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)

Nerve growth factor (NGF) binds to two structurally unrelated transmembrane proteins on the surface of PC-12 cells, a 75-kDa glycoprotein with a short cytoplasmic sequence, and the trk protooncogene (pp140c-trk), a protein tyrosine kinase activated by NGF. Immediately after binding to cells, NGF induces changes in serine/threonine phosphorylation of several proteins. We have explored the relative roles of these two NGF binding proteins in mediating the activation of two intracellular kinases that may be responsible for some of these phosphorylations. The raf-1 protooncogene is a serine/threonine kinase activated by several growth factors and oncogenic proteins. Treatment of PC-12 cells with NGF increases the serine and threonine phosphorylation of raf-1 in an anti-raf-1 immunoprecipitate kinase assay. This increased phosphorylation observed in vitro is dose-dependent and transient and is accompanied by the NGF-dependent shift in the mobility of immunoblotted raf-1 on SDS sodium dodecyl sulfate-polyacrylamide gel electrophoresis, an effect thought to reflect phosphorylation. NGF-dependent activation of raf-1 is not dependent on protein kinase C, since prolonged exposure to phorbol esters under conditions that cause down-regulation of cellular protein kinase C activity has no effect on the NGF response. Expression of pp140c-trk in 3T3 fibroblasts (3T3-c-trk), as evidenced by cross-linking of 125I-NGF to the 140-kDa protein, permits the NGF-dependent activation of raf-1 kinase, detected in the immunoprecipitate kinase assay, anti-raf immunoblot shift on gel electrophoresis, and incorporation of [32P]orthophosphate into the raf-1 protein. The concentration dependence of raf-1 activation is identical in 3T3-c-trk and PC-12 cells, despite the absence of the 75-kDa NGF binding protein in 3T3-c-trk cells. NGF is without effect in untransfected 3T3 cells or in Chinese hamster ovary cells overexpressing p75, although raf-1 is present in these cells. Similarly, the NGF-dependent activation of mitogen-activated protein (MAP) kinase is detected in 3T3-c-trk cells, but not in untransfected 3T3 or Chinese hamster ovary cells overexpressing p75. As described for raf-1 activation, the NGF dose responses for MAP kinase activation in 3T3-c-trk and PC-12 cells are virtually superimposable. These data indicate that the activation of these two serine/threonine kinases by NGF is mediated solely by binding to and activating the pp140c-trk receptor.
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PMID:Nerve growth factor stimulates the activities of the raf-1 and the mitogen-activated protein kinases via the trk protooncogene. 132 11

The insulin receptor is a heterotetrameric glycoprotein composed of two 130 kD extracellular alpha subunits and two 95 kD membrane-spanning beta subunits. The insulin receptor functions as an allosteric enzyme which undergoes conformational changes when its alpha subunit binds insulin, resulting in activation and autophosphorylation of the tyrosine kinase contained in the beta subunit. This receptor activation is due to intermolecular reactions responsible for amplification of the hormone-induced response at the receptor level. Activation of the receptor tyrosine kinase initiates a cascade of phosphorylation/dephosphorylation reactions and enzyme activation/deactivation reactions. Insulin causes very rapid activation of the enzymes MAP kinase (Microtubule Associated Protein kinase) and phosphatidylinositol-3 kinase, which may act as key links between the insulin receptor and the cell effectors responsible for hormone-induced responses.
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PMID:[The insulin receptor: mechanism of activation and message transmission]. 133 94

