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)

Two cDNAs encoding novel mosaic proteins with a serine protease domain and potential regulatory modules, consisting of a protein kinase substrate and a low-density lipoprotein receptor, were cloned from a human lung cDNA library by PCR. One with a transmembrane domain (MSPL) and the other without one (MSPS) comprise 581 and 537 amino acids, respectively. Except for the C-terminal ends, the two isoforms had an identical serine protease domain exhibiting 42, 39 and 43% identity with those of plasma kallikrein, hepsin and transmembrane protease serine 2, respectively. Both genes were predominantly expressed in human lung, placenta, pancreas and prostate.
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PMID:Cloning and expression of novel mosaic serine proteases with and without a transmembrane domain from human lung. 1126 81

Aldosterone may play a pivotal role in the pathophysiology of heart failure. To elucidate the beneficial cardioprotective mechanism of eplerenone, a novel selective aldosterone blocker, we hypothesized that eplerenone stimulates endothelial NO synthase (eNOS) through Akt and inhibits inducible NO synthase (iNOS) via nuclear factor kappaB (NF-kappaB) after the development of oxidative stress and activation of the lectin-like, oxidized, low-density lipoprotein receptor 1 (LOX-1) pathway in Dahl salt-sensitive rats with heart failure. Eplerenone (10, 30, and 100 mg/kg per day) was given from the age of the left ventricular hypertrophy stage (11 weeks) to the failing stage (18 weeks) for 7 weeks. The left ventricular end-systolic pressure-volume relationship was evaluated using a conductance catheter. Decreased percentage of fractional shortening by echocardiography and end-systolic pressure-volume relationship in failing rats was significantly ameliorated by eplerenone. Downregulated eNOS expression, eNOS and Akt phosphorylation, and NOS activity in failing rats were increased by eplerenone. Upregulated expression of the mineralocorticoid receptor aldosterone synthase (CYP11B2); NAD(P)H oxidase p22phox, p47phox, gp91phox, iNOS, and LOX-1; and activated p65 NF-kappaB, protein kinase CbetaII, c-Src, p44/p42 extracellular signal-regulated kinase, and p70S6 kinase phosphorylation were inhibited by eplerenone. Eplerenone administration resulted in significant improvement of cardiac function and remodeling and upregulation of sarcoplasmic reticulum Ca(2+)-ATPase expression. These findings suggest that eplerenone may have significant therapeutic potential for heart failure, and these cardioprotective mechanisms of eplerenone may be mediated in part by stimulating eNOS through Akt and inhibiting iNOS via NF-kappaB after activation of the oxidative stress-LOX-1 pathway and signal transduction pathway.
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PMID:Cardioprotective mechanisms of eplerenone on cardiac performance and remodeling in failing rat hearts. 1650 12

Protease nexin-1 (PN-1), an inhibitor of serine proteases, contributes to tissue homeostasis and influences the behavior of some tumor cells. The internalization of PN-1 protease complexes is considered to be mediated by the low-density lipoprotein receptor related protein 1 (LRP1). In this study, both wild-type and LRP1-/- mouse embryonic fibroblasts (MEF) were shown to internalize PN-1. Receptor associated protein (RAP) interfered with PN-1 uptake only in wild-type MEF cells, indicating that another receptor mediates PN-1 uptake in the absence of LRP1. In LRP1-/- MEF cells, inhibitor sensitivity and kinetic values (t(1/2) at 45 min) of PN-1 uptake showed a similarity to syndecan-1-mediated endocytosis. In these cells, PN-1 uptake was increased by overexpression of full-length syndecan-1 and decreased by RNA interference targeting this proteoglycan. Most important, in contrast to PKA activation known to be triggered by LRP1-mediated internalization, our study shows that syndecan-1-mediated internalization of PN-1 stimulated the Ras-ERK signaling pathway.
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PMID:Activation of ERK signaling upon alternative protease nexin-1 internalization mediated by syndecan-1. 1674 52

