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)

We describe here two types of apoptotic cell death observed in the rat CNS-derived neuroblastoma B50 and B104 cells. One type was induced by dibutyryl cyclic AMP (DBcAMP) after differentiation, and the other was induced by treatment of proliferating cells with cycloheximide. When B50 and B104 cells were treated with 1 mM DBcAMP in the presence of 0.5% fetal calf serum, they began to extend neurites within 12 h and differentiated into neurons at 24 h, as reported previously. However, further cultivation with DBcAMP for up to 72 h led to flotation and, finally, death. Death was by apoptosis as shown by chromatin condensation and DNA fragmentation. Addition of a protein kinase A inhibitor or removal of DBcAMP after differentiation suppressed apoptosis, indicating the involvement of cyclic AMP and protein kinase A in apoptotic cell death. Cell death was also induced in proliferating cells without neurite outgrowth by treatment with cycloheximide. The death was also judged to be by apoptosis based on chromatin condensation and apoptotic body formation, although DNA fragmentation into small sizes was not detected. Both types of cell death showed similar responses to inhibitors for protein kinases and protein phosphatases.
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PMID:Two types of apoptotic cell death of rat central nervous system-derived neuroblastoma B50 and B104 cells: apoptosis induced during proliferation and after differentiation. 886 90

Calcium vector protein target (CaVPT), a 26-kDa endogenous target of calcium vector protein from Amphioxus (CaVP), contains three distinct regions: a N-terminal Pro-Ala-Lys-rich motif, segment 36-50 displaying sequence similarity to the calmodulin-binding site in neuromodulin and neurogranin where they are designated as the IQ domain; and two immunoglobulin-like folds. The phosphorylation by protein kinase C of Ser-43 in the IQ domain drastically decreases the affinity of CaVPT for CaVP and CaVP protects CaVPT from phosphorylation. Phosphorylation by the catalytic subunit of cyclic AMP-dependent protein kinase has a similar effect, but in addition to Ser-43 four other phosphorylated sites were identified. Removal of the Pro-Ala-Lys-rich region and the IQ domain in CaVPT by trypsin leads to the loss of binding to CaVP, whereas the chymotryptic fragment, containing these regions and first immunoglobulin-like domain, retained the ability to interact with CaVP. A synthetic IQ domain alone interacts strongly with calmodulin, but not with CaVP. Two main conclusions can be drawn from this study: 1) the regulation of interaction between CaVP and CaVPT is very similar to the mechanism observed in the complex between neuromodulin or neurogranin and calmodulin; 2) in spite of this similarity the entire CaVP-binding site is not restricted to the IQ domain; in addition the Pro-Ala-Lys-rich motif may be necessary for high affinity binding to CaVP.
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PMID:Phosphorylation of the IQ domain regulates the interaction between Ca2+-vector protein and its target in Amphioxus. 890 Jan 39

Recent evidence, including our previous work, indicates that changes in both c-AMP and phospholipid-dependent protein kinases (PKA and PKC) may be involved in neuroadaptive mechanisms occurring in brain after repeated administration of antidepressants. The purpose of this study was to examine the phosphorylation of a major PKC substrate involved in modulation of neurotransmitter release, GAP-43, in a synaptosomal preparation from rat cerebral cortex after repeated administration of fluxetine (FL) and desipramine (DMI). Groups of male rats were treated for 21 days with either FL (5 mg/kg/day, i.p.), DMI (10 mg/kg/day, i.p.) or vehicle (controls) and cortical synaptosomes were prepared 48 h or 24 h after the last injection. Synaptosomal membrane proteins were resolved by SDS-PAGE. Western immunoblotting and immunoprecipitation with anti-GAP-43 antibody have identified the GAP-43 protein as a single distinct band of apparent molecular weight of 56 kDa. The extent of phosphorylation of GAP-43 protein by native PKC in synaptosomes of rats treated with either FL or DMI was not significantly different from that observed in control animals. The previously observed suppression of basal PKC activity in rat cortical synaptosomes by FL and DMI treatment was thus not reflected in altered GAP-43 phosphorylation. It is thus unlikely that changes in GAP-43 phosphorylation are involved in antidepressant-induced modulation of 5-HT release.
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PMID:GAP-43 phosphorylation by PKC in rat cerebrocortical synaptosomes: effect of antidepressants. 917 63

