This cell fraction of limited detergent solubility is a complex mixture of proteins and the adapter protein Grb2, the tyrosine kinases Jak-2 and Lyn, the nucleotide exchange factor Vav, and the serine-threonine kinases p45 MAP kinase, Raf-1, and PKCbeta, were distributed either wholly or partially in the same fraction, as were the cytoskeletal proteins actin and vimentin. Only p52 Shc, however, demonstrated discernibly increased association with this fraction following IL-5 stimulation of eosinophils. These data suggest that IL-5 activates a signal transduction pathway utilizing the adapter proteins Shc and Grb2 in the human eosinophil.
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PMID:Interleukin 5 signals through Shc and Grb2 in human eosinophils. 944 48

Cytokine-mediated inhibition of eosinophil apoptosis is a mechanism causing tissue eosinophilia. Previously published work suggested that activation of the Lyn-Ras-Raf-1-MAP kinase pathway is obligatory for prevention of eosinophil apoptosis by eosinophil hematopoietins. We demonstrate herein that activation of freshly isolated human blood eosinophils by granulocyte-macrophage colony-stimulating factor (GM-CSF) is associated with increased tyrosine phosphorylation of Jak2. The tyrosine kinase blocker, tyrphostin B42, prevented activation of Jak2 but not Lyn, suggesting that Jak2 is the specific target for tyrphostin B42 in eosinophils. In addition, since Lyn remained unaffected by tyrphostin B42, it is unlikely that Jak2 is required for Lyn activation in this model. To test whether tyrosine phosphorylation of Jak2 is linked to GM-CSF-mediated prolonged eosinophil survival, we determined the effect of tyrphostin B42 on eosinophil viability and apoptosis. Prevention of Jak2 activation by tyrphostin B42 was associated with the inability of GM-CSF to prevent eosinophil apoptosis. These data suggest that disruption of not only the Lyn-Ras-Raf-1-MAP kinase but also the Jak-STAT pathway blocks the ability of eosinophil survival factors to prevent apoptosis in eosinophils.
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PMID:Anti-apoptotic signals of granulocyte-macrophage colony-stimulating factor are transduced via Jak2 tyrosine kinase in eosinophils. 946 45


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