Apolipoprotein E (apoE)-containing lipoproteins (LPs) are secreted by glia and play important roles in lipid homeostasis in the CNS. Glia-derived LPs also promote synaptogenesis and stimulate axon growth of CNS neurons. Here, we provide evidence that glia-derived LPs protect CNS neurons from apoptosis by a receptor-mediated signaling pathway. The protective effect was greater for apolipoprotein E3 than for apolipoprotein E4, the expression of which is a risk factor for Alzheimer's disease. The anti-apoptotic effect of LPs required the association of apolipoprotein E with lipids but did not require cholesterol. Apoptosis was not prevented by lipids alone or by apoA1- or apoJ-containing lipoproteins. The prevention of neuronal apoptosis was initiated after the binding of LPs to the low-density lipoprotein receptor-related protein (LRP), a multifunctional receptor of the low-density lipoprotein receptor family. We showed that inhibition of LRP activation, by treatment of neurons with receptor-associated protein or anti-LRP antibodies, or by LRP gene-silencing experiments, reduced the protective effect of LPs. Furthermore, another LRP ligand, alpha2-macroglobulin, also protected the neurons from apoptosis. After binding to LRP, LPs initiate a signaling pathway that involves activation of protein kinase Cdelta and inactivation of glycogen synthase kinase-3beta. These findings indicate the potential for using glial lipoproteins or an activator of the LRP signaling pathway for treatment for neurodegenerative disorders such as Alzheimer's disease.
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PMID:Apolipoprotein E-containing lipoproteins protect neurons from apoptosis via a signaling pathway involving low-density lipoprotein receptor-related protein-1. 1731 89

Low-density lipoprotein receptor-related protein 6 (LRP6) is a member of low-density lipoprotein receptor (LDLR) family which cooperates with Frizzled receptors to transduce the canonical Wnt signal. As a critical component of the canonical Wnt pathway, LRP6 is essential for appropriate brain development, however, the mechanism by which LRP6 facilitates Wnt canonical signaling has not been fully elucidated. Interestingly, LRP6 which lacks its extracellular domain can constitutively activate TCF/LEF and potentiate the Wnt signal. Further, the free cytosolic tail of LRP6 interacts directly with glycogen synthase kinase (GSK3) and inhibits GSK3's activity in the Wnt canonical pathway which results in increased TCF/LEF activation. However, whether these truncated forms of LRP6 are physiologically relevant is unclear. Recent studies have shown that other members of the LDLR family undergo gamma-secretase dependent regulated intramembrane proteolysis (RIP). Using independent experimental approaches, we show that LRP6 also undergoes RIP. The extracellular domain of LRP6 is shed and released into the surrounding milieu and the cytoplasmic tail is cleaved by gamma-secretase-like activity to release the intracellular domain. Furthermore, protein kinase C, Wnt 3a and Dickkopf-1 modulate this process. These findings suggest a novel mechanism for LRP6 in Wnt signaling: induction of ectodomain shedding of LRP6, followed by the gamma-secretase involved proteolytic releasing its intracellular domain (ICD) which then binds to GSK3 inhibiting its activity and thus activates the canonical Wnt signaling pathway.
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PMID:Regulated proteolytic processing of LRP6 results in release of its intracellular domain. 1732 69

