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)

The human mu-opioid receptor (HmuOR) is a G-protein coupled receptor that mediates analgesia, euphoria and other important central and peripheral neurological functions. In this study, we found in a yeast two-hybrid screen that a protein kinase C-interacting protein (PKCI) specifically interacts with the C terminus of HmuOR. The interaction of PKCI with HmuOR was recapitulated in Chinese hamster ovary cells that express the full-length HmuOR and PKCI proteins. The affinity of HmuOR for an opioid ligand and its ability to mediate the activation of a G-protein were not altered by their interaction. However, the association of PKCI with HmuOR reduced agonist-induced inhibition of adenylyl cyclase and suppressed HmuOR desensitization partially at the G protein level and completely at the adenylyl cyclase level. Furthermore, PMA-induced, but not DAMGO-induced, HmuOR phosphorylation was partially inhibited by the coexpression of PKCI, suggesting that PKCI exerts a selective regulatory effect on HmuOR signaling. This effect was specific to the mu-opioid receptor because delta-opioid receptor desensitization was unaffected by PKCI. In addition, behavioral studies revealed that both basal and morphine-induced analgesia were significantly enhanced in the mutant mice that lacked expression of PKCI gene, and these mice developed a greater extent of tolerance to morphine analgesia. Taken together, these results suggest that PKCI functions as a negative regulator in HmuOR desensitization, phosphorylation, and in mediating morphine analgesia.
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PMID:Role of mPKCI, a novel mu-opioid receptor interactive protein, in receptor desensitization, phosphorylation, and morphine-induced analgesia. 1549 10

Two mutant Rat2 fibroblast cell lines, R3-2 and R4-7, have been previously isolated by a selection for retrovirus resistance. We have now further analyzed the basis of the block to retroviral infection in the R3-2 line. Using Affymetrix GeneChip analysis, several genes were identified as differentially expressed in the mutant R3-2 line compared with the wild-type cells. One of the candidate gene products, FEZ1 (fasciculation and elongation protein zeta-1), a protein kinase C (PKC)zeta-interacting protein homologous to the Caenorhabditis elegans synaptic transport protein UNC-76, was found to be up-regulated >30-fold in the resistant R3-2 line. FEZ1 overexpression in Rat2 cells conferred a potent resistance to infection by genetically marked retroviruses, and the degree of retroviral resistance in both Rat2 fibroblasts and 293T cells tightly correlated with the expression level of FEZ1 transcripts. FEZ1-overexpressing Rat2 cells showed a similar phenotype to that of the mutant R3-2 line: Infection resulted in normal viral DNA synthesis but a reduction in the formation of circular DNA, indicating a block after reverse transcription but before nuclear entry. Partial knockdown of FEZ1 expression in R3-2 by RNA interference (RNAi) significantly reduced the resistance of this line to infection. Thus, our data suggest that FEZ1 overexpression is sufficient to explain the resistant phenotype of R3-2 cells and identify FEZ1 as a new gene capable of causing retrovirus resistance.
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PMID:Overexpression of fasciculation and elongation protein zeta-1 (FEZ1) induces a post-entry block to retroviruses in cultured cells. 1587 57

Several myelin-derived proteins have been identified as components of central nervous system (CNS) myelin, which prevents axonal regeneration in the adult vertebrate CNS. The discovery of the receptor for these proteins was a major step toward understanding the failure of axon regeneration. The receptor complex consists of at least three elements: the p75 receptor (p75NTR), the Nogo receptor and LINGO-1. Downstream from the receptor complex, RhoA activation has been shown to be a key element of the signaling mechanism of these proteins. Rho activation arrests axon growth, and blocking Rho activation promotes axon regeneration in vivo. Recent studies have identified conventional protein kinase C as an additional necessary component for axon growth inhibition. Possible crosstalk downstream of these signals should be explored to clarify all the inhibitory signals and may provide an efficient molecular target against injuries to the CNS.
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PMID:Multiple signals regulate axon regeneration through the Nogo receptor complex. 1621 75

AMPA receptor (AMPAR) trafficking at CNS synapses is regulated by several receptor-binding proteins. One model of AMPAR endocytosis entails the cotargeting of the GluR2-interacting protein PICK1 and activated PKC to synapses. We demonstrate that NMDA receptor (NMDAR) activation mediates bidirectional changes in surface AMPARs through two additional forms of PICK1 redistribution. In neurons, NMDAR activation, which induces AMPAR endocytosis, increases endosomal PICK1 clustering. In contrast, stronger NMDAR activation rapidly reduces PICK1 clustering accompanied by decreases in PICK1/GluR2 association and increases in surface AMPAR levels. PICK1-siRNA similarly increases surface AMPARs and occludes the NMDAR-mediated effect, demonstrating the role of PICK1 in this process. Bidirectional NMDAR-mediated changes in PICK1 localization are determined by the magnitude of receptor-activated dendritic calcium signals. Our results show that PICK1 localization in dendrites is subject to multiple forms of regulation that contribute to surface AMPAR expression, likely by modulating the numbers of AMPARs maintained in intracellular compartments.
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PMID:NMDA receptors mediate calcium-dependent, bidirectional changes in dendritic PICK1 clustering. 1640 32

