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 have examined the expression of A-kinase anchoring protein (AKAP) in the three major salivary glands, i.e. the parotid gland (PG), submandibular gland (SMG), and sublingual gland (SLG), of the rat to elucidate the functional relevance between saliva secretion and Na(+),K(+)-ATPase regulation by protein kinase A (PKA)-dependent phosphorylation, since an AKAP subtype, AKAP-150, is known to be involved in the regulation of the ATPase in PG. Although AKAP-150 and its mRNA were clearly detected in the PG, they were hardly detectable in either the SMG or SLG. The membrane-bound form of the RII regulatory subunit of PKA, an index for the total amount of AKAP subtypes and therefore of the anchored PKA holoenzyme, was also undetectable in membranes from the SMG and SLG but was found in the PG; though a substantial and comparable amount of Na(+),K(+)-ATPase was present in all of these membrane preparations. Incubation with [gamma-32P]ATP revealed that Na(+),K(+)-ATPase in the PG membranes was quickly phosphorylated upon the addition of cAMP, whereas the ATPases in the membranes from SMG and SLG were not; though they were readily and equally phosphorylated by the exogenously added PKA catalytic subunit. AKAP-150 in the basolateral membranes of PG acinar cells was co-immunoprecipitated with RII by an anti-RII antiserum; and AKAP-150 and Na(+),K(+)-ATPase were immunohistochemically co-localized predominantly on the basolateral membranes, suggesting a possibility that the ATPase might directly interact with the AKAP to form an ATPase/AKAP/PKA complex or associate with the AKAP, such association being mediated via some scaffolding molecule. Expression of AKAP-150 and quick down-regulation of Na(+),K(+)-ATPase by AKAP-anchored PKA in response to cAMP elevation are characteristics specific to PG among the three major salivary glands, suggesting the presence of PG-specific regulatory mechanisms for saliva production/secretion.
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PMID:Specific expression of an A-kinase anchoring protein subtype, AKAP-150, and specific regulatory mechanism for Na(+),K(+)-ATPase via protein kinase A in the parotid gland among the three major salivary glands of the rat. 1282 66

Abnormalities in cell proliferation and intracellular signaling are features of inherited human and murine polycystic kidney diseases (PKD), regardless of the primary genetic defects. Loss of protein kinase A regulation of cell proliferation has been reported in the murine C57BL/6JCys1cpk-/- (cpk) model of autosomal recessive PKD. Qualitative differences in protein kinase A subunit distribution were observed between filter-grown cultures of noncystic- (C57BL/6J mice) and cystic cpk-derived principal cells. It was hypothesized that protein kinase A subunit distribution differences were mediated by differences in A-kinase anchoring protein (AKAP) expression, so expression of four AKAPs was examined in filter-grown cultures of primary murine cystic- and noncystic-derived principal cells. AKAP-KL expression was ambiguous, but mAKAP, AKAP95, and ezrin were expressed at expected molecular sizes and cellular locations in noncystic-derived cells. Perinuclear mAKAP and nuclear AKAP95 were distributed normally in cpk-derived cells. Expression of AKAP95 in cystic epithelium was diminished relative to controls, and ezrin expression was modestly decreased and abnormally distributed within a region near the apical surface. Qualitative differences were observed in ezrin location in response to medium change or stimulation with epidermal growth factor which suggested cell-specific differences may result from the cpk mutation or the abnormal epidermal growth factor receptor phenotype that characterizes PKD. Ezrin has been implicated in tubulogenesis, so altered ezrin expression or function could be disruptive. If PKD mutations that contribute to PKD pathogenesis are postulated to disrupt normal tubular development, perhaps the mechanism includes altered ezrin function and abnormal protein kinase A targeting.
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PMID:Ezrin distribution is abnormal in principal cells from a murine model of autosomal recessive polycystic kidney disease. 1284 Jan 61

The precise mechanism by which the hormone-induced minimal cAMP levels act at the mitochondria to activate cholesterol transport and steroid synthesis is unknown. We propose that this mechanism involves a macromolecular signaling complex where a newly identified peripheral-type benzodiazepine receptor (PBR)-associated protein (PAP7) binds the regulatory subunit RIalpha of the cAMP-dependent protein kinase A (PKA), thus allowing for local efficient catalytic activation and phosphorylation of the substrate steroidogenesis acute regulatory protein (StAR), leading to cholesterol transfer from the low affinity StAR to the high affinity PBR cholesterol binding protein. The mouse and human PAP7 proteins were cloned, their genomic organization and chromosomal localization characterized, their tissue distribution evaluated and subcellular localization defined. PAP7 is highly expressed in steroidogenic tissues, where it follows the pattern of PKA-RIalpha expression and data from a human adrenal disease suggest that it participates in PKA-RIalpha-mediated tumorigenesis and hormone-independent hypercortisolism. PAP7 is localized in the Golgi and mitochondria and inhibition of PAP7 expression results in reduced hormone-induced cholesterol transport into mitochondria and decreased steroid formation. Taken together, these data suggest that PAP7 functions as an A-kinase anchoring protein (AKAP) critical in the cAMP-dependent steroid formation.
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PMID:PAP7, a PBR/PKA-RIalpha-associated protein: a new element in the relay of the hormonal induction of steroidogenesis. 1294 13

