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)

Recombinant human 125I-interleukin-6 (IL-6) was cross-linked with the homobifunctional reagent disuccinimidyl suberate to human hepatoma cells (HepG2). Three recombinant human 125I-IL-6-containing complexes of apparent molecular masses of 100, 120, and 200 kDa were immunoprecipitated with specific antibodies to human IL-6 or to the 80-kDa IL-6 receptor subunit. We show by immunoprecipitation, peptide mapping, and by the use of a cleavable heterobifunctional cross-linker (Denny-Jaffe reagent) that different polypeptides are involved in the formation of the 100- and 120-kDa IL-6-containing complexes. The molecular compositions of the 100- and 120-kDa cross-linked complexes were identified. The 100-kDa complex consisted of one ligand and one IL-6 receptor subunit, glycoprotein 80 (gp80), whereas the 120-kDa complex was found to be composed of one ligand and a polypeptide which was immunoprecipitable with the monoclonal antibody AM64 directed against gp130. Exposure of HepG2 cells to phorbol 12-myristate 13-acetate (PMA) or PMA-dexamethasone led to an increase in the 80-kDa IL-6 receptor mRNA and functional receptor protein. Whereas treatment of HepG2 cells with PMA led to an increase in the formation of gp80.gp130.IL-6 complexes determined by cross-linking, no corresponding increase in high affinity binding sites was found. The existence of a third IL-6 receptor subunit present in limiting amounts on HepG2 cells is proposed to explain this discrepancy. Evidence is presented that the 80-kDa IL-6 receptor up-regulation by PMA-dexamethasone is caused by the depletion of protein kinase C since the protein kinase C inhibitor staurosporine mimics the effect of PMA-dexamethasone.
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PMID:The hepatic interleukin-6 receptor. Studies on its structure and regulation by phorbol 12-myristate 13-acetate-dexamethasone. 844 Jul 9

Interleukin (IL)-6, IL-11 and cililary neurotrophic factor (CNTF) belong to the same family of hematopoietic and neurotrophic cytokines. Their receptor complexes contain a cytokine-binding alpha receptor and the common glycoprotein (gp)130 subunit for signal transduction. The extracellular parts of the alpha-receptor subunits consist of a membrane-proximal cytokine-binding domain and an N-terminal immunoglobulin (Ig)-like domain with unknown function. We examined the role of the Ig-like domain of IL-6R by constructing deletion mutants lacking the Ig domain (IL-6RDeltaIg and soluble IL-6RDeltaIg). IL-6RDeltaIg was shed as effectively as wild-type IL-6R from transfected COS-7 cells upon 4beta-phorbol 12-myristate 13-acetate (PMA) treatment, whereas nonstimulated shedding of IL-6RDeltaIg was not observed. The shed sIL-6RDeltaIg from PMA-treated cells, as well as the transmembrane IL-6RDeltaIg, had the same biological activity as wild-type sIL-6R, as measured by the induction of haptoglobin secretion in HepG2-IL-6 cells and IL-6-dependent proliferation of IL-6RDeltaIg transfected BAF/gp130 cells. In COS-7 cells transfected with IL-6RDeltaIg or soluble IL-6RDeltaIg cDNA, transport of the deletion mutants through the secretory pathway appeared to be delayed because a sizeable proportion of the mutants was detected as an endo-beta-N-acetylglucosaminidase-sensitive intermediate, suggesting that transport and processing of the DeltaIg mutants on the secretory pathway were impaired. These experiments suggest that the Ig-like domain of the IL-6R is important for intracellular transport of IL-6R through the secretory pathway. Furthermore, the Ig-like domain is necessary for noninduced shedding of the IL-6R, whereas it has no function in PKC-dependent shedding of the IL-6R.
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PMID:A role for the immunoglobulin-like domain of the human IL-6 receptor. Intracellular protein transport and shedding. 1040 52

