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)

Posttranslational processing of the pro-growth hormone-releasing hormone (proGHRH) peptide can result in the formation of at least two peptide products: GHRH and the C-terminal peptide, GHRH-related peptide (GHRH-RP). While cyclic adenosine monophosphate transduces many of the actions of GHRH, other pathways also have been implicated in its actions. The aims of this study were to examine and characterize the activation of mitogen-activated protein kinase (MAPK) pathways by GHRH, and GHRH-RP in pituitary-derived GH3 cells, as well as the activation of the transcription factors that serve as substrates for these kinases. GHRH rapidly increased p44/p42 MAPK activity in GH3 cells in a protein kinase A-dependent and a protein kinase C-independent manner and stimulated the activation of the transcription factor Elk-1. By contrast, GHRH-RP and p75-92NH2 had no effect on p44/p42 MAPK phosphorylation in these cells. Additionally, we determined that all three peptides, GHRH, GHRH-RP, and p75-92NH2, rapidly and specifically increase phosphorylation of p38 MAPK and stimulate the activation of the nuclear factor CHOP. These are the first studies to demonstrate the activation of Elk-1 by GHRH and the activation of p38 MAPK and CHOP by GHRH, GHRH-RP, and p75-92NH2. We conclude that members of the GHRH family of peptides differentially activate multiple intracellular signaling pathways and suggest that the biologic actions of GHRH may be far more diverse than previously thought.
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PMID:Peptides derived from pro-growth hormone-releasing hormone activate p38 mitogen-activated protein kinase in GH3 pituitary cells. 1157 18

Phosphorylation of yeast 6-phosphofructo-2-kinase and its role for the regulation of glycolysis under hypoosmotic conditions were investigated. 6-Phosphofructo-2-kinase was found to be phosphorylated in vitro by protein kinase C at serine 652 and thereby inactivated. Protein phosphatase 2A reversed the phosphorylative inhibition of the enzyme. When yeast cells were shifted to hypotonic media, 6-phosphofructo-2-kinase was found to be phosphorylated and inactivated. Under in vivo conditions, two phosphate residues were incorporated into the enzyme. One of them is bound to serine 652, indicating that this modification was probably caused by yeast protein kinase C1. The second phosphate is bound to Ser8 within the N-terminal peptide T(1-41) which contains several serine residues but no protein kinase C recognition sequence. Site-directed mutagenesis confirmed that the phosphorylation of serine 652 but not the N-terminal modification is responsible for the in vivo inactivation of 6-phosphofructo-2-kinase. The obtained results suggest that the phosphorylation of 6-phosphofructo-2-kinase mediates a response of the cells to an activation of the hypoosmolarity MAP kinase pathway. Via a suppression of glycolysis, the inactivation of 6-phosphofructo-2-kinase is expected to be responsible for the observed accumulation of glucose 6-phosphate, an essential precursor of the cell wall glucans, and the decrease of glycerol, an important osmolyte.
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PMID:Phosphorylation and inactivation of yeast 6-phosphofructo-2-kinase contribute to the regulation of glycolysis under hypotonic stress. 1172 81

Two cDNAs encoding frog aquaporin (AQP) were cloned from a cDNA library constructed for the ventral skin of the tree frog, Hyla japonica and sequenced. One AQP (Hyla AQP-h1) consisted of 271 amino-acid residues with high homology to toad AQP-t1, Rana CHIP28 (AQP1), and rat AQP1. The other AQP (AQP-h3) consisted of 271 amino-acid residues with higher homology to mammalian AQP2 than to mammalian AQP3. The predicted amino-acid sequence contained the conserved two NPA motifs found in all MIP family members and the putative six transmembrane domains. The sequence also confers mercurial sensitivity, which is common to all the AQPs except AQP0, AQP4 and AQP7. Potential N-glycosylation sites were present at Asn-44 in AQP-h1, and at Asn-124 and Asn-125 in AQP-h3. In addition, AQP-h3 had a putative phosphorylation site by protein kinase A at Ser-255, which is identical to mammalian AQP2. In swelling assays using Xenopus oocytes, AQP-h1 facilitates water permeability, whereas AQP-h3 displayed weak water permeability. Searching for the expression of these two AQP mRNAs revealed that AQP-h1 was expressed in most tissues, whereas AQP-h3 was observed only in the ventral skin. An antibody (ST-141) against the C-terminal peptide of the AQP-h3 protein recognized a 29.0 kDa-protein with a molecular mass close to that of the Hyla AQP-h3 protein and immunostained predominantly in the abdominal pelvic skin. In pelvic skin, the label for AQP-h3 was more intense in the upper layer of the stratum granulosum and was localized to both the apical and basolateral plasma membranes of the principal cells. These findings suggest that Hyla AQP-h3 plays a pivotal role in constitutively absorbing water from ventral pelvic skin.
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PMID:Molecular and cellular characterization of a water-channel protein, AQP-h3, specifically expressed in the frog ventral skin. 1217 46

