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)

In eukaryotic cells, the SH2 and PTB domains mediate protein-protein interactions by recognizing phosphotyrosine residues on target proteins. Here we make the unexpected finding that the C2 domain of PKCdelta directly binds to phosphotyrosine peptides in a sequence-specific manner. We provide evidence that this domain mediates PKCdelta interaction with a Src binding glycoprotein, CDCP1. The crystal structure of the PKCdelta C2 domain in complex with an optimal phosphopeptide reveals a new mode of phosphotyrosine binding in which the phosphotyrosine moiety forms a ring-stacking interaction with a histidine residue of the C2 domain. This is also the first example of a protein Ser/Thr kinase containing a domain that binds phosphotyrosine.
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PMID:The C2 domain of PKCdelta is a phosphotyrosine binding domain. 1585 Oct 22

Prepro-vasoactive intestinal peptide (VIP) mRNA codes for two neuropeptides: VIP and peptide histidine isoleucine (PHI). Two VIP receptors, shared with a similar affinity by pituitary adenylate cyclase-activating polypeptide (PACAP), have been cloned: VPAC(1) and VPAC(2). PHI binds to these receptors with a lower affinity. VPAC receptors are classically associated with a cAMP-dependent pathway, although other pathways, including calcium mobilization and protein kinase C activation have been described. We previously showed that intracerebral administration of the glutamate agonist ibotenate to postnatal day 5 mice induces white matter lesions mimicking human periventricular leukomalacia. In this model, coinjection of VIP protects against white matter lesions. This neuroprotection is independent from cAMP and is mediated by protein kinase C. Using this model, this study aimed to determine the receptor involved in VIP-induced neuroprotection. VIP effects were mimicked with a similar potency by VPAC(2) agonists and PHI but not by VPAC(1) agonists, PACAP 27, or PACAP 38. VIP neuroprotective effects were lost in mice lacking VPAC(2) receptor. In situ hybridization confirmed the presence of VPAC(2) mRNA in the postnatal day 5 white matter. When analyzed between embryonic life and adulthood, VIP-specific binding site density peaked at postnatal day 5. These data suggest that, in this model, VIP-induced neuroprotection is mediated by VPAC(2) receptors. The pharmacology of this VPAC(2) receptor seems unconventional because 1) PACAP does not mimic VIP effects, 2) PHI acts with a comparable potency, and 3) PACAP 27 modestly inhibited the VIP-specific binding, whereas for PHI or VIP, inhibition was complete.
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PMID:VPAC2 receptors mediate vasoactive intestinal peptide-induced neuroprotection against neonatal excitotoxic brain lesions in mice. 1587 42

Previous studies performed at our laboratory have shown that agonist-induced contraction of smooth muscle is associated with translocation of protein kinase C (PKC)-alpha and RhoA to the membrane and that this interaction is due to a direct protein-protein interaction. To determine the domains of PKC-alpha involved in direct interaction with RhoA, His-tagged PKC-alpha proteins of individual domains and different combinations of PKC-alpha domains were used to perform in vitro binding assays with the fusion protein glutathione-S-transferase (GST)-RhoA. Coimmunoprecipitation was also performed using smooth muscle cells transfected with truncated forms of PKC-alpha in this study. The data indicate that RhoA directly bound to full-length PKC-alpha, both in vitro (82.57 +/- 15.26% above control) and in transfected cells. RhoA bound in vitro to the C1 domain of PKC-alpha [PKC-alpha (C1)] (70.48 +/- 20.78% above control), PKC-alpha (C2) (72.26 +/- 29.96% above control), and PKC-alpha (C4) (90.58 +/- 26.79% above control), but not to PKC-alpha (C3) (0.64 +/- 5.18% above control). RhoA bound in vitro and in transfected cells to truncated forms of PKC-alpha, PKC-alpha (C2, C3, and C4), and PKC-alpha (C3 and C4) (94.09 +/- 12.13% and 85.10 +/- 16.16% above control, respectively), but not to PKC-alpha (C1, C2, and C3) or to PKC-alpha (C2 and C3) (0.47 +/- 1.26% and 7.45 +/- 10.76% above control, respectively). RhoA bound to PKC-alpha (C1 and C2) (60.78 +/- 13.78% above control) only in vitro, but not in transfected cells, and PKC-alpha (C2, C3, and C4) and PKC-alpha (C3 and C4) bound well to RhoA. These data suggest that RhoA bound to fragments that may mimic the active form of PKC-alpha. The studies using cells transfected with truncated forms of PKC-alpha indicate that PKC-alpha (C1 and C2), PKC-alpha (C1, C2, and C3), and PKC-alpha (C2 and C3) did not associate with RhoA. Only full-length PKC-alpha, PKC-alpha (C2, C3, and C4), and PKC-alpha (C3 and C4) associated with RhoA. The association increased upon stimulation with acetylcholine. These results suggest that the functional association of PKC-alpha with RhoA may require the C4 domain.
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PMID:Direct association of RhoA with specific domains of PKC-alpha. 1593 Jan 43

