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)

Syndecan-4, a transmembrane heparan sulfate proteoglycan, is a coreceptor with integrins in cell adhesion. It has been suggested to form a ternary signaling complex with protein kinase Calpha and phosphatidylinositol 4,5-bisphosphate (PIP2). Syndecans each have a unique, central, and variable (V) region in their cytoplasmic domains, and that of syndecan-4 is critical to its interaction with protein kinase C and PIP2. Two oligopeptides corresponding to the variable region (4V) and whole domain (4L) of syndecan-4 cytoplasmic domain were synthesized for nuclear magnetic resonance (NMR) studies. Data from NMR and circular dichroism indicate that the cytoplasmic domain undergoes a conformational transition and forms a symmetric dimer in the presence of phospholipid activator PIP2. The solution conformations of both free and PIP2-complexed 4V have been determined by two-dimensional NMR spectroscopy and dynamical simulated annealing calculations. The 4V peptide in the presence of PIP2 formed a compact dimer with two twisted strands packed parallel to each other and the exposed surface of the dimer consisted of highly charged and polar residues. The overall three-dimensional structure in solution exhibits a twisted clamp shape having a cavity in the center of dimeric interface. In addition, it has been observed that the syndecan-4V strongly interacts not only with fatty acyl groups but also the anionic head group of PIP2. These findings reveal that PIP2 promotes oligomerization of syndecan-4 cytoplasmic domain for transmembrane signaling and cell-matrix adhesion.
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PMID:Solution structure of a syndecan-4 cytoplasmic domain and its interaction with phosphatidylinositol 4,5-bisphosphate. 958 38

In order to characterize the hepatitis B virus (HBV) hepatocellular receptor, several proteins have previously been identified in HepG2 hepatoma cells and in primary cultured normal human hepatocytes (PCHs) that reacted with an anti-idiotypic antibody against a preS1(21-47)-specific MAb (F35.25). Here, we report the identification of one of these preS1-binding proteins, a 35 kDa protein (preS1-BP35), as glyceraldehyde-3-phosphate dehydrogenase (GAPD). GAPD is well-known as a key enzyme involved in glycolysis and gluconeogenesis. Nevertheless, GAPD has also been shown to have many other functions such as protein kinase activity (GAPD-PK). HBV core particles derived from infected hepatocytes possess an associated kinase activity that phosphorylates HBcAg, and the nucleocapsid may acquire sequential functions through selective phosphorylation. Therefore, we have investigated the potential role of GAPD-PK in HBV replication. In this study, we found that the endogenous PK associated with human liver-derived HBV core particles (hL-HBcAg) and GAPD-PK were sensitive to the same types of inhibitors. Interestingly, capsid protein phosphorylation decreased in a concentration-dependent manner (at concentrations of 5-30 mM) in the presence of specific inhibitors for GAPD-PK (NADH and GAP). Furthermore, we demonstrated in vitro that GAPD-PK could phosphorylate the major core protein P22 in hL-HBcAg particles. The data suggest that GAPD is an additional cellular kinase which might interfere in the life-cycle of HBV.
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PMID:Phosphorylation of the hepatitis B virus core protein by glyceraldehyde-3-phosphate dehydrogenase protein kinase activity. 968 Jan 29

Recent studies have demonstrated that the cytoplasmic tail of syndecan-4, a widely expressed transmembrane proteoglycan, can activate protein kinase Calpha in vitro, in combination with phosphatidylinositol-4,5-bisphosphate (PI-4,5-P(2)). Syndecan-4 is involved in growth factor binding as well as in adhesion to extracellular matrix proteins, while PI-4,5-P(2) synthesis is modulated by growth factor and adhesion-generated signaling. The cooperative activation of PKCalpha by the proteoglycan and the phosphatidylinositol may constitute, therefore, an essential part of the cell's response to these extracellular signals. To characterize the activation mechanism of PKCalpha, we addressed here the nature of the interplay between syndecan-4, PI-4,5-P(2), and PKCalpha by measuring their mutual binding affinities and the specificity of their interactions. We found that the cytoplasmic tail of syndecan-4 is unlikely to bind directly to PKCalpha, and that this interaction critically depends on PI-4,5-P(2). The PI-4,5-P(2) specificity of the activation of PKCalpha is conferred by the cytoplasmic tail of syndecan-4, which has higher binding affinity for this phosphatidylinositol over phosphatidylinositol-3,4-bisphosphate and the -3,4,5-trisphospate. The activation is specific to PKCalpha and does not encompass the novel protein kinase C delta isoenzyme.
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PMID:Phosphatidylinositol-4,5-bisphosphate mediates the interaction of syndecan-4 with protein kinase C. 1062 52