The movement protein (MP) of Tomato mosaic virus (ToMV) was reported previously by us to be phosphorylated in vitro by a cellular protein kinase(s) that exhibited several characteristics of casein kinase 2 (CK2). To characterize further this CK2-like cellular kinase, we have cloned cDNAs encoding the CK2 catalytic subunit from tobacco and compared the properties of the recombinant protein with those of the CK2-like cellular kinase. The recombinant CK2 catalytic subunit formed a complex with ToMV MP and phosphorylated it, similar to the CK2-like cellular kinase. Phosphoamino acid analyses of various mutant MPs altered near the C terminus revealed that the recombinant CK2 catalytic subunit phosphorylated serine-261, while the CK2-like cellular kinase phosphorylated both serine-261 and threonine-256. Both kinases were suggested to phosphorylate an additional serine residue(s) in regions other than the C-terminal peptide. The results are consistent with our previous prediction of involvement of CK2 in phosphorylation of ToMV MP.
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PMID:The catalytic subunit of protein kinase CK2 phosphorylates in vitro the movement protein of Tomato mosaic virus. 1256 May 84

The conserved C-terminal peptide motif (1476DTRL) of the cystic fibrosis transmembrane conductance regulator (CFTR) ensures high affinity binding to different PSD-95/Disc-large/zonula occludens-1 (PDZ) domain-containing molecules, including the Na+/H+ exchanger regulatory factor (NHERF)/ezrin-radixin-moesin-binding phosphoprotein of 50 kDa. The physiological relevance of NHERF binding to CFTR is not fully understood. Individuals with mutations resulting in premature termination of CFTR (S1455X or Delta26 CFTR) have moderately elevated sweat Cl- concentration, without an obvious lung and pancreatic phenotype, implying that the CFTR function is largely preserved. Surprisingly, when expressed heterologously, the Delta26 mutation was reported to abrogate channel activity by destabilizing the protein at the apical domain and inducing its accumulation at the basolateral membrane (Moyer, B., Denton, J., Karlson, K., Reynolds, D., Wang, S., Mickle, J., Milewski, M., Cutting, G., Guggino, W., Li, M., and Stanton, B. (1999) J. Clin. Invest. 104, 1353-1361). The goals of this study were to resolve the contrasting clinical and cellular phenotype of the Delta26 CFTR mutation and evaluate the role of NHERF in the functional expression of CFTR at the plasma membrane. Complex formation between CFTR and NHERF was disrupted by C-terminal deletions, C-terminal epitope tag attachments, or overexpression of a dominant negative NHERF mutant. These perturbations did not alter CFTR expression, metabolic stability, or function in nonpolarized cells. Likewise, inhibition of NHERF binding had no discernible effect on the apical localization of CFTR in polarized tracheal, pancreatic, intestinal, and kidney epithelia and did not influence the metabolic stability or the cAMP-dependent protein kinase-activated chloride channel conductance in polarized pancreatic epithelia. On the other hand, electrophysiological studies demonstrated that NHERF is able to stimulate the cAMP-dependent protein kinase-phosphorylated CFTR channel activity in intact cells. These results help to reconcile the discordant genotype-phenotype relationship in individuals with C-terminal truncations and indicate that apical localization of CFTR involves sorting signals other than the C-terminal 26 amino acid residues and the PDZ-binding motif in differentiated epithelia.
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PMID:The role of the C terminus and Na+/H+ exchanger regulatory factor in the functional expression of cystic fibrosis transmembrane conductance regulator in nonpolarized cells and epithelia. 1265 58