We here examined the role of the interleukin-6 (IL-6) family of cytokines in endothelin-1 (ET-1)-induced hypertrophic responses using cultured cardiac myocytes of neonatal rats. ET-1 induced expression of IL-6 and leukemia inhibitory factor (LIF) genes. ET-1-induced LIF gene expression was abolished by inhibition of protein kinase C activity. ET-1 activated the promoter of atrial natriuretic peptide and beta-type myosin heavy chain genes through the tyrosine kinase pathway and IL-6 receptor gp130. These results suggest that the IL-6 family of cytokines mediates ET-1-induced expression of some fetal genes in cardiac myocytes.
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PMID:Endothelin-1 induces expression of fetal genes through the interleukin-6 family of cytokines in cardiac myocytes. 1045 39

This study was designed to investigate whether insulin-like growth factor-1 (IGF-1) transduces signaling through the Janus kinase (JAK)/signal transducers and activators of transcription (STAT) pathway in cardiomyocytes and to assess the upstream signals of serine and tyrosine phosphorylation of STAT family proteins. Primary cultured neonatal rat cardiomyocytes were stimulated with IGF-1 (10(-8) mol/L). JAK1, but not JAK2 or Tyk2, was phosphorylated by IGF-1 as early as 2 minutes and peaked at 5 minutes. IGF-1 induced both tyrosine and serine phosphorylation of STAT1 and STAT3. Tyrosine phosphorylation of STAT1 peaked at 15 minutes and correlated with that of JAK1, whereas that of STAT3 was sustained up to 120 minutes and was dissociated from the activation of JAK1. Tyrosine phosphorylation of STAT3 was unaffected by the preincubation with CV11974 (AT(1) blocker), TAK044 (endothelin-1 receptor blocker), RX435 (anti-gp130 blocking antibody), PD98058, wortmannin, EDTA, or KN62 but was significantly attenuated by BAPTA-AM and chelerythrine. The time course of a gel mobility shift of SIE (sis-inducing element) coincided with the phosphorylation of STAT3. Serine phosphorylation of STAT1 peaked at 30 minutes and that of STAT3 was observed from 5 to 60 minutes. These results indicated that (1) IGF-1 activated JAK1 but not JAK2 or Tyk2 in rat cardiomyocytes; (2) IGF-1 induced both tyrosine and serine phosphorylation of STAT1 and STAT3; and (3) the tyrosine phosphorylation of STAT3 was not caused by JAK1 alone, and protein kinase C and intracellular Ca(2+) were required for phosphorylation.
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PMID:Characterization of insulin-like growth factor-1-induced activation of the JAK/STAT pathway in rat cardiomyocytes. 1055 34

Immunoreceptor tyrosine-based inhibitory motifs (ITIMs) have the restricted consensus sequence V/I/xYxxL/V, but may be more broadly defined by the sequence V/I/L/SxYxxL/V/I/S. If one includes the ITIM of CTLA-4, then the sequence becomes psixYxxpsi, where psi represents amino acids with nonpolar side chains. Aside from their presence in various inhibitory molecules, ITIMs are also found on many activating receptors and pathways. ITIMs with the restricted consensus sequence occur on IL-4Ralpha, IL-3Rbeta type II, gp130 cytokineR, OB-R (leptinR), LIF-Rbeta TNF-RI, G-CSF-R, PDGF-R, Blk, Ctk/Ntk, Lsk, Zap-70, PKB/RACalpha, PKC-alpha, PKC-beta, PKC-gamma, PKC-delta, PKC-zeta, PKC-epsilon, PKC-eta, PKC-phi, PKC-mu, calmodulin-dependent kinase IIdelta, SLP-76-associated protein, FYN-binding protein, Shc binding protein, RasGRF2, CDC25 homologue, Jak2, Jak3, PLCbeta1, and PLCbeta3. If ITIMs are defined by a broader consensus sequence, the list of ITIMs on activating molecules becomes even larger. In some instances, these ITIMs have been shown to associate with inhibitory phosphatases. Whether these ITIMs on activating receptors/pathways are necessary and sufficient for negative control of activating events and for immunologic tolerance is not yet known. In some instances, ITIMs on coinhibitory receptors are also required for appropriate negative regulation. By studying events leading to negative control during activation and to immunologic tolerance, it should be possible to discern the balance between antigen receptor-based negative events and coinhibition.
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PMID:Immunoreceptor tyrosine-based inhibitory motifs on activating molecules. 1087 92

