Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.24 (mitogen-activated protein kinase)
 95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The myelomonocytic lineage of hematopoiesis is regulated by the growth factor granulocyte-macrophage colony-stimulating factor (GM-CSF). This cytokine has proven to be safe for use in coordination with the treatments for bone marrow transplants and acute myelogenous leukemia. GM-CSF and related cytokines operate through specific receptors in the membranes of target cells of the myelopoietic lineages (both immature and mature cells). The exact signal transduction mechanisms in the cell are only beginning to be clarified and involve a plethora of signaling molecules. With a wealth of new information from studies in GM-CSF-induced cell activation, three major experimental approaches are emerging as gold standards in the exploration of those signaling pathways initiated by hematopoietic growth factors. We consider here: (1) a protein-protein interaction, as exemplified by the association between the cytokine membrane receptor and JAK kinase; (2) a covalent modification of an enzyme, as studied in the phosphorylation of MAP kinase; and (3) a protein-DNA interaction, as demonstrated by the translocation of STAT from the cytosol to the nucleus where it can bind to the promoters of specific genes.
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PMID:Emerging paradigms in granulocyte-macrophage colony-stimulating factor signaling. 895 Mar 14

Cardiac myocyte survival is of central importance in the maintenance of the function of heart, as well as in the development of a variety of cardiac diseases. To understand the molecular mechanisms that govern this function, we characterized apoptosis in cardiac muscle cells following serum deprivation. Cardiotrophin 1 (CT-1), a potent cardiac survival factor (Sheng, Z., Pennica, D., Wood, W. I., and Chien, K. R. (1996) Development (Camb.) 122, 419-428), is capable of inhibiting apoptosis in cardiac myocytes. To explore the potential downstream pathways that might be responsible for this effect, we documented that CT-1 activated both signal transducer and activator of transcription 3 (STAT3)- and mitogen-activated protein (MAP) kinase-dependent pathways. The transfection of a MAP kinase kinase 1 (MEK1) dominant negative mutant cDNA into myocardial cells blocked the antiapoptotic effects of CT-1, indicating a requirement of the MAP kinase pathway for the survival effect of CT-1. A MEK-specific inhibitor (PD098059) (Dudley, D. T., Pang, L., Decker, S.-J., Bridges, A. J., and Saltiel, A. R. (1995) Proc. Natl. Acad. Sci. USA 92, 7686-7689) is capable of blocking the activation of MAP kinase, as well as the survival effect of CT-1. In contrast, this inhibitor did not block the activation of STAT3, nor did it have any effect on the hypertrophic response elicited following stimulation of CT-1. Therefore, CT-1 promotes cardiac myocyte survival via the activation of an antiapoptotic signaling pathway that requires MAP kinases, whereas the hypertrophy induced by CT-1 may be mediated by alternative pathways, e.g. Janus kinase/STAT or MEK kinase/c-Jun NH2-terminal protein kinase.
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PMID:Cardiotrophin 1 (CT-1) inhibition of cardiac myocyte apoptosis via a mitogen-activated protein kinase-dependent pathway. Divergence from downstream CT-1 signals for myocardial cell hypertrophy. 903 92

Angiotensin II is a multifunctional hormone that affects both contraction and growth of vascular smooth muscle cells through a complex series of intracellular signaling events initiated by the interaction of angiotensin II with the AT1 receptor. The cellular response to angiotensin II is multiphasic, involving stimulation within seconds of phospholipase C and Ca2+ mobilization; activation within minutes of phospholipase D, A2, protein kinase C, and MAP kinase; and stimulation after a period of hours of gene transcription and NADH/NADPH oxidase activity. Angiotensin II also activates numerous intracellular tyrosine kinases. In this respect, it shares some aspects of signaling with growth factor and cytokine receptors, including activation of phospholipase C-gamma, src, and ras; association of shc with grb2; and stimulation of the Jak/STAT pathway. The cellular events responsible for this unique series of events may involve receptor movement and the creation of a signaling domain. Elucidation of these pathways is important to our understanding of AT1 receptor function as a final effector of the renin-angiotensin system.
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PMID:Angiotensin II signaling in vascular smooth muscle. New concepts. 903 29

