Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.13 (protein kinase C)
 49,245 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptin is a versatile 16 kDa peptide hormone, with a tertiary structure resembling that of members of the long-chain helical cytokine family. It is mainly produced by adipocytes in proportion to fat size stores, and was originally thought to act only as a satiety factor. However, the ubiquitous distribution of OB-R leptin receptors in almost all tissues underlies the pleiotropism of leptin. OB-Rs belong to the class I cytokine receptor family, which is known to act through JAKs (Janus kinases) and STATs (signal transducers and activators of transcription). The OB-R gene is alternatively spliced to produce at least five isoforms. The full-length isoform, OB-Rb, contains intracellular motifs required for activation of the JAK/STAT signal transduction pathway, and is considered to be the functional receptor. Considerable evidence for systemic effects of leptin on body mass control, reproduction, angiogenesis, immunity, wound healing, bone remodelling and cardiovascular function, as well as on specific metabolic pathways, indicates that leptin operates both directly and indirectly to orchestrate complex pathophysiological processes. Consistent with leptin's pleiotropic role, its participation in and crosstalk with some of the main signalling pathways, including those involving insulin receptor substrates, phosphoinositide 3-kinase, protein kinase B, protein kinase C, extracellular-signal-regulated kinase, mitogen-activated protein kinases, phosphodiesterase, phospholipase C and nitric oxide, has been observed. The impact of leptin on several equally relevant signalling pathways extends also to Rho family GTPases in relation to the actin cytoskeleton, production of reactive oxygen species, stimulation of prostaglandins, binding to diacylglycerol kinase and catecholamine secretion, among others.
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PMID:Intracellular signalling pathways activated by leptin. 1633 96

Among the three G-protein-linked acetylcholine receptors (GARs) in Caenorhabditis elegans (C. elegans), GAR-3 is structurally and pharmacologically most similar to mammalian muscarinic acetylcholine receptors (mAChRs). Using Chinese hamster ovary (CHO) cells stably expressing GAR-3b, the major alternatively spliced isoform of GAR-3, we observed that carbachol stimulated cyclic AMP (cAMP) production in a dose- and time-dependent manner. The stimulating effect of carbachol was abolished by atropine, a muscarinic antagonist, indicating that the cAMP production is specifically mediated by GAR-3b. When the cells were treated with BAPTA-AM and EGTA, which reduce the cytosolic Ca(2+) level, carbachol-stimulated cAMP accumulation was inhibited by approximately 56%. Inhibition of protein kinase C (PKC) by chronic treatment with phorbol 12-myristate 13-acetate (PMA) or by GF109203X decreased carbachol-stimulated cAMP production by as much as 68%. It thus appears that Ca(2+) and PKC are critically involved in GAR-3b-mediated cAMP formation. We also observed that carbachol-stimulated cAMP production was further enhanced by pertussis toxin (PTX) treatment. This observation indicates that GAR-3b couples to a PTX-sensitive G protein, presumably Gi, to attenuate the cAMP accumulation. Taken together, our data show that GAR-3b stimulates cAMP production in CHO cells and suggest that GAR-3b couples to both stimulatory and inhibitory pathways to modulate the intracellular cAMP level.
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PMID:Stimulation of cyclic AMP production by the Caenorhabditis elegans muscarinic acetylcholine receptor GAR-3 in Chinese hamster ovary cells. 1663 94

