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)

Dietary sugars regulate expression of the intestinal Na+/glucose cotransporter, SGLT1, in many species. Using sheep intestine as a model, we showed that lumenal monosaccharides, both metabolisable and nonmetabolisable, regulate SGLT1 expression. This regulation occurs not only at the level of transcription, but also at the post-transcriptional level. Introduction of d-glucose and some d-glucose analogues into ruminant sheep intestine resulted in > 50-fold enhancement of SGLT1 expression. We aimed to determine if transport of sugar into the enterocytes is required for SGLT1 induction, and delineate the signal-transduction pathways involved. A membrane impermeable d-glucose analogue, di(glucos-6-yl)poly(ethylene glycol) 600, was synthesized and infused into the intestines of ruminant sheep. SGLT1 expression was determined using transport studies, Northern and Western blotting, and immunohistochemistry. An intestinal cell line, STC-1, was used to investigate the signalling pathways. Intestinal infusion with di(glucos-6-yl)poly(ethylene glycol) 600 led to induction of functional SGLT1, but the compound did not inhibit Na+/glucose transport into intestinal brush-border membrane vesicles. Studies using cells showed that increased medium glucose up-regulated SGLT1 abundance and SGLT1 promoter activity, and increased intracellular cAMP levels. Glucose-induced activation of the SGLT1 promoter was mimicked by the protein kinase A (PKA) agonist, 8Br-cAMP, and was inhibited by H-89, a PKA inhibitor. Pertussis toxin, a G-protein (Gi)-specific inhibitor, enhanced SGLT1 protein abundance to levels observed in response to glucose or 8Br-cAMP. We conclude that lumenal glucose is sensed by a glucose sensor, distinct from SGLT1, residing on the external face of the lumenal membrane. The glucose sensor initiates a signalling pathway, involving a G-protein-coupled receptor linked to a cAMP-PKA pathway resulting in enhancement of SGLT1 expression.
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PMID:Glucose sensing in the intestinal epithelium. 1289 95

Recent work shows that the G-protein-coupled receptor proteinase activated receptor-2 activates signals that stimulate melanosome uptake in keratinocytes in vivo and in vitro. The Rho family of GTP-binding proteins is involved in cytoskeletal remodeling during phagocytosis. We show that proteinase-activated receptor-2 mediated phagocytosis in human keratinocytes is Rho dependent and that proteinase-activated receptor-2 signals to activate Rho. In contrast, Rho activity did not affect either proteinase-activated receptor-2 activity or mRNA and protein levels. We explored the signaling mechanisms of proteinase-activated receptor-2 mediated Rho activation in human keratinocytes and show that activation of proteinase-activated receptor-2, either through specific proteinase-activated receptor-2 activating peptides or through trypsinization, elevates cAMP in keratinocytes. Proteinase-activated receptor-2 mediated Rho activation was pertussis toxin insensitive and independent of the protein kinase A signaling pathway. These data are the first to show that proteinase-activated receptor-2 mediated phagocytosis is Rho dependent and that proteinase-activated receptor-2 signals to Rho and cAMP in keratinocytes. Because phagocytosis of melanosomes is recognized as an important mechanism for melanosome transfer to keratinocytes, these results suggest that Rho is a critical signaling intermediate in melanosome uptake in keratinocytes.
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PMID:The proteinase-activated receptor-2 mediates phagocytosis in a Rho-dependent manner in human keratinocytes. 1292 12