Erythropoietin (EPO) exerts its activities by the induction of multiple signalling pathways through interaction with the erythropoietin receptor (EPOR). Previous studies have suggested that the Ras/MAP kinase as well as the JAK/STAT signalling cascades play significant roles in the induction of EPO-responsive genes. Here we show that, in HCD-57 erythroleukemic cells, both pathways are activated by EPO in a dose-dependent manner with similar sensitivities and kinetics. The activation of signalling molecules is closely related to the proliferative status of the cells. Using an antisense strategy, we were able to show that the downregulation of the JAK2 protein level in HCD-57 cells results in a distinct reduction of the ability to induce not only STAT5 DNA-binding, but also MAP kinase activity. Our results thus provide evidence for a significant contribution of the cytosolic tyrosine kinase JAK2 to the EPO-induced activation of the Ras/MAP kinase cascade.
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PMID:Requirement for JAK2 in erythropoietin-induced signalling pathways. 906 35

Lymphocytes employ a complex assembly of signaling elements that have been organized on a spatiotemporal map to define their role in stimulating both proliferation and apoptosis. The antigen/major histocompatibility complex (MHC) initiates the sequence by organizing the assembly of an active T-cell receptor (TCR) complex responsible for transmitting information down various signaling cassettes (e.g., the IP3/Ca2+, DAG/PKC, ras/MAPK, and the PI 3-K pathways). It is proposed that CD28 may exert its costimulatory action by facilitating the assembly of an effective scaffold of signaling elements within the TCR complex. The absence of costimulation through CD28 seems to result in the assembly of a defective scaffold that reverses slowly and may thus account for the state of unresponsiveness responsible for peripheral T-cell tolerance. The signaling cassettes activated by the TCR and CD28 then engage cytosolic factors that transmit information into the nucleus to activate the genes that code for the IL-2 and Fas signaling pathways. The IL-2 and Fas receptors employ additional signaling cassettes (e.g., the JAK/STAT and the sphingomyelinase/ceramide pathways) to mediate their effects on proliferation and apoptosis, respectively. Information concerning these signaling systems is beginning to provide therapeutic strategies to manipulate the immune system to overcome human immunodeficiency virus (HIV) infection, autoimmune diseases, and graft rejection.
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PMID:Lymphocyte activation in health and disease. 909 51

Interleukin-11 (IL-11) is a pleiotropic cytokine which regulates the growth of hematopoietic progenitor cells and activates platelet maturation. Previous studies have shown that, IL-11 activates a set of signaling cascades involving the JAK/STAT and Raf/MAPK pathways. The purpose of the current studies was to obtain evidence about the possible involvement of PKC in the IL-11 signaling pathway. Evidence presented in this report suggests that IL-11 stimulates rapid PKC activation and markedly induces cytosolic to particulate (membrane) association of alpha and beta PKC isoforms. These findings provide preliminary evidence that PKC may be involved in the IL-11 signaling cascade.
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PMID:Interleukin-11 induces rapid PKC activation and cytosolic to particulate translocation of alpha and beta PKC isoforms in human erythroleukemia K562 cells. 912 52