The effects of dipeptide cyclo-[His-Pro] (CHP), known to participate in the appetite behavior and food intake control, have been investigated using PC12 cells in culture as model system. We found that only in the presence of experimental conditions that cause cellular stress the cyclic dipeptide affect cellular proliferation and protects from apoptosis. It greatly enhances the phosphorylation of hsp27, alpha-B-crystallin, Cdc2, and p-38 MAPK, whereas it decreases the phosphorylation of MEK1, Cav 2, GSK3a, PKB/Akt, PKCdelta, PKCgamma, and Erk2. PKA and PKG are involved in ERK1/2 deactivation via a receptor that appears to be dually coupled to Gs and Gq protein subfamilies.
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PMID:Phosphoproteomic analysis of the effect of cyclo-[His-Pro] dipeptide on PC12 cells. 1613 90

MinK-related peptide 2 (MiRP2) and Kv3.4 subunits assemble in skeletal muscle to create subthreshold, voltage-gated potassium channels. MiRP2 acts on Kv3.4 to shift the voltage dependence of activation, speed recovery from inactivation, suppress cumulative inactivation and increase unitary conductance. We previously found an R83H missense mutation in MiRP2 that segregated with periodic paralysis in two families and diminished the effects of MiRP2 on Kv3.4. Here we show that MiRP2 has a single, functional PKC phosphorylation site at serine 82 and that normal MiRP2-Kv3.4 function requires phosphorylation of the site. The R83H variant does not prevent PKC phosphorylation of neighboring S82; rather, the change shifts the voltage dependence of activation and endows MiRP2-Kv3.4 channels with sensitivity to changes in intracellular pH across the physiological range. Thus, current passed by single R83H channels decreases as internal pH is lowered (pK(a) approximately 7.3, consistent with histidine protonation) whereas wild-type channels are largely insensitive. These findings identify a key regulatory domain in MiRP2 and suggest a mechanistic link between acidosis and episodes of periodic paralysis.
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PMID:Phosphorylation and protonation of neighboring MiRP2 sites: function and pathophysiology of MiRP2-Kv3.4 potassium channels in periodic paralysis. 1644 2

The review summarizes current data on transduction mechanisms of stress signals by protein kinase cascades in unicellular eukaryotes. The role of sensor histidine kinases, tyrosine kinases, PKC, and cyclic nucleotid-dependent kinases are reviewed. Special attention is paid to a comparative analysis of transduction mechanisms of stress signals in vertebrates and unicellular eukaryotes.
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PMID:[The role of protein kinase cascades in stress signal transduction in unicellular eukaryotes]. 1673 76

The product of gene RSC1A1, named RS1, participates in transcriptional and posttranscriptional regulation of the sodium-d-glucose cotransporter SGLT1. Using coexpression in oocytes of Xenopus laevis, posttranscriptional inhibition of human SGLT1 (hSGLT1) and some other transporters by human RS1 (hRS1) was demonstrated previously. In the present study, histidine-tagged hRS1 was expressed in oocytes or Sf9 cells and purified using nickel(II)-charged nitrilotriacetic acid-agarose. hRS1 protein was injected into oocytes expressing hSGLT1 or the human organic cation transporter hOCT2, and the effect on hSGLT1-mediated uptake of methyl-alpha-D-[14C]glucopyranoside ([14C]AMG) or hOCT2-mediated uptake of [14C]tetraethylammonium ([14C]TEA) was measured. Within 30 min after the injection of hRS1 protein, hSGLT1-expressed AMG uptake or hOCT2-expressed TEA uptake was inhibited by approximately 50%. Inhibition of AMG uptake was decreased when a dominant negative mutant of dynamin I was coexpressed and increased after stimulation of PKC. Inhibition remained unaltered when endocytosis was inhibited by chlorpromazine, imipramine, or filipin but was prevented when exocytosis was inhibited by botulinum toxin B or when the release of vesicles from the TGN and endosomes was inhibited by brefeldin A. Inhibition of hSGLT1-mediated AMG uptake and hOCT2-mediated TEA uptake by hRS1 protein were decreased at an enhanced intracellular AMG concentration. The data suggest that hRS1 protein exhibits glucose-dependent, short-term inhibition of hSGLT1 and hOCT2 by inhibiting the release of vesicles from the trans-Golgi network.
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PMID:RS1 (RSC1A1) regulates the exocytotic pathway of Na+-D-glucose cotransporter SGLT1. 1678 46