In boar spermatozoa, the capacitating agent bicarbonate has been shown to induce rapid changes both in plasma membrane lipid architecture and in motility; in each case, a PKA-dependent pathway is involved. Early bicarbonate-induced changes in protein phosphorylation were probed using a commercial antibody against the phosphorylated form of the consensus substrate site for cyclic AMP-dependent protein kinase. The antibody detected relatively few bands in sperm extracts, of which only a small number showed incubation-dependent changes. While the quantitative response varied between boar ejaculates, in general terms bicarbonate induced phosphorylation increases in bands of 96, 64, and 59 kDa within 80 sec. The changes reached a maximum after about 160 sec, declined somewhat thereafter, and then increased again slowly as incubation progressed further (up to 21 min). The bicarbonate-induced increases were strongly dependent on the presence of BSA in the incubation medium. They were inhibited by H89 (PKA inhibitor) but not by GF (PKC inhibitor), and were enhanced by papaverine (phosphodiesterase inhibitor) and by calyculin (protein phosphatase inhibitor). The cyclic AMP analogue cBIMPS was able to mimic bicarbonate action though its effect was less dramatic. Stearated Ht31, a permeable inhibitor of PKA's binding to A-kinase anchoring protein, did not affect either the intensity or the specificity of the bicarbonate-induced phosphorylation changes, though it blocked motility entirely. Immunocytochemical studies revealed marked bicarbonate-dependent phosphorylation changes in the post-acrosomal region of the head and in the neck, midpiece, and anterior regions of the tail. Fractionation of stimulated spermatozoa showed that all bands detectable with the antibody were bound to heads and to midpieces and associated large tail fragments; no bands were detected in either small tail or membrane fragments or in the cytoplasmic fraction. Differential extraction of the midpiece/large tail fraction revealed two protein bands with closely similar electrophoretic mobilities to the 96- and 59-kDa phosphorylated bands; MALDI-TOF analyses of these bands revealed both to be members of the Odf2 family.
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PMID:Rapid PKA-catalysed phosphorylation of boar sperm proteins induced by the capacitating agent bicarbonate. 1473 95

It was once believed that sperm protein 17 (Sp17) was expressed exclusively in the testis and that its sole function was to bind to the oocyte during fertilization. However, immunohistochemistry of the human respiratory airways and reproductive systems show that it is abundant in ciliated cells but not in human cells with stereocilia and microvilli. The high degree of sequence conservation throughout its N-terminal half, and the presence of an A-kinase anchoring protein (AKAP)-binding motif within this region, suggest that Sp17 plays a regulatory role in a PKA-independent AKAP complex in both male germinal and ciliated somatic cells.
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PMID:Sperm protein 17 is expressed in human somatic ciliated epithelia. 1503 7

A-kinase anchoring proteins (AKAPs) function to target protein kinase A (PKA) to specific locations within the cell. AKAPs are functionally identified by their ability to bind the type II regulatory subunits (RII) of PKA in an in vitro overlay assay. We previously showed that follicle-stimulating hormone (FSH) induces the expression of an 80-kDa AKAP (AKAP 80) in ovarian granulosa cells as they mature from a preantral to a preovulatory phenotype. In this report, we identify AKAP 80 as microtubule-associated protein 2D (MAP2D), a low molecular weight splice variant of the neuronal MAP2 protein. MAP2D is induced in granulosa cells by dexamethasone and by FSH in a time-dependent manner that mimics that of AKAP 80, and immunoprecipitation of MAP2D depletes extracts of AKAP 80. MAP2D is the only MAP2 protein present in ovaries and is localized to granulosa cells of preovulatory follicles and to luteal cells. MAP2D is concentrated at the Golgi apparatus along with RI and RII and, based on coimmunoprecipitation results, appears to bind both RI and RII in granulosa cells. Reduced expression of MAP2D resulting from treatment of granulosa cells with antisense oligonucleotides to MAP2 inhibited the phosphorylation of cAMP-response element-binding protein. These results suggest that this classic neuronal RII AKAP is a dual RI/RII AKAP that performs unique functions in ovarian granulosa cells that contribute to the preovulatory phenotype.
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PMID:Neuronal microtubule-associated protein 2D is a dual a-kinase anchoring protein expressed in rat ovarian granulosa cells. 1505 65

