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)

The interaction of Entamoeba histolytica trophozoites with collagen involves cell adherence, formation, and release of electron dense granules (EDGs) containing collagenase activity leading to the degradation of the bound protein. The binding is thought to be mediated by an "integrin-like" collagen receptor. Since the signal transduction mechanisms triggered by the collagen-trophozoite interaction are unknown, but clearly involve cytoskeletal organization, we decided to explore the role of protein tyrosine phosphorylation in this process. Collagen induces a time-dependent increase in the phosphorylation of several polypeptides migrating around 67 and 110 kDa. One polypeptide of the high-molecular-weight component was identified as a 125-kDa protein with very similar epitopes to the focal treatment was a 42-kDa polypeptide related to the mitogen activated protein kinase (MAPK) family. Our results suggest that tyrosine phosphorylation is involved in collagen signaling in amoebas and that pp125FAK and p42MAPK homologs may play an active role in turning on the genetic program that enables the parasite to invade its host.
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PMID:Entamoeba histolytica: involvement of pp125FAK in collagen-induced signal transduction. 861 43

Phosphorylation of rap 1b in human platelets correlates with both an upward shift of the protein on sodium dodecyl sulfate polyacrylamide gels and the translocation of the phosphorylated protein to the cytosolic fraction of platelets. We reported that this phenomenon occurs in platelets in response to agents that stimulate adenylate cyclase and thereby activate the cyclic AMP-dependent protein kinase. We now have evidence that phosphorylation of rap1b in platelets is also induced by nitric oxide generating compounds through stimulation of guanylate cyclase and activation of the cyclic GMP-dependent protein kinase. We observed time-dependent phosphorylation of rap1b and dose-dependent inhibition of collagen-stimulated aggregation in washed platelets incubated with S-nitroso serum albumin. In the presence of a combination of iloprost and 3-morpholinosydnonimine, when both PKA and PKG are activated, phosphorylation of rap1b increased synergistically to a level three times higher than the sum of their individual actions.
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PMID:Nitric oxide stimulates the phosphorylation of rap1b in human platelets and acts synergistically with iloprost. 861 88

The cellular mechanisms associated with the replicative response of hepatocytes to growth factor simulation is incompletely understood. Murine hepatocyte DNA synthesis is altered by cyclic AMP, suggesting that protein kinase A is involved in the cellular mechanisms associated with liver growth. The purpose of this study was to evaluate the role of protein kinase A in human hepatocyte DNA synthesis. human hepatocytes were isolated and maintained in primary culture on rat tail collagen. DNA synthesis was evaluated by determining [3H] thymidine incorporation. Human hepatocytes between 24 and 96 hr following harvest increased DNA synthesis in response to epidermal growth factor but not in response to glucagon, a stimulant of adenyl cyclase, or dibutyryl cyclic AMP. Mitogen-stimulated DNA synthesis was decreased by dibutyryl cyclic AMP. Cyclic AMP isomers that block or stimulate the effect of cyclic AMP on protein kinase A did not significantly alter resting or mitogens-stimulated human hepatocyte DNA synthesis. The results suggest that increased protein kinase A activity does not produce human hepatocyte replicative DNA synthesis.
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PMID:Role of protein kinase A in human hepatocyte DNA synthesis. 862 44