Microtubule-associated protein-2 (MAP2) is a brain specific A-kinase anchoring protein that targets the cyclic AMP-dependent protein kinase holoenzyme (PKA) to microtubules. Phosphorylation of MAP2 by different protein kinases is crucial for neuronal growth. The N-terminus of MAP2 contains the binding site for regulatory subunit II of cAMP-dependent protein kinase (PKA-RIIbeta). Using homologous recombination, we created a mutant line of mice (delta1-158) that express truncated MAP2 lacking the N-terminal peptide and the PKA binding site. Deletion of the PKA binding site from the MAP2 gene resulted in decreased efficiency of MAP2 phosphorylation. Biochemical and immunohistochemical studies demonstrate major changes in the morphology of hippocampal neurons in delta1-158 mice. Behavioral tests indicate that delta1-158 mice were impaired (exhibited less conditioned freezing) relative to Wild-Type (WT) controls during a test of contextual, but not during auditory cue, fear conditioning when tested at 8 weeks or 8 months of age. The delta1-158 mice displayed a heightened sensitivity to shock at 8 weeks, but not at 8 months of age. We conclude that PKA binding to MAP2 and MAP2 phosphorylation is essential for the selective development of contextual memory.
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PMID:Deletion of the N-terminus of murine map2 by gene targeting disrupts hippocampal ca1 neuron architecture and alters contextual memory. 1276 72

Parathyroid hormone-related protein (PTHrP) is secreted by skin epithelial cells and is thought to play an important role in the development and function of the hair follicle. It was hypothesized that PTHrP binds to receptors in dermal papilla cells and modulates intracellular signaling systems in these cells. We tested the effects of PTHrP on protein synthesis, protein kinase A (PKA) and protein kinase C (PKC) activities as well as tyrosine phosphorylation in rat vibrissa dermal papilla and capsular fibroblast cells. Cells were cultured in the presence or absence of the N-terminal peptide PTHrP1-34 for 48 h and detergent extracts prepared. Proteins were separated by electrophoresis. Phosphotyrosine and the PTH/PTHrP receptor immunoreactivity was identified by Western blot analysis. PKC and PKA activities in the cells were measured using colorimetric enzyme assays. Extracts of both dermal papilla cells and capsular fibroblasts displayed immunoreactivity to the PTH/PTHrP receptor. Electrophoresis showed that PTHrP treatment reduced the density of a 50-kDa protein in dermal papilla cells but not in capsular fibroblasts. Media conditioned by the cells showed similar changes, indicating that the PTHrP-modulated 50-kDa protein was secreted. Furthermore, 2-D gel electrophoresis indicated that the protein had a number of phosphorylation sites. Western analysis with antiphosphotyrosine antibodies confirmed a significant decrease in the intensity of a phosphorylated 50-kDa protein in papilla cells and papilla cell-conditioned medium. PKC and PKA activities of papilla cells were unaffected by PTHrP. However, activities of PKC were increased and PKA reduced in capsular fibroblasts following peptide treatment. These cell-specific effects showed that endogenous PTHrP may activate different intracellular pathways in mesenchymal cells of skin and elicit changes in levels of locally secreted proteins that specifically modulate normal follicular function.
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PMID:Parathyroid hormone-related peptide modulates signal pathways in skin and hair follicle cells. 1293 Feb 94