The growth-associated protein B-50 (GAP-43) is a presynaptic protein. Its expression is largely restricted to the nervous system. B-50 is frequently used as a marker for sprouting, because it is located in growth cones, maximally expressed during nervous system development and re-induced in injured and regenerating neural tissues. The B-50 gene is highly conserved during evolution. The B-50 gene contains two promoters and three exons which specify functional domains of the protein. The first exon encoding the 1-10 sequence, harbors the palmitoylation site for attachment to the axolemma and the minimal domain for interaction with G0 protein. The second exon contains the "GAP module", including the calmodulin binding and the protein kinase C phosphorylation domain which is shared by the family of IQ proteins. Downstream sequences of the second and non-coding sequences in the third exon encode species variability. The third exon also contains a conserved domain for phosphorylation by casein kinase II. Functional interference experiments using antisense oligonucleotides or antibodies, have shown inhibition of neurite outgrowth and neurotransmitter release. Overexpression of B-50 in cells or transgenic mice results in excessive sprouting. The various interactions, specified by the structural domains, are thought to underlie the role of B-50 in synaptic plasticity, participating in membrane extension during neuritogenesis, in neurotransmitter release and long-term potentiation. Apparently, B-50 null-mutant mice do not display gross phenotypic changes of the nervous system, although the B-50 deletion affects neuronal pathfinding and reduces postnatal survival. The experimental evidence suggests that neuronal morphology and communication are critically modulated by, but not absolutely dependent on, (enhanced) B-50 presence.
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PMID:B-50, the growth associated protein-43: modulation of cell morphology and communication in the nervous system. 944 16

Casein kinase II (CKII) phosphorylates the rat neuronal growth-associated protein B-50 (GAP-43) at serines 191/192 and threonines 88, 89 and/or 95 both in vitro and in neuronal growth cones. Since little is known concerning regulation of the phosphorylation of these sites, these studies were undertaken to characterize the factors which determine the degree of B-50 phosphorylation by CKII in vitro. Phosphorylation of rat B-50 on serine and threonine residues by recombinant human CKII is stimulated by polylysine. Maximal stimulation occurs at 10 microg/ml of polylysine, a concentration which has no effect on protein kinase C (PKC)-mediated phosphorylation of B-50. Digestion with Staphylococcus aureus V8 protease demonstrates CKII-mediated phosphorylation of B-501-132 and the C-terminal fragment S3/S4. Phosphorylation of B-50 by either CKII or PKC is inhibited by the N-terminal monoclonal antibody NM2, while the C-terminal antibody NM6 has no effect on phosphorylation by either protein kinase. Protein phosphatase 2A dephosphorylates both the CKII and PKC sites, while protein phosphatases 2B and 1 are more selective for the PKC site. These results indicate that the phosphorylations of B-50 by CKII and PKC are determined by distinct regulatory signals in vivo.
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PMID:Regulation of in vitro phosphorylation of the casein kinase II sites in B-50 (GAP-43). 950 76

Although purinergic compounds are widely involved in the intra- and intercellular communication of the nervous system, little is known of their involvement in the growth and regeneration of neuronal connections. In dissociated cultures, the addition of adenosine or guanosine in the low micromolar range induced goldfish retinal ganglion cells to extend lengthy neurites and express the growth-associated protein GAP-43. These effects were highly specific and did not reflect conversion of the nucleosides to their nucleotide derivatives; pyrimidines, purine nucleotides, and membrane-permeable, nonhydrolyzable cyclic nucleotide analogs were all inactive. The activity of adenosine required its conversion to inosine, because inhibitors of adenosine deaminase rendered adenosine inactive. Exogenously applied inosine and guanosine act directly upon an intracellular target, which may coincide with a kinase described in PC12 cells. In support of this, the effects of the purine nucleosides were blocked with purine transport inhibitors and were inhibited competitively with the purine analog 6-thioguanine (6-TG). In PC12 cells, others have shown that 6-TG blocks nerve growth factor-induced neurite outgrowth and selectively inhibits the activity of protein kinase N, a partially characterized, nerve growth factor-inducible serine-threonine kinase. In both goldfish and rat retinal ganglion cells, 6-TG completely blocked outgrowth induced by other growth factors, and this inhibition was reversed with inosine. These results suggest that axon outgrowth in central nervous system neurons critically involves an intracellular purine-sensitive mechanism.
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PMID:Axon outgrowth is regulated by an intracellular purine-sensitive mechanism in retinal ganglion cells. 979 72

Evidence is accumulating that suggests that Ca2+-calmodulin (Ca2+-CaM) and the protein kinase Cs (PKCs) obstruct each other's actions because of the embedding of PKC phosphorylation sites in CaM or Ca2+-CaM-binding domains of a growing number of crucial substrates in neurons (and other cells). These substrates include the CaM storage proteins (neurogranin, neuromodulin), the membrane-associated MARCKS (myristoylated alanine-rich C-kinase substrate) protein, the NMDA receptor RI subunit and the autoinhibitory domain of the plasma membrane Ca2+ pump. In this review, the emerging data are woven into a hypothetical picture of the conflicting, timing-dependent convergence of two major signalers on neuronal functions.
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PMID:Ca2+-calmodulin and protein kinase Cs: a hypothetical synthesis of their conflicting convergences on shared substrate domains. 1008 94