PGs play an important role in regulating articular chondrocyte function in both normal and pathological states. However, the mechanisms of the effects of PG on chondrocyte function remain undefined. We, therefore, examined the effects of PGE1, PGE2, and PGE2 alpha on second messenger generation in relation to DNA and aggrecan synthesis in the nontransformed rat RCJ 3.1C5.18 (RCJ) chondrocyte cell line. RCJ cells were grown under minimal attachment conditions on a composite collagen-agarose (0.15%/0.8%) gel to maintain a differentiated phenotype. PGE1 and PGE2 (0.001-100 microM) produced a similar dose-related increase in cAMP accumulation, with a maximal 8-fold increase over basal values, whereas PGF2 alpha produced a minimal 1.3-fold increase in cAMP levels only at 100 microM. On the other hand, both PGE2 and PGE2 alpha raised the intracellular free calcium ([Ca2+]i) concentration, derived primarily from extracellular sources, whereas PGE1 was without effect on [Ca2+]i. These three PGs also had divergent effects on DNA synthesis, as measured by [3H]thymidine ([3H]TdR) incorporation. PGF2 alpha (0.001-5 microM) produced a dose-related increase in [3H]TdR incorporation, with a maximal 1.6-fold increase over baseline values at 5 microM and a slight decline to below maximal levels at 10 microM. PGE2 exhibited a contrasting inverse biphasic response, with an initial small suppressive effect that was maximal at 0.1 microM and a secondary stimulatory phase producing a small increase over control values at 5 microM. PGE1 had a uniformly suppressive effect, producing a 30% decrease at 10 microM. Despite the divergent effects of PGE1, PGE2, and PGE2 alpha on second messenger generation and DNA synthesis, all three PGs produced a dose-related stimulation of aggrecan synthesis. PGF2 alpha was the most potent, producing significant stimulation at 0.001 microM and a maximal 104% increase at 5 microM. PGE1 and PGE2 were approximately equipotent and approximately 60% as effective as PGF2 alpha in stimulating aggrecan synthesis. Northern analysis demonstrated that the effects of PG on aggrecan synthesis were not accompanied by changes in aggrecan core protein steady state messenger RNA levels. Thus, the effects of PG on aggrecan production in RCJ cells appear to be regulated at the posttranscriptional level. Forskolin and (Bu)2cAMP mimicked the suppressive effects of PGE1 on [3H]TdR incorporation, as well as the stimulatory effect of PGE1 on aggrecan synthesis. In addition, the phorbol ester 12-O-tetradecanoyl phorbol acetate mimicked PGF2 alpha stimulation of [3H]TdR incorporation and aggrecan synthesis, and the effects of PGE2 alpha on these processes were blocked by protein kinase C inhibitors. Therefore, it appears that in mammalian chondrocytes, PGE1 primarily activates the cAMP-protein kinase A second messenger system, PGE2 alpha affects primarily the Ca2(+)-protein kinase C system, and PGE2 activates both pathways. Moreover, PG posttranscriptional regulation of aggrecan synthesis in chondrocytes involves both the cAMP-protein kinase A and Ca2(+)-protein kinase C second messenger systems.
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PMID:Effects of prostaglandins on deoxyribonucleic acid and aggrecan synthesis in the RCJ 3.1C5.18 chondrocyte cell line: role of second messengers. 864 Nov 67

Tumor cell adhesion to and migration through the extracellular matrix (ECM) can influence their capacity to disseminate. Since prior studies with Lewis lung carcinoma (LLC) tumors had shown metastatic clones to have more protein kinase A (PKA) activity than nonmetastatic clones, the present study assessed if PKA regulates the interaction between tumor and the ECM, and how this may be associated with the metastatic capacity of the tumor cells. This was accomplished with the use of metastatic (LLC-LN7) and nonmetastatic (LLC-C8) variants that had been stably transfected to overexpress the PKA Calpha subunit or to have blocked PKA activity. Cells with increased PKA activity were less adherent to vitronectin, laminin, and collagen I, and could more readily migrate through these ECM components than could transfectants with reduced PKA activity. PKA did not regulate adhesion to or migration through fibronectin, and did not appear to be associated with changes in expression of surface integrins. In addition to modulating tumor adhesion and migration in vitro, PKA activation caused an increased formation of metastases from s.c. tumors, but did not regulate formation of experimental metastases by i.v. injected tumor cells. These results suggest that PKA signaling is important for modulating the tumor-ECM interaction and can facilitate tumor transit from the primary tumor site.
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PMID:Protein kinase A regulates Lewis lung carcinoma adherence to extracellular matrix components and spontaneous metastasis. 867 86

The mineralization process associated with the conversion of predentin to dentin is believed to be initiated and controlled by a set of acidic regulatory noncollagenous proteins (NCPs) which include phosphophoryn, the major NCP in dentin. Phosphophoryn binds tightly to collagen and is believed to initiate the formation of apatite crystals which play a central role in the mineralization process. During the process of analyzing the 3' end of an odontoblast-specific cDNA which codes for dentin sialoprotein (Ritchie, H. H., Hou, H., Veis, A., and Butler, W. T. (1994) J. Biol. Chem. 269, 3698-3702), we discovered a 801-base pair open reading frame. This downstream open reading frame encodes a putative leader sequence and a very acidic mature protein sequence having a deduced amino acid composition containing high percentages of both Ser (43%) and Asp (31%) residues which closely coincides with the amino acid composition of phosphophoryns from human, bovine, rat, and rabbit (i. e. Asp (30-40%) and Ser (38-50%)). This newly identified cDNA therefore encodes a protein with characteristics similar to phosphophoryn. Here we present the cDNA sequence, the deduced amino acid sequence, and the prospective Ser residue-specific casein kinase I and II phosphorylation sites for this putative phosphophoryn.
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PMID:Sequence determination of an extremely acidic rat dentin phosphoprotein. 870 61

