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:2.7.11.24 (mitogen-activated protein kinase)
95,810 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Granulocyte-macrophage colony-stimulating factor (GM-CSF) is a hematopoietic growth factor that has been shown to support call proliferation in murine fibroblasts engineered to stably express both chains of the human GM-CSF receptor (NIH-GMR). Because the proto-oncogene c-fos is believed to provide a link between short-term signals elicited at the membrane and long-term cellular response, we chose to study the mechanism of GM-CSF-dependent cell regulation using c-fos promoter activity as a molecular marker in both NIH-GMR transfectants and in the CD34+ cell line TF-1. The importance of c-fos and related AP-1 activity in GM-CSF signalling was suggested by a tight correlation between GM-CSF-dependent activation of the c-fos promoter and cell proliferation and by the inhibitory effect of a trans-dominant c-fos mutant on cell growth. To evaluate the contribution of the serum response factor (SRF) associated with the ternary complex factor (TCF) and of STAT proteins to c-fos promoter activation in response to GM-CSF, the SRF binding site (SRE) and/or the STAT binding site (SIE) were inactivated. In serum-free medium, both SRE and SIE are essential to c-fos promoter activation by GM-CSF in NIH-GMR transfectants and in TF-1 cells. No response to GM-CSF was observed when both sites were mutated. The nature of the STAT family member was further investigated by Wester blots and DNA retardation assays using an SIE probe. Our data indicate that GM-CSF induced DNA binding of both STAT1 and STAT3 in NIH-GMR and mainly of STAT3 in TF-1 cells. STAT5 tyrosine phosphorylation was also observed in TF-1 cells. Finally, expression of a dominant negative MAPK mutant, ERK192A, resulted in a decrease of both SRE- and SIE-dependent activation of c-fos promoter by GM-CSF, suggesting that STAT1/3 are regulated not only by tyrosine kinases, but also partially by MAPK.
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PMID:Contribution of both STAT and SRF/TCF to c-fos promoter activation by granulocyte-macrophage colony-stimulating factor. 887 87

The proto-oncogene c-eyk, the cellular counterpart of a transforming oncogene, v-eyk, encodes a receptor protein tyrosine kinase with a distinctive extracellular region. We now demonstrate that c-Eyk can be constitutively activated through dimerization, and that the active Eyk displays a unique signaling pattern. When the kinase domain of c-Eyk was fused to the extracellular and transmembrane domains of CD8, the resulting chimera showed elevated kinase activity and caused cellular transformation. We found that the activated Eyk kinases, both v- and c-Eyk, constitutively stimulate the JAK-STAT pathway, while exerting little effect on other signaling routes such as the Ras-MAP kinase and the JNK pathways. The activated Eyk kinases specifically stimulate tyrosine phosphorylation of STAT1, STAT3 and JAK1. These downstream molecules also co-immunoprecipitate with the constitutively dimerized form of Eyk. The Eyk kinase activity is required for STAT1 stimulation. We found that the activation of STAT1 but not STAT3 correlates well with cellular transformation. In constitutively stimulating the JAK-STAT pathway, particularly STAT1, Eyk is unique in its downstream signaling and may be dependent on this pathway for cellular transformation.
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PMID:Unique signal transduction of Eyk: constitutive stimulation of the JAK-STAT pathway by an oncogenic receptor-type tyrosine kinase. 888 43

The AP-1 transcription factor family is subject to sophisticated regulation in response to cell growth and stress stimuli. We show here that the transcriptional activity of c-Jun, a key AP-1 component, is stimulated by overexpression of the c-Mos proto-oncogene product in mammalian cells. This stimulation requires serines 63 and 73 of c-Jun, indicating that it is likely to be mediated by proline-directed kinase(s). Co-transfection of MKP-1, a specific MAP kinase antagonist, blocks the stimulation of c-Jun by c-Mos, while co-transfection of a dominant negative form of c-Raf-1 does not. Conditioned medium from c-Mos transfected cells fails to activate c-Jun in recipient cells, arguing against the involvement of a diffusible mitogen. These data suggest that c-Mos exerts its effect on c-Jun directly through a MAP kinase, acting downstream of c-Raf-1.
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PMID:The c-Mos proto-oncogene product stimulates c-Jun transcriptional activity by a MAP kinase-dependent mechanism. 892 Sep 3