IL-6 is a multifunctional cytokine involved in hemopoiesis, immune regulation, inflammation, neural development, and infection. IL-6 belongs to a family of related cytokines that includes leukemia inhibitory factor, oncostatin M, IL-11, ciliary neurotropic factor, and cardiotropin-1, all of which initiate signaling through a receptor-associated gp130. IL-6 induces homodimerization of gp130 and activates the Jak/STAT pathway of signal transduction. In addition, IL-6 stimulates the mitogen-activated protein kinases designated ERK (extracellular signal-regulated kinase)-1 and -2. Activation of ERK-1 and -2 may involve the Src homology-2 containing proteins Shc and Grb2. Here we provide evidence that Shc could function as signaling molecules for IL-6 in DeFew-IL-6R/gp130 cells, a human B lymphoma cell line engineered to express high levels of both the IL-6R (p80) and the gp130 subunit. IL-6 was shown to promote the rapid tyrosine phosphorylation of gp130, Jak2, and Shc proteins. Moreover, Shc associated both in vivo and in vitro with phosphorylated gp130 through the Shc-Src homology-2 domain. We also report that Shc bound to activated Jak2 by using the Shc amino terminal phosphotyrosine interaction domain. Following IL-6 stimulation, Shc physically associated with Grb2. Thus, the data point to Shc proteins as a functional link between the Jak2 and Ras pathways of IL-6 signal transduction.
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PMID:Shc mediates IL-6 signaling by interacting with gp130 and Jak2 kinase. 912 68

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

Upon the corresponding ligand's stimulation, the cytokine receptors activate several signal pathways: JAK-STAT pathway, Ras-MAP kinase pathway and so on. Recently, we demonstrated that one of the STAT3 (signal transducer and activator of transcription-3) target genes could suppress the function of STAT3 and designated as SSI-1(STAT induced STAT inhibitor-1). SSI-1 is thought to play a critical role in negative feedback control of JAK-STAT signaling pathway. In the present study, we identified two novel human genes which products have homologous region in their SH2 domain and its COOH-terminal region to mouse SSI-1. Northern blotting analysis and functional studies demonstrated that SSI-2 and SSI-3 mRNA were also induced by cytokine stimulation and their forced expression in mouse myeloid leukemia cell, M1, suppressed the apoptotic effect of LIF, like SSI-1. We also demonstrated the structure of human SSI-1.
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PMID:Cloning and functional analysis of new members of STAT induced STAT inhibitor (SSI) family: SSI-2 and SSI-3. 926 33

Protein tyrosine kinases activate the STAT (signal transducer and activator of transcription) signaling pathway, which can play essential roles in cell differentiation, cell cycle control, and development. However, the potential role of the STAT signaling pathway in the induction of apoptosis remains unexplored. Here we show that gamma interferon (IFN-gamma) activated STAT1 and induced apoptosis in both A431 and HeLa cells, whereas epidermal growth factor (EGF) activated STAT proteins and induced apoptosis in A431 but not in HeLa cells. EGF receptor autophosphorylation and mitogen-activated protein kinase activation in response to EGF were similar in both cell lines. The breast cancer cell line MDA-MB-468 exhibited a similar response to A431 cells, i.e., STAT activation and apoptosis correlatively resulted from EGF or IFN-gamma treatment. In addition, in a mutant A431 cell line in which STAT activation was abolished, no apoptosis was induced by either EGF or IFN-gamma. We further demonstrated that both EGF and IFN-gamma induced caspase 1 (interleukin-1beta converting enzyme [ICE]) gene expression in a STAT-dependent manner. IFN-gamma was unable to induce ICE gene expression and apoptosis in either JAK1-deficient HeLa cells (E2A4) or STAT1-deficient cells (U3A). However, ICE gene expression and apoptosis were induced by IFN-gamma in U3A cells into which STAT1 had been reintroduced. Moreover, both EGF-induced apoptosis and IFN-gamma-induced apoptosis were effectively blocked by Z-Val-Ala-Asp-fluoromethylketone (ZVAD) in all the cells tested, and studies from ICE-deficient cells indicated that ICE gene expression was necessary for IFN-gamma-induced apoptosis. We conclude that activation of the STAT signaling pathway can induce apoptosis through the induction of ICE gene expression.
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PMID:Activation of the STAT signaling pathway can cause expression of caspase 1 and apoptosis. 927 10


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