One of the consequences of G-protein-coupled receptor activation is stimulation of phosphoinositol metabolism, leading to the generation of IP3 and its metabolites 1,3,4,5-tetrakisphosphate (IP4) and inositol 1,2,3,4,5,6-hexakisphosphate (IP6). Previous reports indicate that high inositol polyphosphates (IP4 and IP6) are involved in clathrin-coated vesicular recycling. In this study, we examined the effects of IP4 and IP6 on spontaneous transmitter release in the form of miniature endplate potentials (MEPP) and on enhanced vesicular recycling by high K+ at frog motor nerve endings. In resting conditions, IP4 and IP6 delivered intracellularly via liposomes, caused concentration-dependent increases in MEPP frequency and amplitude. Pretreatment with the protein kinase A (PKA) inhibitor H-89 or KT 5720 reduced the IP4-mediated MEPP frequency increase by 60% and abolished the IP6-mediated MEPP frequency increases as well as the enhancement in MEPP amplitude. Pretreatment with antibodies against phosphatidylinositol 3-kinase (PI 3-K), enzyme also associated with clathrin-coated vesicular recycling, did not alter the IP4 and IP6-mediated MEPP frequency increases, but reduced the MEPP amplitude increase by 50%. In our previous reports, IP3, but not other second messengers releasing Ca2+ from internal Ca2+ stores, is able to enhance the MEPP amplitude. In order to dissociate the effect of Ca2+ release vs. metabolism to IP4 and IP6, we evaluated the effects of 3-deoxy-3-fluoro-inositol 1,4,5-trisphosphate (3F-IP3), which is not converted to IP4 or IP6. 3F-IP3 produced an increase then decrease in MEPP frequency and a decrease in MEPP amplitude. In elevated vesicle recycling induced by high K+-Ringer solution, IP4 and IP6 have similar effects, except decreasing MEPP frequency at a higher concentration (10(-4) M). We conclude that (1) high inositol polyphosphates may represent a link between IP3 and cAMP pathways; (2) the IP3-induced increase of MEPP amplitude is likely to be due to its high inositol metabolites; (3) PI 3-K is not involved in the IP4 and IP6-mediated MEPP frequency increases, but may be involved in MEPP size.
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PMID:Inositol derivatives modulate spontaneous transmitter release at the frog neuromuscular junction. 1294 82

Regulation of vascular smooth muscle cell contractile state is critical for the maintenance of blood vessel tone. Abnormal vascular smooth muscle cell contractility plays an important role in the pathogenesis of hypertension, blood vessel spasm, and atherosclerosis. Myosin phosphatase, the key enzyme controlling myosin light chain dephosphorylation, regulates smooth muscle cell contraction. Vasoconstrictor and vasodilator pathways inhibit and activate myosin phosphatase, respectively. G-protein-coupled receptor agonists can inhibit myosin phosphatase and cause smooth muscle cell contraction by activating RhoA/Rho kinase, whereas NO/cGMP can activate myosin phosphatase and cause smooth muscle cell relaxation by activation of cGMP-dependent protein kinase. We have used yeast two-hybrid screening to identify a 116-kDa human protein that interacts with both myosin phosphatase and RhoA. This myosin phosphatase-RhoA interacting protein, or M-RIP, is highly homologous to murine p116RIP3, is expressed in vascular smooth muscle, and is localized to actin myofilaments. M-RIP binds directly to the myosin binding subunit of myosin phosphatase in vivo in vascular smooth muscle cells by an interaction between coiled-coil and leucine zipper domains in the two proteins. An adjacent domain of M-RIP directly binds RhoA in a nucleotide-independent manner. M-RIP copurifies with RhoA and Rho kinase, colocalizes on actin stress fibers with RhoA and MBS, and is associated with Rho kinase activity in vascular smooth muscle cells. M-RIP can assemble a complex containing both RhoA and MBS, suggesting that M-RIP may play a role in myosin phosphatase regulation by RhoA.
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PMID:Myosin phosphatase-Rho interacting protein. A new member of the myosin phosphatase complex that directly binds RhoA. 1450 64

3-Phosphoinositide-dependent protein kinase 1 (PDK1) is a signal integrator that activates the AGC superfamily of serine/threonine kinases. PDK1 is phosphorylated on tyrosine by oxidants, although its regulation by agonists that stimulate G-protein-coupled receptor signaling pathways and the physiological consequences of tyrosine phosphorylation in this setting have not been fully identified. We found that angiotensin II stimulates the tyrosine phosphorylation of PDK1 in vascular smooth muscle in a calcium- and c-Src-dependent manner. The calcium-activated tyrosine kinase Pyk2 acts as a scaffold for Src-dependent phosphorylation of PDK1 on Tyr9, which permits phosphorylation of Tyr373 and -376 by Src. This critical function of Pyk2 is further supported by the observation that Pyk2 and tyrosine-phosphorylated PDK1 colocalize in focal adhesions after angiotensin II stimulation. Importantly, infection of smooth muscle cells with a Tyr9 mutant of PDK1 inhibits angiotensin II-induced tyrosine phosphorylation of paxillin and focal adhesion formation. These observations identify a novel interaction between PDK1 and Pyk2 that regulates the integrity of focal adhesions, which are major compartments for integrating signals for cell growth, apoptosis, and migration.
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PMID:Pyk2- and Src-dependent tyrosine phosphorylation of PDK1 regulates focal adhesions. 1458 63