Previously, we have shown that nuclear envelope assembly in cell-free extracts of Xenopus eggs requires two distinct vesicle-containing fractions, called Nuclear Envelope Precursor Fractions A and B (NEP-A and NEP-B). These fractions are characterized further in this paper and the manner in which they are regulated during metaphase is examined. Antisera against the NEP-B fraction recognized several proteins common to NEP-B and Xenopus oocyte or liver nuclei, but not to NEP-A or cytosol. A known glycoprotein component of the nuclear pore complex, p62, also co-fractionated with NEP-B, whereas the Xenopus egg lamin LIII did not. Together, these results provide further evidence that the NEP-B fraction contains precursors of the nuclear envelope. The regulation of NEP-A and -B function during metaphase, when the nuclear envelope is disassembled, was examined by treating each fraction with metaphase cytosol or purified protein kinase preparations isolated from metaphase-arrested eggs. Treatment of NEP-B with metaphase cytosol, under conditions where proteins are irreversibly phosphorylated, inhibited the subsequent assembly of the nuclear envelope by preventing the binding of NEP-B to chromatin. In contrast, similar treatment of NEP-A did not affect its ability to form nuclear envelopes. The changes in NEP-B during metaphase did not appear to be regulated directly by either p34cdc2/cyclin B, S6 kinase II or MAP kinase.
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PMID:Regulation of nuclear envelope precursor functions during cell division. 140 Jun 33

Previous studies suggested that interleukin-11 (IL-11) induces the activation of mitogen-activated protein kinase (MAPK) in mouse 3T3L1 cells. However, the mechanisms by which IL-11 activates MAPK remain elusive. Our present results show that IL-11 promotes the formation of the active GTP-bound form of Ras, suggesting that IL-11 actions may be transduced in part through the Ras/MAPK signaling pathway. By immunoblotting and immunoprecipitation, we further demonstrate the association of tyrosine phosphoproteins with Grb2, an adaptor protein serving as a key intermediate for Ras activation. These phosphotyrosine-containing proteins have been subsequently identified to be JAK2, Fyn, and Syp. JAK2 and Fyn are transiently associated with Grb2 upon stimulation with IL-11, suggesting that JAK2 and Fyn may be involved in transducing signals from the IL-11 receptor-glycoprotein 130 to the Ras system through Grb2. Taken together, these results suggest that IL-11-induced interactions of JAK2, Fyn, and Grb2 may not only provide a novel mechanism for the activation of the Ras/MAPK system but also indicate cross-talk among diverse signaling pathways.
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PMID:Interleukin-11 induces complex formation of Grb2, Fyn, and JAK2 in 3T3L1 cells. 749 80

Gonadotropin-releasing hormone (GnRH) interacts with a G protein-coupled receptor and increases the transcription of the glycoprotein hormone alpha-subunit gene. We have explored the possibility that mitogen-activated protein kinase (MAPK) plays a role in mediating GnRH effects on transcription. Activation of the MAPK cascade by an expression vector for a constitutively active form of the Raf-1 kinase led to stimulation of the alpha-subunit promoter in a concentration-dependent manner. GnRH treatment was found to increase the phosphorylation of tyrosine residues of MAPK and to increase MAPK activity, as determined by an immune complex kinase assay. A reporter gene assay using the MAPK-responsive, carboxy-terminal domain of the Elk1 transcription factor was also consistent with GnRH-induced activation of MAPK. Interference with the MAPK pathway by expression vectors for kinase-defective MAPKs or vectors encoding MAPK phosphatases reduced the transcription-stimulating effects of GnRH. The DNA sequences which are required for responses to GnRH include an Ets factor-binding site. An expression vector for a dominant negative form of Ets-2 was able to reduce GnRH effects on expression of the alpha-subunit gene. These findings provide evidence that GnRH treatment leads to activation of the MAPK cascade in gonadotropes and that activation of MAPK contributes to stimulation of the alpha-subunit promoter. It is likely that an Ets factor serves as a downstream transcriptional effector of MAPK in this system.
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PMID:A role for mitogen-activated protein kinase in mediating activation of the glycoprotein hormone alpha-subunit promoter by gonadotropin-releasing hormone. 779 60