Although they have distinct functions, the signaling of dopamine-D(2) receptor short and long isoforms (D(2)S and D(2)L) is virtually identical. We compared inhibitory regulation of extracellular signal-regulated kinases (ERK1/2) in GH4 pituitary cells separately transfected with these isoforms. Activation of rat or human dopamine-D(2)S, muscarinic or somatostatin receptors inhibited thyrotropin-releasing hormone-induced ERK1/2 phosphorylation, while the D(2)L receptor failed to inhibit this response. In order to address the structural basis for the differential signaling of D(2)S and D(2)L receptors, we examined the D(2)L-SS mutant, in which a protein kinase C (PKC) pseudosubstrate site that is present in the D(2)L but not D(2)S receptor was converted to a consensus PKC site. In transfected GH4 cells, the D(2)L-SS mutant inhibited thyrotropin-releasing hormone-induced ERK1/2 phosphorylation almost as strongly as the D(2)S receptor. A D(2)S-triple mutant that eliminates PKC sites involved in D(2)S receptor desensitization also inhibited ERK1/2 activation. Similarly, in striatal cultures, the D(2)-selective agonist quinpirole inhibited potassium-stimulated ERK1/2 phosphorylation, indicating the presence of this pathway in neurons. In conclusion, the D(2)S and D(2)L receptors differ in inhibitory signaling to ERK1/2 due to specific residues in the D(2)L receptor alternatively spliced domain, which may account for differences in their function in vivo.
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PMID:Differential signaling of dopamine-D2S and -D2L receptors to inhibit ERK1/2 phosphorylation. 1776 2

The striated muscle Z line, a multiprotein complex at the boundary between sarcomeres, plays an integral role in maintaining striated muscle structure and function. Multiple Z-line-associated proteins have been identified and shown to play an increasingly important role in the pathogenesis of human muscle disease. Cypher/Z-band alternatively spliced PDZ-motif protein, a PDZ-LIM protein in the Z line, binds to alpha-actinin (via its PDZ domain) and has been suggested to function as a linker-strut to maintain cytoskeletal structural integrity during contraction. Cypher may also participate in signaling pathways by binding to protein kinase C via its LIM domains. Analysis of Cypher-deficient mice has revealed that Cypher plays an integral role in Z-line maintenance/integrity of striated muscles and the pathogenesis of congenital myopathies, including cardiomyopathy. These studies have led to the subsequent discovery of Cypher mutations in human patients with dilated cardiomyopathy, hypertrophic cardiomyopathy, as well as skeletal muscle myopathies, which have been recently termed zaspopathies. The recent discovery of various alternatively spliced isoforms of Cypher with potentially distinct structural and signaling roles brings a different level of complexity to the mechanisms underlying Cypher-based human myopathies. This review will focus on recent developments on the role of Cypher and its isoforms in striated muscle structure, signaling, and disease to provide insights into the mechanisms involved in the pathogenesis of Z-line-associated human myopathies.
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PMID:"Z"eroing in on the role of Cypher in striated muscle function, signaling, and human disease. 1802 35

Calcitonin (CT) is a peptide hormone that is secreted by the parafollicular cells of the thyroid in response to elevated serum calcium levels. It acts to reduce serum calcium by inhibiting bone resorption and promoting renal calcium excretion. In addition to this hypocalcemie effect, calcitonin modulates the renal transport of water and several ions other than calcium and acts on the central nervous system to induce analgesia, anorexia, and gastric secretion. The CT receptor, a member of a newly described family of serpentine G protein-coupled receptors, has recently been shown to couple to multiple trimeric G proteins, thereby activating several signaling proteins, including protein kinase C, cAMP-dependent protein kinase and calcium/calmodulin-dependent protein kinase. In kidney proximal tubule cells (LLC-PK1), the CT-activated signaling mechanisms vary in a cell cycle-dependent manner, with the receptor coupling through a G(s) protein during G(2) phase and through a G(i) protein and possibly a G(q) protein during S phase. These signaling mechanisms differentially modulate the activities of Na(+)/K(+)-ATPase and the apical Na(+)/H(+) exchanger, effector molecules that play important roles in transepithelial Na(+) transport. Cloning of CT receptors has revealed the presence of alternatively spliced cassettes, resulting in the expression of different isoforms of the receptor. The availability of these recombinant CT receptors has allowed preliminary characterization of the effects of changes in the receptor's structure on its ligand binding and signal transduction properties. Thus, the cellular and molecular biology of CT is complex, with several structurally related peptide ligands and multiple isoforms of the CT receptor that can independently activate diverse signaling pathways. As the recent exciting results in this field are extended, we can expect rapid progress in understanding the molecular basis of the diverse effects of CT and, possibly, of the CT-related peptides CGRP and amylin.
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PMID:Signal transduction by calcitonin Multiple ligands, receptors, and signaling pathways. 1840 35

