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)

During rat embryogenesis, fibers containing nerve growth factor (NGF) are present near the target destinations of migratory spinal neuroblasts, suggesting that diffusible gradients of NGF provide signals to newly generated neurons in the developing cord. In vitro, pM concentrations of NGF induce neuroblast chemotaxis (directed migration along a chemical gradient), indicating evoked motility is mediated by high-affinity receptors. Binding of 125I-labelled NGF to fetal cord cells provides additional evidence that rat spinal neuroblasts express the high-affinity receptors; however, their presence has not been directly demonstrated. In the present study, we used immunocytochemistry to show that the high-affinity NGF receptor protein, gp140trk (trk) is detectable in embryonic spinal tissue sections and in cord dissociates. Correlation of trk expression with NGF-induced chemotaxis revealed that both the receptor protein expression and functional responses to NGF develop along a ventro-dorsal gradient that parallels the in vivo pattern of neurogenesis and migration. Analysis of the temporal changes in trk immunoreactivity demonstrated that expression of gp140trk is bimodal, possibly reflecting multiple effects of NGF during development. Chemotaxis to NGF was blocked by nM concentrations of the kinase inhibitor, K252a, suggesting that NGF stimulates motility via high-affinity receptors coupled to kinase activity. Elevated 3',5'-cyclic adenosine monophosphate (cAMP) also attenuated NGF-induced chemotaxis, presenting preliminary evidence that protein kinase A (PKA) may regulate motility responses to NGF.
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PMID:Correlation of gp140trk expression and NGF-induced neuroblast chemotaxis in the embryonic rat spinal cord. 789 25

We have examined the effects of ciliary neurotrophic factor (CNTF) on the development of rat Purkinje cells in vitro. Cerebellar cells, derived from embryonic day 16 rat fetuses, were found to respond rapidly to CNTF treatment by induction of c-Fos protein, such that 40% of the cells were immunopositive after 60 min. Treatment with low doses of CNTF (10-100 pg/ml) for 8 days resulted in an approximately 1.6-fold increase in the number of Purkinje cells, identified by immunohistochemical staining for calbindin. Immunohistochemical staining for other Purkinje cell markers--cyclic-GMP-dependent protein kinase and the low-affinity nerve growth factor receptor--verified increased Purkinje cell survival following CNTF treatment. In addition, CNTF increased specific high-affinity GABA uptake by 45%, and the number of GABAergic neurons by 70%. A maximal increase in the number of Purkinje cells and GABA-uptake was only achieved if CNTF was added within 48 h of plating the cells, further suggesting that CNTF enhances Purkinje cell survival in vitro. These results taken together strongly support a direct effect of CNTF in promoting the survival of Purkinje cells and possibly other GABAergic cerebellar neurons.
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PMID:Ciliary neurotrophic factor enhances the survival of Purkinje cells in vitro. 795 72

CD27 is a T-cell surface antigen expressed on the majority of peripheral T cells and belongs to a newly defined receptor family including the low-affinity nerve growth factor receptor, tumour necrosis factor (TNF) receptors, the B-cell activation antigen CD40, and the Fas antigen. Although the function of CD27 has not been defined, several experimental observations support the notion that this molecule plays an important role in the process of T-cell activation. In this paper, we have demonstrated that a rapid hyperphosphorylation of CD27 is induced by a cyclic AMP-inducing agent, forskolin, and a membrane-permeable cAMP analogue, 8-bromo-cAMP, as well as phorbol 12-myristate 13-acetate (PMA). In addition, increased phosphorylation of CD27 in T-cell activation either via CD2 or CD3 pathways was strongly suppressed by a cyclic nucleotide-dependent kinase inhibitor, H-8, but only slightly by a protein kinase C inhibitor, staurosporine. These results suggest that protein kinase A might be a key kinase responsible for CD27 phosphorylation in the process of T-cell activation. CD27 is the first T-cell surface antigen demonstrated to be phosphorylated by the cyclic AMP-protein kinase A-mediated pathway.
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PMID:Protein kinase A-mediated phosphorylation of the T-cell surface antigen CD27. 826 50