GnRH regulates gonadotropin biosynthesis and secretion. Multiple intracellular signaling pathways are activated by GnRH, including phosphoinositol turnover, release of intracellular calcium and influx of extracellular calcium, and activation of protein kinase C (PKC), among others. In this study, we investigated whether GnRH stimulates mitogen-activated protein kinase (MAPKs), and whether this pathway plays a role in the transcriptional activation of the gonadotropin alpha-gene. In alpha T3-1 gonadotrope cells, treatment with GnRH caused 4- to 5-fold induction of MAPK activity. Stimulation of MAPK activity was detected within 5 min of GnRH treatment and persisted for 60 min. MAPK activation by GnRH was also seen in primary cultures of rat pituitary cells. Treatment with phorbol 12-myristate 13-acetate (TPA) caused 4- to 5-fold induction of MAPK activity in alpha T3-1 cells. Pretreatment with TPA, however, decreased both GnRH- and TPA-induced MAPK activation, suggesting that PKC is involved in GnRH-mediated activation of MAPK. Western blot analyses of PKC isoforms alpha and epsilon confirmed that they were depleted by chronic treatment with TPA, whereas MAPK protein levels were unaffected. Because transcriptional stimulation of the glycoprotein hormone alpha-gene by GnRH is also inhibited by PKC depletion, additional experiments were performed to explore a potential role for MAPK in alpha-gene expression. Cotransfection of a dominant negative inhibitors of MAPK isoforms (ERK1 and ERK2) suppressed basal expression of the alpha-promoter by 60%, but had less effect on the extent of GnRH stimulation in alpha T3-1 cells. These experiments indicate that GnRH stimulates MAPK activity, probably through a pathway involving PKC. Although PKC depletion inhibits both MAPK- and GnRH-stimulated alpha-gene transcription, pathways other than MAPK are also likely to be involved in mediating the transcriptional effects of GnRH.
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PMID:Stimulation of mitogen-activated protein kinase by gonadotropin-releasing hormone: evidence for the involvement of protein kinase C. 853 29

A variety of growth factors and guanosine triphosphate (GTP) binding protein-linked receptors are known to activate mitogen activated protein kinases (MAPK); however, no evidence exists demonstrating activation of the MAPK pathway by glycoprotein hormones. Using porcine granulosa cells (PGC), we show that physiological concentrations of LH and FSH increase enzymatic activity 1) of p44MAPK extracellular regulated kinase 1 (ERK1) but not that of p42MAPK (ERK2) in the cytosol and 2) of both ERK1 and ERK2 in the nucleus. Cytosolic ERK1 was activated by LH more rapidly than by FSH. Cyclic AMP increased kinase activities of both ERK1 and ERK2 in the cytoplasm as well as in the nucleus. Activation of ERK1 by gonadotropins and cAMP was accompanied by increased tyrosine phosphorylation of the kinase. Immunohistochemical studies demonstrated predominantly cytoplasmic staining for MAPK in untreated PGC cultures whereas treatment with gonadotropins led to increased nuclear immunoreactivity indicating translocation of MAPK to the nucleus. The translocation as well as increase in nuclear ERK1 and ERK2 was delayed and coincided with a decrease in cytosolic ERK1 activity. Epidermal growth factor (EGF) increased ERK1 and ERK2-associated kinase activity 7-8-fold in the cytoplasm of PGC, while kinase activity of cytoplasmic ERK1 was enhanced 3-4-fold by LH, FSH, or cAMP. In summary, we have for the first time demonstrated that gonadotropins (and cAMP) can activate MAPK in appropriate target cells.
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PMID:Activation of mitogen-activated protein kinases by gonadotropins and cyclic adenosine 5'-monophosphates in porcine granulosa cells. 879 65