Receptor activator of nuclear factor-kappaB ligand (RANKL) and osteoprotegerin (OPG) produced by osteoblasts/stromal cells are involved as positive and negative regulators in osteoclast formation. Three independent signals have been proposed to induce RANKL expression in osteoblasts/stromal cells: vitamin D receptor-, cAMP-, and gp130-mediated signals. We previously reported that intracellular calcium-elevating compounds such as ionomycin, cyclopiazonic acid, and thapsigargin induced osteoclast formation in cocultures of mouse bone marrow cells and primary osteoblasts. Increases in calcium concentration in culture medium also induced osteoclast formation in cocultures. Treatment of primary osteoblasts with these compounds or with high calcium medium stimulated the expression of both RANKL and OPG messenger RNAs (mRNAs). 1,2-Bis(o-aminophenoxy)ethane-N,N,N',N'-tetraacetic acid)-tetra(acetoxymethyl)ester, an intracellular calcium chelator, suppressed both ionomycin-induced osteoclast formation in cocultures and expression of RANKL and OPG mRNAs in primary osteoblasts. Phorbol 12-myristate 13-acetate (PMA), an activator of protein kinase C, also stimulated osteoclast formation in these cocultures and the expression of RANKL and OPG mRNAs in primary osteoblasts. Protein kinase C inhibitors such as calphostin and staurosporin suppressed ionomycin- and PMA-induced osteoclast formation in cocultures and expression of RANKL and OPG mRNAs in primary osteoblasts. Ionomycin stimulated RANKL mRNA expression in ST2 and MC3T3-G2/PA6 cells, but not in MC3T3-E1 or NIH-3T3 cells. These effects were closely correlated with osteoclast formation in response to ionomycin in cocultures with these stromal cell lines. OPG strongly inhibited osteoclast formation induced by calcium-elevating compounds and PMA in cocultures, suggesting that RANKL expression in osteoblasts is a rate-limiting step for osteoclast induction. Forskolin, an activator of cAMP signals, also stimulated osteoclast formation in cocultures. Forskolin enhanced RANKL mRNA expression but suppressed OPG mRNA expression in primary osteoblasts. These results suggest that the calcium/protein kinase C signal in osteoblasts/stromal cells is the fourth signal for inducing RANKL mRNA expression, which, in turn, stimulates osteoclast formation.
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PMID:Intracellular calcium and protein kinase C mediate expression of receptor activator of nuclear factor-kappaB ligand and osteoprotegerin in osteoblasts. 1110 86

Although regulated ectodomain shedding affects a large panel of structurally and functionally unrelated proteins, little is known about the mechanisms controlling this process. Despite a lack of sequence similarities around cleavage sites, most proteins are shed in response to the stimulation of protein kinase C by phorbol esters. The signal-transducing receptor subunit gp130 is not a substrate of the regulated shedding machinery. We generated several chimaeric proteins of gp130 and the proteins tumour necrosis factor alpha (TNF-alpha), transforming growth factor alpha (TGF-alpha) and interleukin 6 receptor (IL-6R), which are known to be subject to shedding. By exchanging small peptide sequences of gp130 for cleavage-site peptides of TNF-alpha, TGF-alpha and IL-6R we showed that these short sequences conferred susceptibility to spontaneous and phorbol-ester-induced shedding of gp130. Importantly, these chimaeric gp130 proteins were functional, as shown by the phosphorylation of gp130 and the activation of signal transduction and activators of transcription 3 ('STAT3') on stimulation with cytokine. To investigate minimal requirements for shedding, truncated cleavage-site peptides of IL-6R were inserted into gp130. The resulting chimaeras were susceptible to shedding and showed the same cleavage pattern as observed in the chimaeras containing the complete IL-6R cleavage site. Surprisingly, we could also generate cleavable chimaeras by exchanging the juxtamembrane sequence of gp130 for the corresponding region of leukaemia inhibitory factor ('LIF') receptor, a protein that like gp130 is not subject to regulated or spontaneous shedding. Thus it seems that there is no minimal consensus shedding sequence. We speculate that structural changes allow the access of the protease to a membrane-proximal region, leading to shedding of the protein.
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PMID:Recognition sequences and structural elements contribute to shedding susceptibility of membrane proteins. 1117 Oct 64