Nerve growth factor (NGF) treatment of PC12 cells activates a protein kinase that phosphorylates c-Fos protein at a site near its C terminus, as well as a peptide corresponding to a C-terminal region of c-Fos (Taylor, L. K., Marshak, D. R., and Landreth, G. E. (1993) Proc. Natl. Acad. Sci. U. S. A. 90, 368-372). This serine/threonine kinase, termed Fos kinase, has been purified > 24,000-fold through five column steps to near homogeneity and is shown to be a 37-kDa protein as determined by SDS-polyacrylamide gel electrophoresis (PAGE) with a pI = 6.0. Fos kinase is distinguishable from previously characterized NGF-regulated kinases by its chromatographic behavior, its response to specific kinase inhibitors, and its substrate specificity. The concentration of NGF required to activate Fos kinase is consistent with signaling from the high affinity NGF receptor. Fos kinase phosphorylates c-Fos at its C terminus as indicated by competitive inhibition with a peptide corresponding to C-terminal phosphorylation sites and lack of phosphorylation of a C-terminal deletion mutant of c-Fos. Hyperphosphorylation of c-Fos in vivo, as detected by reduced electrophoretic mobility of c-Fos, is induced by the same ligands which activate Fos kinase. Moreover, Fos kinase phosphorylation of c-Fos in vitro results in a similar electrophoretic mobility shift, demonstrating that Fos kinase may be responsible for growth factor-stimulated alterations in mobility on SDS-PAGE and phosphorylation of this transcription factor. The ability of this unique growth factor-responsive kinase to phosphorylate c-Fos at its C terminus, a region essential for the transrepressive properties of c-Fos, suggests that Fos kinase may play a role in the regulation of the transcriptional repressive activity of c-Fos.
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PMID:Isolation and characterization of a nerve growth factor-regulated Fos kinase from PC12 cells. 827 12

The neuron-like differentiation of PC12 cells is induced by nerve growth factor (NGF) through stimulation of a membrane-bound protooncoprotein signaling pathway containing the NGF receptor Trk, the tyrosine kinase Src, and the GTP-binding protein Ras. The Raf-1 and B-raf protooncogenes encode cytoplasmic serine/threonine kinases that are stimulated by NGF in a Ras-dependent manner. To investigate the possible roles of cytoplasmic Raf kinases in eliciting neuronal differentiation, we have expressed the activated Raf-1 oncogene in PC12 cells. Expression of the raf oncogene results in the elaboration of a neuron-like phenotype, including neurite growth and the induction of the NGF-responsive genes NGFI-A and transin. The actions of activated Raf-1 and NGF are not additive. Furthermore, activated Raf-1 oncoprotein can prime cells for transcription-independent neurite growth by NGF and can elicit rapid neurite growth from NGF-primed cells. Our data indicate that the pathways utilized by NGF and activated raf to effect PC12 differentiation overlap and lead to the suggestion that cellular raf kinase activities play significant roles in transducing the differentiating signals of neuronal growth factors.
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PMID:The cytoplasmic raf oncogene induces a neuronal phenotype in PC12 cells: a potential role for cellular raf kinases in neuronal growth factor signal transduction. 838 63