A plethora of signals induce the c-fos proto-oncogene via phosphorylation of the transcription factor Elk-1 by MAP kinase. We show that the coactivator CBP cooperates with Elk-1 to stimulate c-fos. Elk-1 physically interacts with CBP, which is dependent on the transactivation domain of Elk-1 but is independent of MAP kinase phosphorylation. However, functional cooperation between Elk-1 and CBP requires phosphorylation of Elk-1. Importantly, a carboxy-terminal transactivation domain of CBP itself is phosphorylated by MAP kinase, whereby the transactivation potential of CBP is enhanced. Thus, MAP kinase may not solely activate specific transcription factors but also the coactivator CBP, identifying a novel aspect of MAP kinase function. Thereby MAP kinase stimulation can pleiotropically affect activation of genes regulated by different transcription factors interacting with the same coactivator CBP.
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PMID:MAP kinase-dependent transcriptional coactivation by Elk-1 and its cofactor CBP. 894 62

Angiotensin II (Ang II), a potent hypertrophic factor for vascular smooth muscle cells (VSMC), induces activation of the ras proto-oncogene product (Ras) and mitogen-activated protein (MAP) kinases, and tyrosine phosphorylation of a focal adhesion-associated protein, paxillin. Forskolin, a direct activator of adenylate cyclase, and dibutyryl cAMP (Bt2 cAMP), a membrane permeable cAMP analogue, potently inhibited Ang II-stimulated protein synthesis. However, they did not inhibit Ang II-induced activation of Ras and MAP kinases. Although both forskolin and Bt2 cAMP potently reduced background tyrosine phosphorylation of paxillin, they allowed Ang II to induce the same reaction. These results indicate that increasing cAMP antagonizes the hypertrophic response to Ang II without affecting Ras and MAP kinase activation in VSMC and suggest that it does not interrupt signaling from the Ang II receptor to focal adhesions.
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PMID:Increasing cAMP antagonizes hypertrophic response to angiotensin II without affecting Ras and MAP kinase activation in vascular smooth muscle cells. 894 20

During meiotic maturation, numerous cytoplasmic and nuclear events take place that prepare the oocytes for fertilization. These changes are initiated by an increase in the activity of several kinases, most notably maturation-promoting factor, also called histone H1 kinase. Another kinase, mitogen-activated protein (MAP) kinase, is also stimulated during this period. In this study, we investigated the role of MAP kinase in bovine oocyte maturation. First, the kinetics of activation of histone H1 and MAP kinases during maturation were assessed simultaneously by evaluating their catalytic activities in vitro. We found that they are activated at approximately the same time, around germinal vesicle breakdown (GVBD). Then, at approximately 15 h of maturation, the activity of H1 kinase temporarily decreases, whereas MAP kinase remains high through the metaphase II stage. Second, the activation and catalytic activity of MAP kinase was directly evaluated by Western blotting and by an in-gel kinase assay. We determined that MAP kinase becomes activated and exhibits a decreased mobility through SDS-polyacrylamide gels, and that its catalytic activity increases as maturation progresses. In our system, most of the MAP kinase activity can be attributed to p42MAPK2. Third, the activation pathway of MAP kinase was explored. In Xenopus oocytes, MAP kinase is activated by a kinase cascade that includes several upstream activators; one of them is the product of the proto-oncogene mos. In bovine oocytes, injection of Mos RNA elicited a rapid maximal activation of MAP kinase that resulted in accelerated resumption of meiosis and GVBD. These results were thought to be mediated by an expression of a kinase-active Mos RNA failed to activate MAP kinase. Together, these results suggest a role for MAP kinase during the initiation and progression of meiosis in bovine oocytes. The data also suggest the presence of an MAP kinase-activating cascade that can be initiated by the Mos protein.
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PMID:Potential role of mitogen-activated protein kinase during meiosis resumption in bovine oocytes. 894 82