WNTs (Wingless-type MMTV integration site family member) are involved in critical developmental and growth processes in animals. These studies investigated WNT pathways in the ovine uterus and conceptus during the periimplantation period of pregnancy. WNT2 and WNT2B mRNAs were detected in endometrial stroma. WNT5A and WNT5B mRNAs were most abundant in the stroma and less so in the luminal epithelium, whereas WNT11 mRNA was detected primarily in the glands. WNT7A mRNA was present in the luminal epithelium on d 10, absent on d 12 and 14, and increased between d 16 and 20. Only WNT2, WNT2B, and WNT4 were detected in conceptus trophectoderm. FZD6/8 (frizzled receptor) and GSK3B (glycogen synthase kinase 3beta) mRNAs were detected primarily in endometrial epithelia and conceptus trophectoderm, whereas the LRP5/6 (low-density lipoprotein receptor-related proteins 5 and 6) coreceptor was present in all endometrial cells and the trophectoderm. DKK1 (Dickkopf), a WNT signaling inhibitor, increased in the endometrium from d 16-20. CTNNB1 [catenin (cadherin associated protein) beta1] and CDH1 (E-cadherin) mRNAs were most abundant in the endometrial epithelia and trophectoderm. LEF1 (lymphoid enhancer-binding factor 1) mRNA was expressed primarily in uterine epithelia, whereas TCF7L2 [(transcription factor 7-like 2 (T-cell specific, HMG-box)] was primarily in the conceptus. CTNNB1 and TCF7L2 proteins were both abundant in the nuclei of trophoblast giant binucleate cells. WNT7A stimulated a TCF/LEF-luciferase reporter activity in ovine trophectoderm cells that was inhibited by dominant-negative TCF and Sfrp2 (secreted FZD-related protein 2). WNT7A increased trophectoderm cell proliferation as well as MSX2 (msh homeobox 2) and MYC (myelocytomatosis oncogene) mRNA levels. Wnt5a increased trophectoderm cell migration in a Rho kinase-dependent manner. These results support the hypotheses that canonical and noncanonical WNT signaling pathways are conserved regulators of conceptus-endometrial interactions in mammals and regulate periimplantation ovine conceptus development.
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PMID:WNTs in the ovine uterus: potential regulation of periimplantation ovine conceptus development. 1743 Oct 4

After transmission by infected mosquitoes, malaria sporozoites rapidly travel to the liver. To infect hepatocytes, sporozoites traverse Kupffer cells, but surprisingly, the parasites are not killed by these resident macrophages of the liver. Here we show that Plasmodium sporozoites and recombinant circumsporozoite protein (CSP) suppress the respiratory burst in Kupffer cells. Sporozoites and CSP increased the intracellular concentration of cyclic adenosyl mono-phosphate (cAMP) and inositol 1,4,5-triphosphate in Kupffer cells, but not in hepatocytes or liver endothelia. Preincubation with cAMP analogues or inhibition of phosphodiesterase also inhibited the respiratory burst. By contrast, adenylyl cyclase inhibition abrogated the suppressive effect of sporozoites. Selective protein kinase A (PKA) inhibitors failed to reverse the CSP-mediated blockage and stimulation of the exchange protein directly activated by cAMP (EPAC), but not PKA inhibited the respiratory burst. Both blockage of the low-density lipoprotein receptor-related protein (LRP-1) with receptor-associated protein and elimination of cell surface proteoglycans inhibited the cAMP increase in Kupffer cells. We propose that by binding of CSP to LRP-1 and cell surface proteoglycans, malaria sporozoites induce a cAMP/EPAC-dependent, but PKA-independent signal transduction pathway that suppresses defence mechanisms in Kupffer cells. This allows the sporozoites to safely pass through these professional phagocytes and to develop inside neighbouring hepatocytes.
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PMID:Malaria circumsporozoite protein inhibits the respiratory burst in Kupffer cells. 1757 5