The effects of a series of protein kinase inhibitors on nerve growth factor (NGF)-dependent and NGF-independent neurite outgrowth in PC12 cells have established an ordered relationship among those protein kinases sensitive to down regulation by bryostatin, stimulation by staurosporine, inhibition by sphingosine, or inhibition by 6-thioguanine (6-TG). Quantitation of the biphasic staurosporine effects on NGF-induced neurite outgrowth (Hashimoto and Hagino: J Neurochem 53:1675-1685, 1989) gave an IC50 of 2-4 nM for inhibition and an EC50 of 15-20 nM for induction of neurite extension. Both sphingosine and 6-TG inhibited neurite outgrowth induced by staurosporine and basic fibroblast derived growth factor (bFGF), as well as by NGF; therefore, sphingosine- and 6-TG-sensitive protein kinase steps occur after the convergence of the NGF, bFGF, and staurosporine signal pathways. Down regulation of protein kinase C by bryostatin chronic treatment, which inhibits NGF- and bFGF-induced neuritogenesis (Singh et al.: Biochemistry 33:542-551, 1994), did not inhibit the staurosporine-induced neurite outgrowth. Thus, the bryostatin-sensitive protein kinase C must occur subsequent to the convergence of the bFGF and NGF pathways, but before (or parallel to) staurosporine initiation of neurite outgrowth. In contrast, low concentrations of phorbol myristoyl acetate (PMA) or bryostatin, which activate protein kinase C activity, enhanced the staurosporine- or NGF-induced neurite extension. These data indicate that stimulation of one or more protein kinase C isozymes can synergistically interact with the signaling pathway to increase the rate of neuritogenesis. Inhibition by 5-7.5 nM staurosporine acted rapidly to arrest and decrease development of neurites up to 24 hr after NGF treatment, as did K252a and NGF polyclonal antibody addition. Our cellular data support the concept that staurosporine acts to inhibit the NGF receptor Trk (Nye et al.: Mol Biol Cell 3:677-686, 1992), but that downstream steps can be activated by the higher concentration of staurosporine to bypass Trk and lead to neurite generation. Effects of staurosporine, 6-TG, and sphingosine on c-fos gene induction with or without NGF were not correlated with the generation of neurites. The sequence of protein kinases sensitive to these effectors appears to be in the order (but not consecutive) bryostatin, staurosporine, sphingosine, and 6-TG.
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PMID:Hierarchical analysis of the nerve growth factor-dependent and nerve growth factor-independent differentiation signaling pathways in PC12 cells with protein kinase inhibitors. 856 21

The role of the low affinity nerve growth factor receptor (p75(NGFR)) in NGF-mediated signaling is not yet understood. Here we show by co-immunoprecipitation that NGF activates a protein kinase that is directly associated with p75(NGFR) in dorsal root ganglion (DRG) cells and PC12 cells in culture. Two proteins of 120 and 104 kDa constitute the majority of this activity. In PC12 cells, TrkA activation was necessary to elicit p75(NGFR)-associated kinase activity. Although NGF binding to p75(NGFR) was not necessary for kinase activation, it accelerated the activation of the kinase at low NGF concentrations. Deletion analysis showed that a 43 amino acid region in the cytoplasmic domain of p75(NGFR) was responsible for this effect. These findings show that p75(NGFR) accelerates TrkA-mediated signaling and, in addition, demonstrate that p75NGFR and TrkA collaborate to activate a previously undescribed p75(NGFR)-associated protein kinase.
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PMID:p75(NGFR) and TrkA receptors collaborate to rapidly activate a p75(NGFR)-associated protein kinase. 869 38

Suramin is a polysulfonated naphthylurea with demonstrated antineoplastic activity. Toxicity includes adrenal insufficiency and peripheral neuropathy. Although the mechanism of antitumor activity is unknown, inhibition of binding of growth factors to their receptors has been suggested. Growth factors inhibited by suramin include platelet-derived growth factor, fibroblast growth factor, transforming growth factor, epidermal growth factor, insulin-like growth factor, and nerve growth factor (NGF). In these studies, suramin was shown to be cytotoxic to PC12 cells in a dose-dependent manner. At lower doses and in surviving cells, we observed the induction of neurite outgrowth. To determine the mechanism of suramin-induced neurite outgrowth, PC12 cells were exposed to suramin and/or NGF for various time periods and treated cells were analyzed, by western blot analysis, for expression of tyrosine phosphoproteins. There was a similarity in the pattern of tyrosine-phosphorylated proteins in PC12 cells stimulated with suramin or NGF. Of particular interest was the rapid phosphorylation (by 1 min) of the high-affinity NGF (TrkA) receptor. Activation of other members of the signal-transduction cascade (Shc, p21ras, Raf-1, ERK-1) revealed similar phosphorylation levels induced by suramin and NGF. Parallel studies were performed in rat dorsal root ganglion cultures; suramin potentiated neurite outgrowth and activated the NGF receptor on these cells. This finding of specific patterns of tyrosine phosphorylation of cellular proteins in response to suramin treatment demonstrated that suramin is a partial agonist for the NGF receptor in both PC12 cells and dorsal root ganglion neurons.
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PMID:Suramin induces phosphorylation of the high-affinity nerve growth factor receptor in PC12 cells and dorsal root ganglion neurons. 876 55