The c-myb proto-oncogene encodes a transcription factor that is implicated in regulatory events during hematopoiesis. It contains negative regulatory domains at both the amino- and carboxy-termini. Here we describe that human c-Myb can be phosphorylated by mitogen-activated protein kinases (MAPK's) at serine 532 of the carboxy (C-) terminal regulatory domain in vitro. This serine residue can also be phosphorylated in vivo upon serum-stimulation of Jurkat cells. Expression of a constitutively active form of Ras together with c-Myb in transient transfection experiments had no effect on the transcriptional activity of c-Myb, while expression of a polypeptide containing the c-Myb C-terminal domain stimulated c-Myb activity. This effect is reduced upon MAPK-dependent phosphorylation of serine 532. Our data suggest that the MAPK-dependent state of phosphorylation modifies the cellular function of c-Myb by modulating its interaction with a putative inhibitory factor.
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PMID:Functional analysis of phosphorylation at serine 532 of human c-Myb by MAP kinase. 896 Mar 73

The proto-oncogene-encoded transcription factor c-Jun activates genes in response to a number of inducers that act through mitogen-activated protein kinase (MAPK) signal transduction pathways. The activation of c-Jun after phosphorylation by MAPK is accompanied by a reduction in c-Jun ubiquitination and consequent stabilization of the protein. These results illustrate the relevance of regulated protein degradation in the signal-dependent control of gene expression.
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PMID:Reduced ubiquitin-dependent degradation of c-Jun after phosphorylation by MAP kinases. 899 40

The HER-2/neu proto-oncogene encodes a 185 kDa transmembrane receptor tyrosine kinase with significant sequence homology to other members of the class I receptor tyrosine kinase family. The HER-2/neu gene is amplified and/or overexpressed in 25%-30% of human breast and ovarian cancers, and overexpression of the receptor is associated with poor prognosis. Tyrosine phosphorylation and activation of the HER-2 receptor lead to activation of specific signal transduction pathways in breast and ovarian cancer cells, including the ras/MAP kinase cascade, phosphatidylinositol 3-kinase, and phospholipase C-gamma. HER-2/neu signal transduction pathways ultimately converge on the cell nucleus, where the expression of diverse genes is induced after activation of the receptor. A more complete understanding of HER-2/neu signal transduction pathways may allow the development of specific therapeutics for the treatment of those human breast and ovarian cancers containing this alteration.
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PMID:HER-2/neu signal transduction in human breast and ovarian cancer. 900 17

One distinguishing feature of vertebrate oocyte meiosis is its discontinuity; oocytes are released from their prophase I arrest, usually by hormonal stimulation, only to again halt at metaphase II, where they await fertilization. The product of the c-mos proto-oncogene, Mos, is a key regulator of this maturation process. Mos is a serine-threonine kinase that activates and/or stabilizes maturation-promoting factor (MPF), the master cell cycle switch, through a pathway that involves the mitogen-activated protein kinase (MAPK) cascade. Oocytes arrested at prophase I lack detectable levels of Mos, which must be synthesized from a pool of maternal mRNAs for proper maturation. While Mos is necessary throughout maturation in Xenopus, it seems to be required only for meiosis II in the mouse. The translational activation of c-mos mRNA at specific times during meiosis requires cytoplasmic polyadenylation. Cis- and trans-acting factors for polyadenylation are, therefore, essential elements of maturation.
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PMID:Synthesis and function of Mos: the control switch of vertebrate oocyte meiosis. 900 14


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