Cell adhesion to extracellular matrix involves signaling mechanisms which control attachment, spreading and the formation of focal adhesions and stress fibers. Fibronectin can provide sufficient signals for all three processes, even when protein synthesis is prevented by cycloheximide. Primary fibroblasts attach and spread following integrin ligation, but do not form focal adhesions unless treated with a heparin-binding fragment of fibronectin (HepII), a peptide from this domain, or phorbol esters to activate protein kinase C. Syndecan-4 heparan sulfate proteoglycan is a transmembrane component present together with integrins in focal adhesions. Syndecan-4 binds and activates protein kinase Calpha, whose activity is needed for focal adhesion formation. We now report that the glycosaminoglycan chains of syndecan-4 bind recombinant HepII and it is incorporated into forming focal adhesions.
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PMID:Syndecan-4 binding to the high affinity heparin-binding domain of fibronectin drives focal adhesion formation in fibroblasts. 1064 Mar 97

Persistent hepatitis C virus (HCV) infection is a major cause of chronic liver dysfunction in humans and is epidemiologically closely associated with the development of human hepatocellular carcinoma. Among HCV components, core protein has been reported to be implicated in cell growth regulation both in vitro and in vivo, although mechanisms explaining those effects are still unclear. In the present study, we identified that members of the 14-3-3 protein family associate with HCV core protein. 14-3-3 protein bound to HCV core protein in a phosphoserine-dependent manner. Introduction of HCV core protein caused a substantial increase in Raf-1 kinase activity in HepG2 cells and in a yeast genetic assay. Furthermore, the HCV core-14-3-3 interaction was essential for Raf-1 kinase activation by HCV core protein. These results suggest that HCV core protein may represent a novel type of Raf-1 kinase-activating protein through its interaction with 14-3-3 protein and may contribute to hepatocyte growth regulation.
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PMID:Hepatitis C virus core protein interacts with 14-3-3 protein and activates the kinase Raf-1. 1064 44

Persistent hepatitis C virus (HCV) infection is associated with the development of human hepatocellular carcinoma (HCC), although the mechanism of HCV-related hepatocarcinogenesis remains unclear. Recently, however, the close relationships between the development of HCC and the mitogen-activated protein kinase (MAPK)/extracellular signal-regulated protein kinase (ERK) cascade have been described. In the present study, we investigated the effects of HCV core protein on this MAPK/ERK cascade. HCV core protein significantly activated the MAPK/ERK cascade, including Elk1. We also examined whether HCV core protein acted synergistically along with hepatocyte mitogen-mediated MAPK/ERK activation. Interestingly, Elk-1 activities were further enhanced by the tumor promoter, 12-O-tetradecanoyl phorbol 13-acetate (TPA), but not by hepatocyte mitogens (epidermal growth factor [EGF] and transforming growth factor alpha [TGF-alpha]) in NIH3T3 cells and HepG2 cells expressing HCV core protein. Moreover, the MAPK/ERK activation by HCV core protein was blocked in the presence of the specific MEK1 inhibitor, PD98059. These results indicate that ERK activation by HCV core protein may be independent of hepatocyte mitogen-mediated signaling but synergistic with TPA, and HCV core protein may function at MEK1 or farther upstream of that component.
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PMID:Hepatitis C virus core protein activates the MAPK/ERK cascade synergistically with tumor promoter TPA, but not with epidermal growth factor or transforming growth factor alpha. 1105 45