ADP-induced platelet responses play an important role in the maintenance of hemostasis. There has been disagreement concerning the identity of an ADP receptor on the platelet surface. The chemical structure of 7-chloro-4-nitrobenz-2-oxa-1,3-diazole (NBD-CI) shows considerable resemblance to that of the adenine moiety of adenine-based nucleotides. The reagent has been previously used by other investigators as an affinity label for adenine nucleotide-requiring enzymes, such as mitochondrial ATPase and the catalytic subunit of cAMP-dependent protein kinase. Since ADP-induced platelet responses depend on the binding of ADP to its receptor, we investigated the effect on ADP-induced platelet responses and the nature of ADP-binding protein modified by NBD-CI. NBD-CI inhibited ADP-induced shape change and aggregation of platelets in platelet-rich plasma in a concentration- and time-dependent manner. NBD-CI also inhibited ADP-induced shape change, aggregation, exposure of fibrinogen binding sites, secretion, and calcium mobilization in washed platelets. NBD-CI did not act as an agonist for platelet shape change and aggregation. Covalent modification of platelets by NBD-CI blocked the ability of ADP to antagonize the increase in intracellular levels of cAMP mediated by iloprost (a stable analogue of prostaglandin I2). NBD-CI was quite specific in inhibiting platelet aggregation by those agonists, e.g., ADP, collagen, and U44619 (a thromboxane mimetic), that completely or partially depend on the binding of ADP to its receptor. Autoradiogram of the gel obtained by SDS-PAGE of solubilized platelets modified by [14C]-NBD-CI showed the presence of a predominant radiolabeled protein band at 100 kDa corresponding to aggregin, a putative ADP receptor. The intensity of this band was considerably decreased when platelets were either preincubated with ADP and ATP or covalently modified by a sulfhydryl group modifying reagent before modification by [14C]-NBD-CI. These results (1) indicate that covalent modification of aggregin by NBD-CI contributed to loss of the ADP-induced platelet responses, and (2) suggest that there is a sulfhydryl group in the ADP-binding domain of aggregin.
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PMID:Inhibition of ADP-induced platelet activation by 7-chloro-4-nitrobenz-2-oxa-1,3-diazole: covalent modification of aggregin, a putative ADP receptor. 872 59

Myofibroblasts of the lamina propria of human seminiferous tubules were studied in testes having normal or slightly reduced spermatogenesis by means of electron microscopy, confocal laser microscopy and immunocytochemistry. Myofibroblasts are large, flat individual cells braced in a network of microfibrils and collagen fibrils in the tubular wall. They are arranged in discontinuous cell layers with interposed layers of an extracellular matrix. Myofibroblasts of the lamina propria exhibit an unique cell shape with the peripheral cytoplasm split up in two or more layers. After FITC-phalloidin staining and by means of confocal laser microscopy, actin filaments of variable orientation are visible in their cytoplasm. The thickness and preferential direction of actin filaments differ in the outer and innermost cell layers. The myofibroblasts express both antigens of smooth muscle cells (alpha-smooth muscle actin, pan-actin, desmin, GB 42, smooth muscle myosin), and of connective tissue cells (vimentin, fibroblast surface protein). The variable expression of these antigens evidenced the existence of different phenotypes of myofibroblasts. Immunoreactivity for basic fibroblast growth factor and transforming growth factor beta as well as for components of the extracellular matrix indicate that these agents may be important for the phenotypic differentiation of the lamina propria cells. The detection of CNPase-and galactocerebroside-immunoreactivity in a number of lamina propria cells and some cells of the intertubular tissue gives rise to the hypothesis that components of the testicular tissue share some structural similarities with glia cells of the nervous system. Finally, immunoreactivities for the neuronal and endothelial nitric oxide synthase, soluble guanylyl cyclase, cyclic GMP, calmodulin, calcium-dependent protein kinase II and glutamate indicate that the contractility of myofibroblasts in the lamina propria of human seminiferous tubules may be in part modulated by the NO/cGMP-system.
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PMID:Myofibroblasts in the lamina propria of human semi-niferous tubules are dynamic structures of heterogeneous phenotype. 879 Aug 58