There is increasing evidence that subcellular targeting of signaling molecules is an important means of regulating the protein kinase A (PKA) pathway. Subcellular organization of the signaling molecules in the PKA pathway insures that a signal initiated at the receptor level is transferred efficiently to a PKA substrate eliciting some cellular response. This subcellular targeting appears to regulate the function of a highly specialized cell such as the cardiac myocyte. This review focuses on A-kinase anchoring proteins (AKAPs) which are expressed in the heart. It has been determined that, of the approximately 13 different AKAPs expressed in cardiac tissue, several of these are expressed in cardiac myocytes. These AKAPs bind several PKA substrates and some appear to regulate PKA-dependent phosphorylation of these substrates. AKAP tethering of PKA may be essential for efficient regulation of cardiac muscle contraction. The ability of an AKAP to anchor PKA may be altered in the failing heart, thus compromising the ability of the myocyte to respond to stimuli which elicit the PKA pathway.
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PMID:A-kinase anchoring protein targeting of protein kinase A in the heart. 1535 Aug 38

The transmission of cellular signals often proceeds through multiprotein complexes where enzymes are positioned in proximity to their upstream activators and downstream substrates. In this report we demonstrate that the A-kinase anchoring protein AKAP-Lbc assembles an activation complex for the lipid-dependent enzyme protein kinase D (PKD). Using a combination of biochemical, enzymatic, and immunofluorescence techniques, we show that the anchoring protein contributes to PKD activation in two ways: it recruits an upstream kinase PKCeta and coordinates PKA phosphorylation events that release activated protein kinase D. Thus, AKAP-Lbc synchronizes PKA and PKC activities in a manner that leads to the activation of a third kinase. This configuration illustrates the utility of kinase anchoring as a mechanism to constrain the action of broad-spectrum enzymes.
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PMID:AKAP-Lbc nucleates a protein kinase D activation scaffold. 1538 79

Communication between dopaminergic and glutamatergic synapses is critical for several functions related to cognition and emotion. Here, we examined whether dopamine receptor activity regulates phosphorylation and trafficking of the alpha-amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) receptor subunit, GluR1. We find treatment with a dopamine D1 receptor agonist enhanced GluR1 phosphorylation at Ser845, the PKA phosphorylation site, in both striatal and prefrontal cortical neurons. Enhanced phosphorylation of GluR1 also correlated with increased amounts of GluR1 on the cell surface. These effects were disrupted by expression of mutant forms of the A-kinase anchoring protein (AKAP79/150) and the postsynaptic density protein, PSD-95, that fail to target synaptic sites. Similar enhancement of the phosphorylation of GluR1 was observed in the nucleus accumbens upon stimulation of dopamine release in vivo using electrical stimulation of dopamine cell bodies in the ventral tegmental area. These results suggest in vivo stimulation of dopamine release directly influences AMPA receptor phosphorylation and together with in vitro data indicate that coupling of the AMPA receptor to AKAP79/150 and PSD-95 modulate this process.
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PMID:Modulation of dopamine mediated phosphorylation of AMPA receptors by PSD-95 and AKAP79/150. 1545 48

Using whole-cell patch-clamp methods, we examined the hypothesis that serotonin [5-hydroxytryptamine (5-HT)] receptor activation enhances TRPV1 function in mouse colon sensory neurons in lumbosacral dorsal root ganglia, which were identified by retrograde labeling with DiI (1,1'-dioctadecyl-3,3,3',3-tetramethlindocarbocyanine methanesulfonate) injected into multiple sites in the wall of the descending colon. 5-HT increased membrane excitability at a temperature below body temperature in response to thermal ramp stimuli in colon sensory neurons from wild-type mice, but not from TRPV1 knock-out mice. 5-HT significantly enhanced capsaicin-, heat-, and proton-evoked currents with an EC50 value of 2.2 microm. 5-HT (1 microm) significantly increased capsaicin-evoked (100 nm) and proton-evoked (pH 5.5) currents 1.6- and 4.7-fold, respectively, and significantly decreased the threshold temperature for heat current activation from 42 to 38 degrees C. The enhancement of TRPV1 by 5-HT was significantly attenuated by selective 5-HT2 and 5-HT4 receptor antagonists, but not by a 5-HT3 receptor antagonist. In support, 5-HT2 and 5-HT4 receptor agonists mimicked the facilitating effects of 5-HT on TRPV1 function. Downstream signaling required G-protein activation and phosphorylation as intracellularly administered GDP-beta-S [guanosine 5'-O-(2-thiodiphosphate], protein kinase A inhibitors, and an A-kinase anchoring protein inhibitor significantly blocked serotonergic facilitation of TRPV1 function; 5-HT2 receptor-mediated facilitation was also inhibited by a PKC inhibitor. We conclude that the facilitation of TRPV1 by metabotropic 5-HT receptor activation may contribute to hypersensitivity of primary afferent neurons in irritable bowel syndrome patients.
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PMID:TRPV1 function in mouse colon sensory neurons is enhanced by metabotropic 5-hydroxytryptamine receptor activation. 1550 39


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