Three G-protein-linked acetylcholine receptors (GARs) exist in the nematode C. elegans. GAR-3 is pharmacologically most similar to mammalian muscarinic acetylcholine receptors (mAChRs). We observed that carbachol stimulated ERK1/2 activation in Chinese hamster ovary (CHO) cells stably expressing GAR-3b, the predominant alternatively spliced isoform of GAR-3. This effect was substantially reduced by the phospholipase C (PLC) inhibitor U73122 and the protein kinase C (PKC) inhibitor GF109203X, implying that PLC and PKC are involved in this process. On the other hand, GAR-3b-mediated ERK1/2 activation was inhibited by treatment with forskolin, an adenylate cyclase (AC) activator. This inhibitory effect was blocked by H89, an inhibitor of cAMP-dependent protein kinase A (PKA). These results suggest that GAR-3b-mediated ERK1/2 activation is negatively regulated by cAMP through PKA. Together our data show that GAR-3b mediates ERK1/2 activation in CHO cells and that GAR-3b can couple to both stimulatory and inhibitory pathways to modulate ERK1/2.
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PMID:Regulation of ERK1/2 by the C. elegans muscarinic acetylcholine receptor GAR-3 in Chinese hamster ovary cells. 1846 Sep 3

Vascular endothelial growth factor receptor-1/fms-related tyrosine kinase 1 (VEGFR-1/FLT1) is expressed as a membrane-bound receptor tyrosine kinase and as an alternatively spliced soluble protein (sVEGFR-1) containing the 1-6 IgG-like domain of its ectodomain. sVEGFR-1 is known as a naturally occurring inhibitor of angiogenesis and as a surrogate marker for cancer progression; it is also linked to pregnancy-induced hypertension called preeclampsia and to avascularity of normal cornea. It remains an open question whether alternative mRNA splicing is the only mechanism by which sVEGFR-1 is generated. In this study, we show that in leukemic cancer cells, PlGF and VEGF-A both induce tyrosine phosphorylation of VEGFR-1 and render it susceptible to ectodomain shedding, resulting in the generation of sVEGFR-1 and an intracellular cytoplasmic fragment. Activation of protein kinase C and tumor necrosis factor-alpha-converting enzyme family metalloproteases are critically required for the occurrence of sVEGFR-1. Following the removal of the ectodomain, the remnant of VEGFR-1 remains attached to the membrane, and the activity of gamma-secretase/presenilin is required for its release from the cell membrane. We propose that sVEGFR-1 produced via ectodomain shedding plays a prominent role in the VEGF receptor system by antagonizing VEGF receptor signaling by acting as a dominant-negative form and/or forming a nonsignaling dimerizing complex with VEGF receptors.
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PMID:Identification of ligand-induced proteolytic cleavage and ectodomain shedding of VEGFR-1/FLT1 in leukemic cancer cells. 1927 74

Tenascin-C (Tnc) is transiently expressed during neural development. Within its alternatively spliced fibronectin type III (TNfn) -motifs the TNfnD domain is crucial for a neurite outgrowth-promoting region that is recognized by the GPI-linked adhesion molecule of the Ig-superfamily contactin. In order to understand the downstream signaling mechanisms, embryonic day E18 rat hippocampal neurons were cultivated on TNfnBD-containing and control substrates in the presence of various inhibitors. As predicted, axon outgrowth promotion could be suppressed by antibodies to the TNfnD domain, to contactin, or to the beta1-integrin subunit. The chelators BAPTA/AM or EGTA as well as blockade of membrane-based calcium channels or of the release of calcium from intracellular stores reduced axon growth to control levels. The inhibition of phospholipase C and its downstream targets protein kinase C or calmodulin kinase likewise blocked outgrowth promotion. We propose that TNfnBD stimulates the outgrowth of hippocampal neurons by activating calcium- and phospholipase C-depending pathways. Digital video microscopy studies revealed that increase of fiber length was caused by an augmentation of growth cone velocity.
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PMID:Tenascin-C stimulates contactin-dependent neurite outgrowth via activation of phospholipase C. 1939 29