The dephosphorylating enzyme alkaline phosphatase, by removing phosphate groups from the external platelet membrane proteins, modulates platelet activation (Hatmi, M., Haye, B., Gavaret, J. M., Vargaftig, B. B., and Jacquemin, C. (1991) Br. J. Pharmacol. 104, 554-558). This observation, together with findings reported by others (Ehrlich, Y. H., Davis, T. B., Bock, E., Kornecki, E., and Lenox, R. H. (1986) Nature 320, 67-70; Dusenbery, K. E., Mendiola, J. R., and Skubitz, K. M. (1988) Biochem. Biophys. Res. Commun. 153, 7-13), indicate the existence of ectoprotein kinase activity on the blood platelet surface. In this study, we demonstrate that washed human platelets phosphorylate the synthetic heptapeptide kemptide in a cAMP-dependent mode. The intensity of the phosphorylation was concentration-dependent for kemptide. In addition, incubation of platelets with [gamma-32P]ATP resulted in a rapid incorporation of [32P] phosphate into proteins at the outer membrane surface that was sensitive to alkaline phosphatase treatment. When cAMP was added to the medium, major phosphorylation of an 88-kDa ectoprotein occurred. Its isoelectric point determined by isoelectric focusing SDS-polyacrylamide gel electrophoresis was around pH 6.2. Phosphorylations of this 88-kDa polypeptide and of the exogenous kemptide substrate were both prevented by the specific protein kinase A inhibitor peptide. When platelets were preincubated with [32P]inorganic phosphate to label intracellular proteins, the protein phosphorylation pattern was different from that obtained with [gamma-32P]ATP, indicating that the latter occurred at the outer surface of the cells. Prostacyclin, which induces the increase of intracellular cAMP levels and, consequently, its liberation into the extracellular medium, increased phosphorylation of both kemptide and platelet 88-kDa polypeptide. The major protein of 88-kDa, which was phosphorylated in the presence of cAMP and external [gamma-32P]ATP, was identified by immunoprecipitation to GPIV (CD36), one of thrombospondin and collagen binding sites on platelets. The phosphorylation of CD36 also occurred in platelet-rich plasma, suggesting a physiological role for this ectoenzyme. In the present study, we clearly demonstrate the presence of an ectoprotein kinase A activity at the surface of intact human platelets, and we revealed its principal endogenous substrate as being CD36.
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PMID:Evidence for cAMP-dependent platelet ectoprotein kinase activity that phosphorylates platelet glycoprotein IV (CD36). 879 48

Hepatocyte growth factor (HGF) has been implicated as a paracrine regulator of organogenesis and repair in many tissues. Here we have studied the expression and actions of HGF in intact rachitic rat growth plate and derived cultures of proliferative zone chondrocytes. In vivo and in vitro chondrocytes express HGF mRNA; 1,25(OH)2 has a three-fold maximal stimulatory effect, which can be blocked by H-7, an inhibitor of protein kinase C. Although HGF elaboration and action generally follow a paracrine model, chondrocytes appear capable of both expressing and responding to HGF. mRNA encoding the HGF receptor (c-met) was detected in both growth cartilage and derived chondrocyte cultures. HGF addition to chondrocyte cultures increased collagen II mRNA and alkaline phosphatase enzymatic activity to degrees comparable to that observed for active vitamin D metabolites. Combining HGF and 1,25-D evoked a synergistic response (ninefold) of alkaline phosphatase activity. To assess whether a similar stimulatory effect might be seen with bioactive peptides and HGF, we investigated the effect of HGF pretreatment on acute responses of chondrocytes to synthetic human calcitonin, an anabolic chondrocyte regulator whose skeletal action are mediated principally by cAMP elevation and subsequent protein kinase A activation. CT's maximal activation of protein kinase A was increased by prior HGF treatment from 56% to 78%. In concert, our findings indicate that in addition to HGF's classical paracrine role during skeletal growth, this growth factor may modulate hormonal sensitivity of the chondrocyte during proliferation, differentiation, and/or apoptosis.
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PMID:Hepatocyte growth factor and its actions in growth plate chondrocytes. 887 66


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