Atherosclerosis is a chronic inflammatory disease and represents the major cause of cardiovascular morbidity and mortality. A critical regulator of inflammatory processes represents the mitogen-activated protein kinase-activated protein kinase-2 (MK2). Therefore, we investigated the functional role of MK2 in atherogenesis in hypercholesterolemic mice as well as potentially underlying mechanisms in vivo and in vitro. Activation of MK2 (phospho-MK2) was predominantly detected in the endothelium and macrophage-rich plaque areas within aortas of hypercholesterolemic LDL receptor-deficient mice (ldlr(-/-)). Systemic MK2 deficiency of hypercholesterolemic ldlr(-/-) mice (ldlr(-/-)/mk2(-/-)) significantly decreased the accumulation of lipids and macrophages in the aorta after feeding an atherogenic diet for 8 and 16 weeks despite a significant increase in proatherogenic plasma lipoproteins compared with ldlr(-/-) mice. Deficiency of MK2 significantly decreased oxLDL-induced foam cell formation in vitro, diet-induced foam cell formation in vivo, and expression of scavenger receptor A in primary macrophages. In addition, systemic MK2 deficiency of hypercholesterolemic ldlr(-/-) mice significantly decreased the aortic expression of the adhesion molecule VCAM-1 and the chemokine MCP-1, key mediators of macrophage recruitment into the vessel wall. Furthermore, silencing of MK2 in endothelial cells by siRNA reduced the IL-1beta-induced expression of VCAM-1 and MCP-1. MK2 critically promotes atherogenesis by fostering foam cell formation and recruitment of monocytes/macrophages into the vessel wall. Therefore, MK2 might represent an attractive novel target for the treatment of atherosclerotic cardiovascular disease.
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PMID:Systemic deficiency of the MAP kinase-activated protein kinase 2 reduces atherosclerosis in hypercholesterolemic mice. 1788 19

Proprotein convertase subtilisin/kexin 9 (PCSK9) is a secreted glycoprotein that regulates the degradation of the low-density lipoprotein receptor. Single nucleotide polymorphisms in its gene associate with both hypercholesterolemia and hypocholesterolemia, and studies have shown a significant reduction in the risk of coronary heart disease for 'loss-of-function' PCSK9 carriers. Previously, we reported that proPCSK9 undergoes autocatalytic processing of its prodomain in the endoplasmic reticulum and that its inhibitory prosegment remains associated with it following secretion. Herein, we used a combination of mass spectrometry and radiolabeling to report that PCSK9 is phosphorylated at two sites: Ser47 in its propeptide and Ser688 in its C-terminal domain. Site-directed mutagenesis suggested that a Golgi casein kinase-like kinase is responsible for PCSK9 phosphorylation, based on the consensus site, SXE/S(p). PCSK9 phosphorylation was cell-type specific and occurs physiologically because human plasma PCSK9 is phosphorylated. Interestingly, we show that the naturally occurring 'loss-of-function' variant PCSK9(R46L) exhibits significantly decreased propeptide phosphorylation in the Huh7 liver cell line by 34% (P < 0.0001). PCSK9(R46L) and the engineered, unphosphorylated variant PCSK9(E49A) are cleaved following Ser47, suggesting that phosphorylation protects the propeptide against proteolysis. Phosphorylation may therefore play an important regulatory role in PCSK9 function. These findings will be important for the future design of PCSK9 inhibitors.
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PMID:PCSK9 is phosphorylated by a Golgi casein kinase-like kinase ex vivo and circulates as a phosphoprotein in humans. 1849 63

Wnt/wingless signaling contributes to the development of neuronal synapses, including the Drosophila neuromuscular junction. Loss of wg (wingless) function alters the number and structure of boutons at this model synapse. Examining Wnt/wingless signaling mechanisms, we find that a distinct pathway operates presynaptically in the motoneuron and can account for many of the effects of wingless at this synapse. This pathway includes the canonical elements arrow/LRP (low-density lipoprotein receptor-related protein), dishevelled, and the glycogen synthase kinase shaggy (GSK3) and regulates the formation of microtubule loops within synaptic boutons as well as the number of synaptic boutons. This pathway, however, appears to be independent of beta-catenin signaling and the transcriptional regulation that is most frequently downstream of these components. Instead, inhibition of shaggy is likely to act locally. This pathway thus provides a parallel mechanism to the postsynaptic activation of frizzled receptors and indicates that synaptic development results from the bidirectional influence of wingless on both presynaptic and postsynaptic structures via distinct intracellular pathways.
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PMID:Presynaptic local signaling by a canonical wingless pathway regulates development of the Drosophila neuromuscular junction. 1894 95


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