Sensing nutrients is a fundamental task for all living cells. For most eukaryotic cells glucose is a major source of energy, having significant and varied effects on cell function. Interest in identifying mechanisms by which cells sense and respond to variations in glucose concentration has increased recently. The epithelial cells lining the intestinal tract are exposed, from the luminal domain, to an environment with continuous and massive fluctuations in the levels of dietary monosaccharides. Enterocytes therefore have to sense and respond to the significant changes in the levels of luminal sugars, and regulate the expression of the intestinal glucose transporter (Na+/glucose co-transporter, SGLT1) accordingly. Our data, using a combination of in vivo and in vitro model systems, suggest that glucose in the lumen of the intestine is sensed by a glucose sensor residing on the external face of the enterocyte luminal membrane. Glucose binds to the sensor and generates an intracellular signal leading to enhancement in the expression of SGLT1. The generated signal is independent of glucose metabolism and is likely to operate via a G-protein-coupled receptor and cAMP/protein kinase A signalling cascade.
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PMID:Mechanism of glucose sensing in the small intestine. 1464 Oct 13

Ras proteins mediate the proliferative effects of G-protein-coupled receptors (GPCRs), but the role of Rap proteins in GPCR signaling is unclear. We have developed a novel cellular proliferation assay for examining signal transduction to Rap utilizing Ras-rap chimeras that respond selectively to Rap-specific exchange factors, but which stimulate cellular proliferation through Ras effectors. Both the D1 dopamine receptor (Gs-coupled) and the 5HT1E serotonin receptor (Gi-coupled) mediated cellular proliferation in a Ras/rap chimera-dependent manner. Responses to both receptors were PKA-independent. Both receptors activated Ras/rap and full-length Rap as measured by activation-specific probes. Pertussis toxin blocked Ras/rap-dependent responses to 5HT1E but not D1. Ras/rap-dependent responses to both receptors were insensitive to beta-gamma scavengers. Responses to 5HT1E, but not D1, were sensitive to inhibition by a dominant-negative C3G fragment, by the Src-like kinase inhibitors PP1 and PP2, and by a dominant-negative mutant of Src. Very similar data were obtained for two other Gi-coupled receptors, the D2 dopamine receptor and the alpha2C adrenergic receptor. A constitutively active mutant of Galphai2 also mediated Ras/rap-dependent responses. These data indicate that GPCRs coupled to pertussis-toxin-sensitive G-proteins activate Rap through a Galpha subunit, C3G, and Src-dependent pathway.
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PMID:G-protein-coupled receptor-mediated activation of rap GTPases: characterization of a novel Galphai regulated pathway. 1471 29

Thromboxane A2 receptors (TPs) are widely distributed among different organ systems and have been localized on both cell membranes and intracellular structures. Following the initial cloning of this receptor class from human placenta, the deduced amino acid sequence predicted seven-transmembrane spanning regions, four extracellular domains and four intracellular domains, making TP a member of the seven-transmembrane G-protein-coupled receptor (GPCR) super family. A single gene on chromosome 19p13.3 leads to the expression of two separate TP isoforms: TPalpha which is broadly expressed in numerous tissues, and a splice variant termed TPbeta which may have a more limited tissue distribution. Mutagenesis, photoaffinity labelling, and immunological studies have indicated that the ligand binding domains for this receptor may reside in both the transmembrane (TM) and extracellular regions of the receptor protein. In addition, separate studies have provided evidence that this receptor can couple to at least four separate G protein families. As a consequence, TP signalling has been shown to result in a broad range of cellular responses including phosphoinositide metabolism, calcium redistribution, cytoskeletal arrangement, integrin activation, kinase activation, and the subsequent nuclear signalling events involved in DNA synthesis, cell proliferation, cell survival and cell death. While activation of these different signalling cascades can all derive from TP stimulation, the relative signalling preference for a given cascade appears to be both tissue and cell specific. Finally, separate studies have indicated that TP signalling capacity can be both down-regulated by protein kinase activation and up-regulated by GPCR cross-signalling. Thus, the multitude of signalling events which derive from TP activation can themselves be modulated by endogenous cellular messengers.
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PMID:Cell signalling through thromboxane A2 receptors. 1475 39