Previous studies have shown that the ceramide analogue, D-threo-1-phenyl-2-decanoylamin-3-morpholino-propanol (D-PDMP), inhibits glucosylceramide synthase and thus leads to extensive depletion of glycosphingolipids derived from glucosyl ceramide. Our previous studies have shown that cholera toxin B subunit, which specifically binds to the cell surface ganglioside GM1, and GM1 itself can enhance the action of nerve growth factor (NGF) in responsive cells by enhancing the NGF-induced autophosphorylation of the high affinity NGF receptor, Trk. Using D-PDMP, we examined the effects of the inhibition of the biosynthesis of glycosphingolipids on intracellular NGF signaling pathway. D-PDMP was found to inhibit NGF-induced neurite outgrowth of PC12 cells. Moreover, D-PDMP clearly inhibited NGF-induced autophosphorylation of Trk and prevented the activation of phosphatidylinositol 3-kinase and mitogen-activated protein kinase, downstream targets of Trk-initiated intracellular protein kinase cascades. These effects of D-PDMP were abolished by the addition of GM1 but not by the addition of other ganglioside subspecies to the culture medium. Furthermore, the effect of D-PDMP seemed to be specific for the Trk receptor, because intracellular signaling pathway of epidermal growth factor was not affected by D-PDMP. Dimethylsphingosine and the cell-permeable analogue, C2-ceramide, did not show such a strong inhibitory effect on neurite outgrowth or on the autophosphorylation of Trk. The present results and our previous observations clearly demonstrate that Trk requires endogenous gangliosides, especially GM1, for its normal function in mediating the neurotrophic activity of NGF at least in PC12 cells.
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PMID:Glucosylceramide synthase inhibitor inhibits the action of nerve growth factor in PC12 cells. 974 78

SH2-B has been shown to be required for nerve growth factor (NGF)-mediated neuronal differentiation and survival, associate with NGF receptor TrkA, and be tyrosyl-phosphorylated in response to NGF. In this work, we examined whether NGF stimulates phosphorylation of SH2-B on serines/threonines. NGF promotes a dramatic upward shift in mobility of SH2-B, resulting in multiple forms that cannot be attributed to tyrosyl phosphorylation. Treatment of SH2-B with protein phosphatase 2A, a serine/threonine phosphatase, reduces the many forms to two. PD98059, a MEK inhibitor, dramatically inhibits NGF-promoted phosphorylation of SH2-B on serines/threonines, whereas depletion of 4beta-phorbol 12-myristate 13-acetate-sensitive protein kinase Cs does not. ERKs 1 and 2 phosphorylate SH2-Bbeta primarily on Ser-96 in vitro. However, NGF still stimulates serine/threonine phosphorylation of SH2-Bbeta(S96A). SH2-Bbeta(S96A), like wild-type SH2-Bbeta, enhances NGF-induced neurite outgrowth. In contrast, SH2-Bbeta(R555E) containing a defective SH2 domain blocks NGF-induced neurite outgrowth and displays greatly reduced phosphorylation on serines/threonines in response to NGF. SH2-Bbeta(R555E), like wild-type SH2-Bbeta, associates with the plasma membrane, suggesting that the dominant negative effect of SH2-Bbeta(R555E) cannot be explained by an abnormal subcellular distribution. In summary, NGF stimulates phosphorylation of SH2-B on serines/threonines by kinases downstream of MEK, which may be important for NGF-mediated neuronal differentiation and survival.
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PMID:SH2-B, a membrane-associated adapter, is phosphorylated on multiple serines/threonines in response to nerve growth factor by kinases within the MEK/ERK cascade. 1047 9


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