This review discusses the rapidly progressing field of cardiomyocyte signal transduction and the regulation of the hypertrophic response. When stimulated by a wide array of neurohumoral factors or when faced with an increase in ventricular-wall tension, individual cardiomyocytes undergo hypertrophic growth as an adaptive response. However, sustained cardiac hypertrophy is a leading predictor of future heart failure. A growing number of intracellular signaling pathways have been characterized as important transducers of the hypertrophic response, including specific G protein isoforms, low-molecular-weight GTPases (Ras, RhoA, and Rac), mitogen-activated protein kinase cascades, protein kinase C, calcineurin, gp130-signal transducer and activator of transcription, insulin-like growth factor I receptor pathway, fibroblast growth factor and transforming growth factor beta receptor pathways, and many others. Each of these signaling pathways has been implicated as a hypertrophic transducer, which collectively suggests an emerging paradigm whereby multiple pathways operate in concert to orchestrate a hypertrophic response
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PMID:Cytoplasmic signaling pathways that regulate cardiac hypertrophy. 1118 61

Neurons in vivo are exposed to a variety of different growth factors and cytokines. A principal signalling pathway for ciliary neurotrophic factor (CNTF)-like cytokines is the Janus kinase (Jak)/signal transducer and activator of transcription (STAT) system of kinases and transcription factors. In the human cell line (SH-SY5Y), STAT1 and STAT3 activation by CNTF-like cytokines showed tyrosine phosphorylation peaking at 0.5 h and inactivating within 2 h. Tyrosine phosphorylation of the receptor-associated tyrosine kinases Jak1 and Jak2 showed a similar time course of activation and inactivation in response to CNTF. The STAT1 response to the non-CNTF-like cytokine, interferon-gamma (IFN-gamma) did not inactivate. Inactivation to CNTF was not due to a decrease in CNTF receptor subunit gp130 or in levels of Jak1 or Jak2. STAT inactivation was inhibited by the protein kinase blocker H7 and a tyrosine phosphatase blocker, but not by inhibitors of protein kinase C, mitogen-activated protein kinase (MAPK) kinase, mTOR-P70/S6 kinase or phosphatidyl inositol-3-kinase (PI-3 kinase). Surprisingly, CNTF caused only a minor increase in levels of suppressors of cytokine signalling, SOCS-1 and SOCS-3. CNTF pretreatment desensitized the cells to the CNTF-like cytokines, leukemia inhibitory factor and oncostatin-M but not to IFN-gamma. These results reveal a complex level of regulation of shared signalling pathways for cytokines that is dependent on both the type of cell and cytokine.
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PMID:Activation and inactivation of signal transducers and activators of transcription by ciliary neurotrophic factor in neuroblastoma cells. 1188 86

The transcriptional regulation of Stat proteins is controlled through their C-terminal domains, which harbor both a tyrosine phosphorylation site, required for dimerization and subsequent nuclear translocation, and a serine phosphorylation site, required for maximum transcriptional activity. Previously, we reported that protein kinase Cdelta (PKCdelta) phosphorylates and interacts with Stat3 in an interleukin (IL)-6-dependent manner. In this study, we further characterized this interaction, and investigated the potential role of such an interaction. We show here that the catalytic domain of PKCdelta interacts with the Src homology 2 domain and part of the adjacent C-terminal transactivation domain of Stat3. This interaction, which does not seem to involve a classical phosphotyrosine SH2-mediated binding, however, significantly enhances the interaction of Stat3 and the IL-6 receptor subunit glycoprotein (gp) 130, which is the initial step for Stat3 activation by IL-6. Expression of a dominant negative PKCdelta or depletion of the endogenous PKCdelta by phorbol 12-myristate 3-acetate treatment abrogates the association of Stat3 with gp130. At the same time, PKCdelta is recruited to gp130 via association with Stat3, which may facilitate its phosphorylation on the gp130 receptor. Finally, we identified Thr-890, a putative PKC phosphorylation site on gp130, to be critical for the effect of PKCdelta. Our data indicate that PKCdelta plays important regulatory roles in IL-6 signaling.
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PMID:Protein kinase C delta associates with the interleukin-6 receptor subunit glycoprotein (gp) 130 via Stat3 and enhances Stat3-gp130 interaction. 1236 54


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