Hepatitis C virus (HCV) core protein has been shown to interact with the death domain (DD) of tumor necrosis factor receptor-1 (TNFR1). In this study, we further examined the interaction of the core protein with the signaling molecules of TNFR1, including FADD, TRADD, and TRAF2, in a human embryonic kidney cell line, HEK-293, that overexpresses the HCV core protein. This core protein-expressing cell line exhibited enhanced sensitivity to TNF-induced apoptosis. By in vitro binding and in vivo coimmunoprecipitation assays, we showed that the HCV core protein interacted with the DD of FADD and enhanced apoptosis induced by FADD overexpression. This enhancement could be blocked by a dominant-negative mutant of FADD. In contrast, the core protein did not directly interact with the DD of TRADD, but could disrupt the binding of TRADD to TNFR1. TRAF2 recruitment to the TNFR1 signaling complex was also disrupted by the core protein. Correspondingly, TRAF2-dependent activation of the protein kinase JNK was suppressed in the core protein-expressing cells. However, NF kappa B activation by TNF was not significantly altered by the HCV core protein, suggesting the existence of TRAF2-independent pathways for NF kappa B activation. These results combined indicate that the HCV core protein sensitizes cells to TNF-induced apoptosis primarily by facilitating FADD recruitment to TNFR1. The inhibition of JNK activation by the HCV core protein may also contribute to the increased propensity of cells for apoptosis. These results, in comparison with other published studies, suggest that the effects of the HCV core protein and their underlying mechanisms vary significantly among cells of different origins.
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PMID:Hepatitis C virus core protein enhances FADD-mediated apoptosis and suppresses TRADD signaling of tumor necrosis factor receptor. 1133 43

Hepatitis C virus (HCV) core protein is known to repress the transcription of p21(waf1) directly in a p53-independent manner. In this study, the region of HCV core protein responsible for the transcriptional repression of p21 promoter was determined. N-terminal half of core protein almost completely lost the ability to repress p21 promoter, indicating that the domain required for the majority of p21 repression is located between amino acid positions 84 and 191. The trans-repression activity of HCV core mutant S99L on p21 gene expression was similar to that of wild type core protein whereas mutation of the 116th amino acid Ser into either Ile or Ala completely abolished the repressive ability of HCV core protein. In addition, the trans-repression activity of HCV core mutant S116D was similar to that of wild type core protein, suggesting that an acidic aspartate residue can mimic the effect of phosphorylation. When treated with a protein kinase A (PKA) inhibitor, H-89, the inhibitory activity of wild-type HCV core protein was dose-dependently decreased and was completely lost at the concentration of 5 microM. On the contrary, the repression activity of HCV core protein was increased by treatment with a PKA activator, dibutyryl-cAMP, indicating that the p21 repressive activity of HCV core protein is regulated by phosphorylation at S-116 by protein PKA
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PMID:The repressive activity of hepatitis C virus core protein on the transcription of p21(waf1) is regulated by protein kinase A-mediated phosphorylation. 1155 51

Dentin sialoprotein (DSP) is a major glycoprotein present in the mineralized dentin matrix that is expressed mainly by young and mature odontoblasts. Mutations in the DSP coding regions are linked to Dentinogenesis imperfecta I and II. indicating the importance of DSP in tooth formation. Previous studies have identified multiple mRNA transcripts in dentin that code for both DSP and phosphophoryns (PPs). Using reverse transcriptase-polymerase chain reaction (RT-PCR) to characterize these mRNA transcripts, we have identified a cDNA that codes for DSP, but not PP. This cDNA codes for a protein with 324 amino acids, 303 amino acids being identical to the published rat DSP sequence. However, the subsequent 21 amino acids are unique to this cDNA. Based on the coding sequence, the core protein is predicted to have a pI=4.24, a net charge of -34, and to contain four potential N-glycosylation sites and six potential sites for phosphorylation by casein kinase. That the corresponding mRNA was present in day 5 molar tooth germs was confirmed using RNA protection assays. These data, therefore, identify a novel transcript in rat tooth germs that codes only for DSP (designated as DSPII).
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PMID:A novel rat dentin mRNA coding only for dentin sialoprotein. 1169 56

UDP-glucuronate decarboxylase (UGD) catalyzes the formation of UDP-xylose from UDP-glucuronate. UDP-xylose is then used to initiate glycosaminoglycan biosynthesis on the core protein of proteoglycans. In a yeast two-hybrid screen with the protein kinase Akt (protein kinase B), we detected interactions with a novel sequence, which we cloned and expressed. The expressed protein displayed UGD activity but did not display the activities of homologous nucleotide sugar epimerases or dehydratases. We did not detect phosphorylation of UGD by Akt nor did we detect any influence of Akt on UGD activity. Effects of UGD on Akt kinase activity were also absent. Northern blot and Western blot analyses revealed the presence of UGD in multiple tissues and brain regions. Subcellular studies and histochemistry localized UGD protein to the perinuclear Golgi where xylosylation of proteoglycan core proteins is known to occur.
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PMID:UDP-glucuronate decarboxylase, a key enzyme in proteoglycan synthesis: cloning, characterization, and localization. 1187 87


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