Kv4.3, with its complex open- and closed-state inactivation (CSI) characteristics, is a primary contributor to early cardiac repolarization. The two alternatively spliced forms, Kv4.3-short (Kv4.3-S) and Kv4.3-long (Kv4.3-L), differ by the presence of a 19-amino acid insert downstream from the sixth transmembrane segment. The isoforms are similar kinetically; however, the longer form has a unique PKC phosphorylation site. To test the possibility that inactivation is differentially regulated by phosphorylation, we expressed the Kv4.3 isoforms in Xenopus oocytes and examined changes in their inactivation properties after stimulation of PKC activity. Whereas there was no difference in open-state inactivation, there were profound differences in CSI. In Kv4.3-S, PMA reduced the magnitude of CSI by 24% after 14.4 s at -50 mV. In contrast, the magnitude of CSI in Kv4.3-L increased by 25% under the same conditions. Mutation of a putatively phosphorylated threonine (T504) to aspartic acid within a PKC consensus recognition sequence unique to Kv4.3-L eliminated the PMA response. The change in CSI was independent of the intervention used to increase PKC activity; identical results were obtained with either PMA or injected purified PKC. Our previously published 11-state model closely simulated our experimental data. Our data demonstrate isoform-specific regulation of CSI by PKC in Kv4.3 and show that the carboxy terminus of Kv4.3 plays an important role in regulation of CSI.
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PMID:Closed-state inactivation in Kv4.3 isoforms is differentially modulated by protein kinase C. 1967 5

Recent studies have identified two alternatively spliced forms of the GABA(A) receptor gamma(2) subunit that differ by the presence (gamma(2L)) or absence (gamma(2S)) of an eight-amino acid segment. This insert in the gamma(2L) isoform exists in the proposed cytoplasmic loop region, between M3 and M4, and contains a consensus sequence for phosphorylation by protein kinase C. To examine the regional distribution of this novel receptor subunit in the brain, gamma(2L) subunit mRNA was detected using both in situ hybridization histochemistry and and PCR amplification methods. Hybridization histochemistry with a gamma(2L), subunit-specific oligonucleotide probe revealed that the gamma(2L), subunit mRNA is widely distributed throughout the mouse brain. The highest levels of expression are found in the cerebral cortex, hippocampus, olfactory lobe, and cerebellum. The presence of the gamma(2L), subunit in these regions was confirmed using PCR. Additionally, PCR experiments detected yes subunit mRNA in the cerebral cortex and hippocampus but not in the cerebellum. To examine the functional properties of the gamma(2) subunit isoforms, gamma(2S) and gamma(2L), subunit mRNAs were coexpressed with alpha(1)beta(1) subunit mRNAs in Xenopus oocytes. These experiments indicate that the gamma(2L) and gamma(2S) subunit variants exhibit similar pharmacological properties, including the ability of both isoforms to confer diazepam sensitivity to the receptor complex. In addition, potentiation of GABA responses by pentobarbital in oocytes expressing either subunit isoform is similar. These data indicate that the presence or absence of the additional eight amino acids in the gamma(2) subunit isoforms does not appear to alter the response of the GABA(A) receptor complex to either benzodiazepines and barbiturates at the level of protein phosphorylation present in the oocyte.
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PMID:Localization and functional expression of alternatively spliced forms of the GABA(A) receptor gamma(2) subunit. 1991 17


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