To examine the role of protein kinase A (EC 2.7.1.37) isozymes in the retinoic acid-induced growth inhibition and neuronal differentiation, we investigated the changes of protein kinase A isozyme patterns in retinoic acid-treated SH-SY5Y human neuroblastoma cells. Retinoic acid induced growth inhibition and neuronal differentiation of SH-SY5Y cells in a dose- and time-dependent manner. Neuronal differentiation was evidenced by extensive neurite outgrowth, decrease of N-Myc oncoprotein, and increase of GAP-43 mRNA. Type II protein kinase A activity increased by 1.5-fold in differentiated SH-SY5Y cells by retinoic acid treatment. The increase of type II protein kinase A was due to the increase of RIIbeta and Calpha subunits. Since type II protein kinase A and RIIbeta have been known to play important role(s) in the growth inhibition and differentiation of cancer cells, we further investigated the role of the increased type II protein kinase A by overexpressing RIIbeta in SH-SY5Y cells. The growth of RIIbeta-overexpressing cells was slower than that of parental cells, being comparable to that of retinoic acid-treated cells. Retinoic acid treatment further increased the RIIbeta level and further inhibited the growth of RIIbeta-overexpressing cells, showing strong correlation between the level of RIIbeta and growth inhibition. However, RIIbeta-overexpressing cells did not show any sign of neuronal differentiation and responded to retinoic acid in the same way as parental cells. These data suggest that protein kinase A participates in the retinoic acid-induced growth inhibition through the up-regulation of RIIbeta/type II protein kinase A.
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PMID:Participation of type II protein kinase A in the retinoic acid-induced growth inhibition of SH-SY5Y human neuroblastoma cells. 1065 9

In lower vertebrates, retinal ganglion cells (RGCs) can regenerate their axons and reestablish functional connections after optic nerve injury. We show here that in goldfish RGCs, the effects of several trophic factors converge on a purine-sensitive signaling mechanism that controls axonal outgrowth and the expression of multiple growth-associated proteins. In culture, goldfish RGCs regenerate their axons in response to two molecules secreted by optic nerve glia, axogenesis factor-1 (AF-1) and AF-2, along with ciliary neurotrophic factor. The purine analog 6-thioguanine (6-TG) blocked outgrowth induced by each of these factors. Previous studies in PC12 cells have shown that the effects of 6-TG on neurite outgrowth may be mediated via inhibition of a 47 kDa protein kinase. Growth factor-induced axogenesis in RGCs was accompanied by many of the molecular changes that characterize regenerative growth in vivo, e.g. , increased expression of GAP-43 and certain cell surface glycoproteins. 6-TG inhibited all of these changes but not those associated with axotomy per se, e.g., induction of jun family transcription factors, nor did it affect cell survival. Additional studies using RGCs from transgenic zebrafish showed that expression of Talpha-1 tubulin is likewise stimulated by AF-1 and blocked by 6-TG. The purine nucleoside inosine had effects opposite to those of 6-TG. Inosine stimulated outgrowth and the characteristic pattern of molecular changes in RGCs and competitively reversed the inhibitory effects of 6-TG. We conclude that axon regeneration and the underlying program of gene expression in goldfish RGCs are mediated via a common, purine-sensitive pathway.
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PMID:A purine-sensitive pathway regulates multiple genes involved in axon regeneration in goldfish retinal ganglion cells. 1105 Jan 24

The membrane phosphoprotein GAP-43 is involved in axon growth and synaptic plasticity. In PC12 pheochromocytoma cells, induction of a neuronal phenotype by nerve growth factor (NGF) is accompanied by a marked increase in GAP-43 levels. NGF regulates GAP-43 expression by altering the half-life of its mRNA. We report here that the phosphoprotein ARPP-19 mediates this regulation. In an NGF-dependent manner, ARPP-19 bound to a region in the 3' end of GAP-43 mRNA previously found to be important for regulating the half-life of the mRNA. Overexpression of wild-type ARPP-19 in PC12 cells increased the NGF-dependent expression of a reporter construct linked to the critical 3' region of GAP-43 mRNA. Mutation of serine 104, the site of phosphorylation by protein kinase A in ARPP-19, to either alanine or aspartate abolished this regulation in PC12 cells. These findings demonstrate that ARPP-19 is an important link between NGF signaling and post-transcriptional control of neuronal gene expression.
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PMID:Nerve growth factor controls GAP-43 mRNA stability via the phosphoprotein ARPP-19. 1222 Dec 79


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