Doxorubicin (DOX) transport activity of Ral-interacting protein (RLIP76) in non-small cell lung cancer (NSCLC) is approximately twice that of in small cell lung cancer (SCLC). Since protein-kinase-C (PKC)alpha mediated phosphorylation of RLIP76 causes doubling of the specific activity of RLIP76, and NSCLC cells are known to have greater PKCalpha activity, we examined the contribution of PKC mediated phosphorylation of RLIP76 towards intrinsic DOX-resistance in human NSCLC. Expression of a deletion mutant RLIP76(delPKCalpha-sites) followed by depletion of the wild-type RLIP76 using a siRNA targeted at one of the deleted regions resulted in generation of cells expressing only the mutant protein, which could not be phosphorylated by PKCalpha. DOX-transport activity of the mutant RLIP76 purified from NSCLC and SCLC was similar and comparable to that of RLIP76 purified from the wild-type SCLC. However, this activity was significantly lower than that of RLIP76 purified from the wild-type NSCLC. After siRNA mediated depletion of PKCalpha, DOX-transport activities of RLIP76 purified from SCLC and NSCLC were indistinguishable. Depletion of PKCalpha inhibited the growth of NSCLC more than SCLC cells (70+/-3% vs. 43+/-5%, respectively). PKCalpha-depletion lowered the IC(50) of NSCLC cell lines for DOX to the same level as that observed for SCLC. RLIP76(-/-) mouse embryonic fibroblasts (MEFs) were significantly more sensitive to DOX as compared with RLIP76(+/+) MEFs (IC(50) 25 vs. 125nM, respectively). However, PKCalpha-depletion did not affect DOX-cytotoxicity towards RLIP76(-/-) MEFs, as opposed to RLIP76(+/+) MEFs which were sensitized by 2.2-fold. These results demonstrate that RLIP76 is a primary determinant of DOX-resistance, and that PKCalpha mediated accumulation defect and DOX-resistance in NSCLC is primarily due to differential phosphorylation of RLIP76 in SCLC and NSCLC.
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PMID:Determinants of differential doxorubicin sensitivity between SCLC and NSCLC. 1657 94

Blockage of the p53 tumor suppressor has been found to impair nerve growth factor (NGF)-induced neurite outgrowth in PC-12 cells. We report herein that such impairment could be rescued by stimulation of the A(2A) adenosine receptor (A(2A)-R), a G protein-coupled receptor implicated in neuronal plasticity. The A(2A)-R-mediated rescue occurred in the presence of protein kinase C (PKC) inhibitors or protein kinase A (PKA) inhibitors and in a PKA-deficient PC-12 variant. Thus, neither PKA nor PKC was involved. In contrast, expression of a truncated A(2A)-R mutant harboring the seventh transmembrane domain and its C terminus reduced the rescue effect of A(2A)-R. Using the cytoplasmic tail of the A(2A)-R as bait, a novel-A(2A)-R-interacting protein [translin-associated protein X (TRAX)] was identified in a yeast two-hybrid screen. The authenticity of this interaction was verified by pull-down experiments, coimmunoprecipitation, and colocalization of these two molecules in the brain. It is noteworthy that reduction of TRAX using an antisense construct suppressed the rescue effect of A(2A)-R, whereas overexpression of TRAX alone caused the same rescue effect as did A(2A)-R activation. Results of [(3)H]thymidine and bromodeoxyuridine incorporation suggested that A(2A)-R stimulation inhibited cell proliferation in a TRAX-dependent manner. Because the antimitotic activity is crucial for NGF function, the A(2A)-R might exert its rescue effect through a TRAX-mediated antiproliferative signal. This antimitotic activity of the A(2A)-R also enables a mitogenic factor (epidermal growth factor) to induce neurite outgrowth. We demonstrate that the A(2A)-R modulates the differentiation ability of trophic factors through a novel interacting protein, TRAX.
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PMID:Rescue of p53 blockage by the A(2A) adenosine receptor via a novel interacting protein, translin-associated protein X. 1670 26