Pituitary adenylate cyclase-activating polypeptide (PACAP), vasoactive intestinal peptide (VIP), and peptide histidine-isoleucine (PHI) are members of a superfamily of structurally related peptides widely distributed in the body and displaying pleiotropic biological activities. All these peptides are known to act via common receptors-VPAC1 and VPAC2. In addition, the effects of PACAP are mediated through its specific receptor named PAC1. The main signal transduction pathway of the mentioned receptors is adenylyl cyclase (AC)-->cAMP system. PACAP and VIP may also signal through receptor-linked phospholipase C (PLC)-->IP3/DAG-->PKC and phospholipase D (PLD)-->phosphatidic acid (PA) pathways. In the present article, we have studied the effects of PACAP, VIP, and PHI (0.001-5000 nM) on the AC-, PLC-, and PLD-driven signaling pathways in rat primary glial cell (astrocytes) cultures. All tested peptides dose-dependently and strongly stimulated cyclic adenosine 3',5'-monophosphate (cAMP) production in this experimental model, displaying the following rank order of potency: PACAP >> VIP > or = PHI. Their effects on PLC-IP3/DAG were weaker, while only PACAP and VIP (0.1-5 microM) significantly stimulated PLD activity. The obtained results showed that rat cerebral cortex-derived astrocytes are responsive to PACAP, VIP and PHI/PHM and possess PAC1 and likely VPAC-type receptors linked to activation of AC-cAMP-, PLC-IP3/DAG-, and PLD-PA signaling systems.
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PMID:PACAP, VIP, and PHI: effects on AC-, PLC-, and PLD-driven signaling systems in the primary glial cell cultures. 1688 70

The present study characterizes the involvement of the N-methyl-D-aspartic acid receptors (NMDARs) in mediating thermal hyperalgesia induced by activation of group I metabotropic glutamate receptors (mGluRs). Intrathecal administration of the mGluR1/5 agonist (S)-3,5-DHPG [(S)-3,5-dihydroxyphenylglycine] to mice resulted in significant hyperalgesia as assessed by the tail immersion test. The pretreatment of mice i.t. with CGS 19755 (selective antagonist of the NMDAR), CGP 78608 [[(1S)-1-[[(7-bromo-1,2,3,4-tetrahydro-2,3-dioxo-5-quinoxalinyl)methyl]amino]ethyl]phosphonic acid] (selective antagonist at the glycine-binding site of the NMDAR), ifenprodil and Ro 25-6981 (selective antagonists of the NR2B subunit of the NMDAR), bisindolylmaleimide I and Go-7874 [12-(2-cyanoethyl)-6,7,12,13-tetrahydro-13-methyl-5-oxo-5H-indolo(2,3-a)pyrrolo(3,4-c)-carbazole] (inhibitors of protein kinase C), or PKI-(14-22)-amide [Myr-N-Gly-Arg-Thr-Gly-Arg-Arg-Asn-Ala-Ile-NH(2)] (inhibitor of protein kinase A) dose-dependently inhibited the hyperalgesia induced by i.t. administration of the mGluR1/5 receptor agonist (S)-3,5-DHPG. In contrast, i.t. pretreatment of mice with NVP-AAM077 [[(R)-[(S)-1-(4-bromophenyl)-ethylamino]-(2,3-dioxo-1,2,3,4-tetrahydroquinoxalin-5-yl)-methyl]-phosphonic acid] (selective antagonist of the NR2A subunit of the NMDAR) or DT-3 [H-Arg-Gln-Ile-Lys-Ile-Trp-Phe-Gln-Asn-Arg-Arg-Met-Lys-Trp-Lys-Lys-Leu-Arg-Lys-Lys-Lys-Lys-Lys-His-OH] (inhibitor of protein kinase G) had no effect on (S)-3,5-DHPG-mediated hyperalgesia. We also show for the first time that i.t. injection of pSM2 (pShag Magic version 2)-grin2b (coding for an short-hairpin RNA to the NR2B subunit of the NMDAR) resulted in a dose-dependent decrease in the NR2B protein and blockade of hyperalgesia induced by activation of the mGluR1/5 in (S)-3,5-DHPG-treated mice. Taken together, our results suggest the hypothesis that mGluRs are coupled to the NMDAR channels through the NR2B subunit in the spinal cord and that this coupling involves the activation of protein kinase C and protein kinase A.
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PMID:Decrease in N-methyl-D-aspartic acid receptor-NR2B subunit levels by intrathecal short-hairpin RNA blocks group I metabotropic glutamate receptor-mediated hyperalgesia. 1740 69

It is well-known that glucagon increases fractional excretion of urea in rats after a protein intravenous infusion. This effect was investigated by using: (a) in vitro microperfusion technique to measure [(14)C]-urea permeability (Pu x 10(-5)cm/s) in inner medullary collecting ducts (IMCD) from normal rats in the presence of 10(-7)M of glucagon and in the absence of vasopressin and (b) immunoblot techniques to determine urea transporter expression in tubule suspension incubated with the same glucagon concentration. Seven groups of IMCDs (n = 47) were studied. Our results revealed that: (a) glucagon decreased urea reabsorption dose-dependently; (b) the glucagon antagonist des-His(1)-[Glu(9)], blocked the glucagon action but not vasopressin action; (c) the phorbol myristate acetate, decreased urea reabsorption but (d) staurosporin, restored its effect; e) staurosporin decreased glucagon action, and finally, (f) glucagon decreased UT-A1 expression. We can conclude that glucagon reduces UT-A1 expression via a glucagon receptor by stimulating PKC.
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PMID:PKC stimulated by glucagon decreases UT-A1 urea transporter expression in rat IMCD. 1844 63


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