The present study for the first time evaluated both the in vitro and in vivo phosphorylation regions of bone sialoprotein (BSP) by utilizing multiple approaches and techniques. The in vitro phosphorylation sites were determined by 32P-labeling of native BSP using purified casein kinase II (CKII), followed by peptide mapping and solid-phase N-terminal sequence analyses. The in vivo phosphorylation sites were determined by (i) derivatization with 1-S-[14C]carboxymethyl-dithiothreitol ([14C] CM-DTT) of the proteolytic digests of BSP, followed by isolation and N-terminal peptide sequence analysis; and (ii) analyzing the proteolytic peptides of native BSP using matrix-assisted laser desorption/ionization-time of flight-mass spectrometry (MALDI-TOF-MS). Native BSP incorporated approximately 2.5 mol of phosphate/mol of BSP by CKII, which were distributed over four major peptide peaks and three shoulder peaks within the peptide map with varying degrees of phosphorylation. Further studies using the [14C] CM-DTT thiol reagent indicated that native and deglycosylated BSP incorporated 5.84 and 5.80 mol of 14C/mol of BSP, respectively. This confirmed that there were approximately 5.8 mol P-Ser/mol of BSP naturally (in vivo) occurring phosphorylation sites and that there was no overlap between the phosphorylation and glycosylation sites. The 5.8 mol P-Ser/mol BSP reflects the total number of mols of naturally occurring phosphorylation, phosphorylated in vivo by CKII (4.1 mol), protein kinase C (0.9 mol), and cGMP-dependent kinase (0.8 mol). Peptide N-terminal sequence analyses of both in vitro (32P) and in vivo (14C) phosphorylated peptides indicated that the phosphorylated residues were predominantly on the N-terminal half of the protein that included recognition sequences for CKII, e.g., LESDEENGVFK (residues 12-22).
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PMID:In vivo and in vitro phosphorylation regions of bone sialoprotein. 1295 2

Bone sialoprotein (BSP) is a multifunctional, highly phosphorylated, and glycosylated protein with key roles in biomineralization and tissue remodeling. This work identifies the complete topographical distribution and precise location of both the in vitro and in vivo phosphorylation sites of bovine BSP by a combination of state-of-the-art techniques and approaches. In vitro phosphorylation of native and deglycosylated BSPs by casein kinase II identified seven phosphorylation sites by solid-phase N-terminal peptide sequencing that were within peptides 12-22 (LEDS(P)EENGVFK), 42-62 (FAVQSSSDSS(P)EENGNGDS(P)S(P)EE), 80-91 (EDS(P)DENEDEES(P)E), and 135-145 (EDES(P)DEEEEEE). The in vivo phosphorylation regions and sites were identified by use of a novel thiol reagent, 1-S-mono[(14)C]carboxymethyldithiothreitol. This approach identified all of the phosphopeptides defined by in vitro phosphorylation, but two additional phosphopeptides were defined at residues, 250-264 (DNGYEIYES(P)ENGDPR), and 282-289 (GYDS(P)YDGQ). Furthermore, use of native BSP and matrix-assisted laser desorption ionization time-of-flight mass spectrometry identified several of the above peptides, including an additional phosphopeptide at residues 125-130 (AGAT(P)GK) that was not defined in either of the in vitro and in vivo studies described above. Overall, 7 in vitro and 11 in vivo phosphorylation sites were identified unequivocally, with natural variation in the quantitative extent of phosphorylation at each in vivo phosphorylation site.
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PMID:Complete topographical distribution of both the in vivo and in vitro phosphorylation sites of bone sialoprotein and their biological implications. 1500 24

Two [NiFe] hydrogenases enable the proteobacterium Ralstonia eutropha H16 to grow on molecular hydrogen as the sole energy source. A third [NiFe] hydrogenase (RH) acts as an H2 sensor in a multiple component signal transduction chain that controls hydrogenase gene transcription. The RH forms a dimeric heterodimer (HoxBC)2 in which HoxC contains the H2-sensing active site and HoxB the electron-transferring components including an organic, not yet identified redox cofactor. This oligomer forms a tight complex with the histidine protein kinase HoxJ. Both the sensor and the kinase were analysed by mutagenesis for functional domains that are instrumental in H2 signal transmission. A mutant deleted for a C-terminal peptide of 55 amino acids in HoxB lost its H2-sensing ability but still catalysed H2 oxidation. The mutant protein failed to form the dimeric heterodimer and a complex with HoxJ. The organic redox cofactor was no longer detectable in the truncated sensor. H2 sensing was also abolished by deletion of the PAS domain of HoxJ, indicating that this domain is involved in signal transduction. A truncated version of HoxJ consisting of only the input domain of the kinase was still capable of forming a complex with the RH. Mass determination of the purified HoxJ protein revealed that the kinase forms a homotetramer. The unique oligomeric structure of the H2-sensing complex with respect to its regulatory function is discussed.
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PMID:The H2-sensing complex of Ralstonia eutropha: interaction between a regulatory [NiFe] hydrogenase and a histidine protein kinase. 1500 94


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