Protein kinase C interacting protein (PKCI-1) was identified among the potential interactors from a yeast two hybrid screen of human brain library using N terminal of RGSZ1 as a bait. The cysteine string region, unique to the RZ subfamily, contributes to the observed interaction because PKCI-1 interacted with N-terminus of RGS17 and GAIP, but not with that of RGS2 or RGS7 where cysteine string motif is absent. The interaction between RGSZ1 and PKCI-1 was confirmed by coimmunoprecipitation and immunofluorescence. PKCI-1 and RGSZ1 could be detected by coimmunoprecipitation using 14-3-3 antibody in cells transfected with PKCI-1 or RGSZ1 respectively, but when transfected with PKCI-1 and RGSZ1 together, only RGSZ1 could be detected. Phosphorylation of Galphaz by protein kinase C (PKC) reduces the ability of the RGS to effectively function as GTPase accelerating protein for Galphaz, and interferes with ability of Galphaz to interact with betagamma complex. We investigated the roles of 14-3-3 and PKCI-1 in phosphorylation of Galphaz. Phosphorylation of Galphaz by PKC was inhibited by 14-3-3 and the presence of PKCI-1 did not provide any further inhibition. PKCI-1 interacts with mu opioid receptor and suppresses receptor desensitization and PKC related mu opioid receptor phosphorylation [W. Guang, H. Wang, T. Su, I.B. Weinstein, J.B. Wang, Mol. Pharmacol. 66 (2004) 1285.]. Previous studies have also shown that mu opioid receptor co-precipitates with RGSZ1 and influence mu receptor signaling by acting as effector antagonists [J. Garzon, M. Rodriguez-Munoz, P. Sanchez-Blazquez, Neuropharmacology 48 (2005) 853., J. Garzon, M. Rodriguez-Munoz, A. Lopez-Fando, P. Sanchez-Blazquez Neuropsychopharmacology 30 (2005) 1632.]. Inhibition of cAMP by mu opioid receptor was significantly reduced by RGSZ1 and this effect was enhanced in combination with PKCI-1. Our studies thus provide a link between the previous observations mentioned above and indicate that the major function of PKCI-1 is to modulate mu opioid receptor signaling pathway along with RGSZ1, rather than directly mediating the Galphaz RGSZ1 interaction.
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PMID:RGSZ1 interacts with protein kinase C interacting protein PKCI-1 and modulates mu opioid receptor signaling. 1712 29

Hypoxia-inducible factor 1 (HIF-1) regulates transcription in response to changes in O(2) concentration. O(2)-dependent degradation of the HIF-1alpha subunit is mediated by prolyl hydroxylase (PHD), the von Hippel-Lindau (VHL)/Elongin-C/Elongin-B E3 ubiquitin ligase complex, and the proteasome. Inhibition of heat-shock protein 90 (HSP90) leads to O(2)/PHD/VHL-independent degradation of HIF-1alpha. We have identified the receptor of activated protein kinase C (RACK1) as a HIF-1alpha-interacting protein that promotes PHD/VHL-independent proteasomal degradation of HIF-1alpha. RACK1 competes with HSP90 for binding to the PAS-A domain of HIF-1alpha in vitro and in human cells. HIF-1alpha degradation induced by the HSP90 inhibitor 17-allylaminogeldanamycin is abolished by RACK1 loss of function. RACK1 binds to Elongin-C and promotes ubiquitination of HIF-1alpha. Elongin-C-binding sites in RACK1 and VHL show significant sequence similarity. Thus, RACK1 is an essential component of an O(2)/PHD/VHL-independent mechanism for regulating HIF-1alpha stability through competition with HSP90 and recruitment of the Elongin-C/B ubiquitin ligase complex.
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PMID:RACK1 competes with HSP90 for binding to HIF-1alpha and is required for O(2)-independent and HSP90 inhibitor-induced degradation of HIF-1alpha. 1724 29

Zipper-interacting protein kinase (ZIPK) is a serine-threonine kinase that has been implicated in Ca2+-independent myosin II phosphorylation and contractile force generation in vascular smooth muscle. However, relatively little is known about the contribution of this kinase to gastrointestinal smooth muscle contraction. The addition of a recombinant version of ZIPK that lacked the leucine zipper domain to permeabilized ileal strips evoked a Ca2+-independent contraction and resulted in myosin regulatory light chain diphosphorylation at Ser19 and Thr18. Neither Ca2+-independent force development nor myosin regulatory light chain phosphorylation was elicited by the addition of kinase-dead ZIPK to the ileal strips. The sensitivity of ZIPK-induced contraction to various kinase inhibitors was similar to the in vitro sensitivity of purified ZIPK to these inhibitors. Staurosporine was the most effective ZIPK inhibitor, with a Ki value calculated to be 2.6 +/- 0.3 micromol/L. Through the use of specific kinase inhibitors, we determined that Rho-associated protein kinase and Ca2+/phospholipid-dependent protein kinase (protein kinase C) do not mitigate ZIPK-induced contraction in ileum. Our findings support a role for ZIPK in Ca2+-independent contractile force generation in gastrointestinal smooth muscle.
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PMID:Staurosporine inhibition of zipper-interacting protein kinase contractile effects in gastrointestinal smooth muscle. 1746 51

The human glutathione S-transferase, GSTs, possess both enzymatic and non-enzymatic functions and are involved in many important cellular processes, such as, phase II metabolism, stress response, cell proliferation, apoptosis, oncogenesis, tumor progression and drug resistance. The non-enzymatic functions of GSTs involve their interactions with cellular proteins, such as, JNK, TRAF, ASK, PKC, and TGM2, during which, either the interacting protein partner undergoes functional alteration or the GST protein itself is post-translationally modified and/or functionally altered. The majority of GST genes harbor polymorphisms that influence their transcription and/or function of their encoded proteins. This overview focuses on recent insights into the biology and pharmacogenetics of GSTs as a determinant of cancer drug resistance and response of cancer patients to therapy.
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PMID:Genetic polymorphism and function of glutathione S-transferases in tumor drug resistance. 1768 92


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