Ciliary neurotrophic factor (CNTF) shares structural and functional properties with members of the hematopoietic cytokine family. It is composed of a four-helix bundle structure and shares the transmembrane signal transducing proteins, glycoprotein-130 (gp130) and leukemia inhibitory factor receptor (LIF-R). Structure-function analysis showed that the gp130-interactive proteins bind in a similar manner to that of growth hormone (site I and II). In addition, gp130-interactive proteins and granulocyte colony-stimulating factor (G-CSF) utilize another binding site (site III) at the boundary between CD loop and helix D. CNTF triggers the association of receptor components, resulting in activation of a signal transduction cascade mediated by specific intracellular protein tyrosine kinases. The Janus kinase (JAK)/signal transducer and activator of transcription (STAT) and Ras/mitogen-activated protein kinase (MAPK) signaling pathways have been characterized in terms of gp130-interactive protein, and there should be other pathways and some crosstalk between them to enhance, prolong, or specify the signals.
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PMID:Activating mechanism of CNTF and related cytokines. 888 48

Prosaposin is a 66 kDa glycoprotein which has neurotrophic activity in vitro and in vivo. The neurotrophic sequence (8CEFLVKEVTKLIDNNKTEKEI29L) within prosaposin has been located to the amino terminal portion of the saposin C domain. This 22-mer peptide, prosaptide, has neurotrophic activity equivalent to prosaposin. We present binding studies using 125I-prosaposin and 125I-prosaptide which revealed a single class of specific binding sites with a Kd of 2.5 nM and 18.3 nM, respectively. Both prosaposin and prosaptide rapidly stimulated protein tyrosine phosphorylation in PC12 cells and increased phosphorylation of MAPK 20-fold especially of p44 MAPK which peaked at 5 minutes of stimulation and then rapidly declined. Treatment of PC12 cells with a mutant 22-mer prosaptide (21Asn to 21Asp) did not induce phosphorylation. These findings suggest a role for MAPK in signal transduction by prosaposin.
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PMID:Induction of MAPK phosphorylation by prosaposin and prosaptide in PC12 cells. 895 61

Angiotensin II (Ang II) interaction with the neuronal AT1 receptor results in a chronic stimulation of neuromodulation that involves the expression of norepinephrine transporter (NET) and tyrosine hydroxylase (TH). In view of this unique property and the presence of putative nuclear localization signal (NLS) consensus sequence in the AT1 receptor, this study was conducted to investigate the hypothesis that Ang II would induce nuclear sequestration of this G protein-coupled receptor and that the sequestration may have implications on Ang II-induced expression of NET and TH genes. Incubation of neuronal cultures with Ang II caused a time- and dose-dependent increase in the levels of AT1 receptor immunoreactivity in the nucleus. A 6.7-fold increase was observed with 100 nM Ang II, in 15 min, that was blocked by losartan, an AT1 receptor-specific antagonist. Ang II-induced nuclear sequestration was specific for AT1 receptor, because Ang II failed to produce a similar effect on neuronal AT2 receptors. The presence of the putative NLS sequence in the cytoplasmic tail of the AT1 receptor seems to be the key in nuclear targeting because: 1) nuclear targeting was attenuated by a peptide of the AT1 receptor that contained the putative NLS sequence; and 2) Ang II failed to cause nuclear translocation of the AT2 receptor, which does not contain the putative NLS. Ang II also caused a time- and dose-dependent stimulation of P62 phosphorylation, a glycoprotein of the nuclear pore complex. A 6-fold stimulation of phosphorylation was observed with 100 nM Ang II, in 15 min, that was completely blocked by losartan and not by PD123,319, an AT2 receptor specific antagonist. Preloading of neurons with p62-pep (a peptide containing consenses of mitogen-activated protein kinase in p62) resulted in a loss of Ang II-induced p62 phosphorylation and stimulation of NET and TH messenger RNA levels. In conclusion, these data demonstrate that Ang II induces nuclear sequestration of AT1 receptor involving NLS in the AT1 receptor and p62 of the nuclear pore complex in brain neurons. A possible role of such a nuclear targeting of the AT1 receptor on chronic neuromodulatory actions of Ang II has been discussed.
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PMID:Angiotensin II-induced nuclear targeting of the angiotensin type 1 (AT1) receptor in brain neurons. 942 35


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