The giant glial cell in the neuropil of segmental ganglia of the leech Hirudo medicinalis responds to the activity of the Leydig interneuron and to a peptide of the myomodulin family, the presumed transmitter mediating the Leydig neuron-to-giant glial cell transmission, with a membrane hyperpolarization due to an increased membrane K+ conductance [Britz et al. (2002) Glia, 38, 215-227]. We have now studied the second messenger cascade initiated by Leydig neuron stimulation and by the endogenous myomodulin (MMHir) in the voltage-clamped giant glial cell. Glial responses to both stimuli are mediated by a G-protein-coupled receptor linked to adenylyl cyclase by the following criteria: (i) injection of GDP-beta-S, but not GDP, resulted in an irreversible decrease of the glial responses to both stimuli; (ii) the responses to both stimuli were reversibly inhibited by the adenylyl cyclase inhibitor SQ22,536; and (3) bath-applied di-butyryl-cyclic AMP, but not di-butyryl-cyclic GMP, elicited an outward current, which reduced the responses elicited by neuronal stimulation or myomodulin. A cocktail of protein kinase (PK) inhibitors (H-8, KT5720), the PKA antagonist Rp-cAMPS, or presumed inhibitors of cyclic nucleotide channels, LY83583 and l-cis-diltiazem, had no effect on the glial responses. Our results suggest that Leydig neuron stimulation and MMHir activate a cAMP-mediated K+ conductance in the glial cell, which appeared neither to be due to the activation of PKA nor of known cyclic nucleotide-gated channels directly.
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PMID:Second messenger cascade of glial responses evoked by interneuron activity and by a myomodulin peptide in the leech central nervous system. 1500 46

There are several lines of evidence showing that synaptic activity regulates the level of expression of inositol 1,4,5-trisphosphate receptor type 1 (IP3R1) in neurons. In this study, we examined the effect of chronic activity blockade on the localization and level of IP3R1 expression in cultured hippocampal neurons. We found that chronic blockade of NMDA receptors (NMDARs), one of the major Ca(2+)-permeable ion channels, increased the number of neurons that express a high level of IP3R1 without any apparent changes in its intracellular localization. Interestingly, this up-regulation was time-dependent; there was no clear change in IP3R1 expression level up to day 5 of the NMDAR blockade, but expression increased at day 6, and the increased expression level persisted for at least a week. The up-regulation of IP3R1 depended on transcription and protein synthesis and required cAMP-dependent protein kinase activity. Moreover, although most of the control neurons did not respond to the metabotropic glutamate receptor (mGluR) stimulation, the 2-amino-5-phosphonopentanoic acid-treated neurons with high IP3R1 expression became sensitive to mGluR stimulation. Furthermore, we also found that hippocampal neurons transiently overexpressing green fluorescent protein-tagged IP3R1 released Ca2+ in response to mGluR and muscarinic acetylcholine receptor stimulation. These findings suggested that chronic NMDAR blockade increased the IP3R1 expression and enhanced sensitivity to mGluR stimulation. The change in IP3R1 expression level in response to alteration of synaptic activity may be an important determinant of the sensitivity of Ca2+ stores to G-protein-coupled receptor stimulation and would help to maintain intracellular Ca2+ homeostasis in hippocampal neurons.
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PMID:Activity-dependent expression of inositol 1,4,5-trisphosphate receptor type 1 in hippocampal neurons. 1501 4


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