Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.11.1 (protein kinase)
 81,284 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

The Wnt signaling pathway has recently been demonstrated to play an important role in bone cell function. In previous studies using DNA microarray analyses, we observed a change in some of the molecular components of the canonical Wnt pathway namely, frizzled-1 (FZD-1) and axil, in response to continuous parathyroid hormone (PTH) treatment in rats. In the present study, we further explored other components of the Wnt signaling pathway in rat distal metaphyseal bone in vivo, and rat osteoblastic osteosarcoma cells (UMR 106) in culture. Several Wnt pathway components, including low-density lipoprotein-receptor-related protein 5 (LRP5), LRP6, FZD-1, Dickkopf-1 (Dkk-1), and Kremen-1 (KRM-1), were expressed in bone in vivo and in osteoblasts in vitro. Continuous exposure to PTH (1-38) both in vivo and in vitro upregulated the mRNA expression of LRP6 and FZD-1 and decreased LRP5 and Dkk-1. These effects in UMR 106 cells were associated with an increase in beta-catenin as measured by Western blots and resulted in functional activation (three to six-fold) of a downstream Wnt responsive TBE6-luciferase (TCF/LEF-binding element) reporter gene. Activation of the TBE6-luciferase reporter gene by PTH (1-38) in UMR 106 cells was inhibited by the protein kinase A (PKA) inhibitor, H89. Activation was mimicked by PTH (1-31), PTH-related protein (1-34), and forskolin, but both PTH (3-34) and (7-34) had no effect. These findings suggest that the effect of PTH on the canonical Wnt signaling pathway occurs at least in part via the cAMP-PKA pathway through the differential regulation of the receptor complex proteins (FZD-1/LRP5 or LRP6) and the antagonist (Dkk-1). Taken together, these results reveal a possible role for the Wnt signaling pathway in PTH actions in bone.
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PMID:Effects of parathyroid hormone on Wnt signaling pathway in bone. 1596 90

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

Although the intermittent administration of PTH is known to stimulate the bone formation, the underlying mechanisms are not fully understood. Here we investigated the crosstalk between PTH/cAMP signaling and canonical Wnt signaling using the human osteoblastic cell line Saos-2. Treatment with PTH or forskolin, an activator of adenylate cyclase, facilitated T-cell factor (TCF)-dependent transactivation in a dose-dependent manner, which was abolished by pre-treatment with a PKA inhibitor, H89. Wnt3a and forskolin synergistically increased the TCF-dependent transactivation. Interestingly, intermittent treatment with PTH enhanced the TCF-dependent transactivation more profoundly than continuous treatment. In addition to the effects on TCF-dependent reporter activity, treatment with PTH or forskolin resulted in the increased expression of endogenous targets of Wnts, Wnt-induced secreted protein 2 (WISP2) and naked cuticle 2 (NKD2). We then investigated the convergence point of PTH/cAMP signaling and the canonical Wnt pathway. Western blotting demonstrated that GSK-3beta was rapidly phosphorylated at Ser(9) on treatment with PTH or forskolin, leading to its inactivation. Moreover, overexpression of a constitutively active mutant of GSK-3beta abolished the TCF-dependent transactivation induced by forskolin. On the other hand, overexpression of the Wnt antagonist Dickkopf-1 (DKK1) failed to cancel the effects of forskolin on the canonical Wnt pathway. Interestingly, treatment with Wnt3a markedly reduced the forskolin-induced expression of receptor activator of NF-kappaB ligand (RANKL), a target gene of PTH/cAMP/PKA. These results suggest that cAMP/PKA signaling activates the canonical Wnt pathway through the inactivation of GSK-3beta, whereas Wnt signaling might inhibit bone resorption through a negative impact on RANKL expression in osteoblasts.
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PMID:PTH/cAMP/PKA signaling facilitates canonical Wnt signaling via inactivation of glycogen synthase kinase-3beta in osteoblastic Saos-2 cells. 1799 Feb 94

3,4-Methylenedioxymethamphetamine (MDMA) ("Ecstasy") produces neurotoxic effects, which result into an impairment of learning and memory and other neurological dysfunctions. We examined whether MDMA induces increases in tau protein phosphorylation, which are typically associated with Alzheimer's disease and other chronic neurodegenerative disorders. We injected mice with MDMA at cumulative doses of 10-50 mg/kg intraperitoneally, which are approximately equivalent to doses generally consumed by humans. MDMA enhanced the formation of reactive oxygen species and induced reactive gliosis in the hippocampus, without histological evidence of neuronal loss. An acute or 6 d treatment with MDMA increased tau protein phosphorylation in the hippocampus, revealed by both anti-phospho(Ser(404))-tau and paired helical filament-1 antibodies. This increase was restricted to the CA2/CA3 subfields and lasted 1 and 7 d after acute and repeated MDMA treatment, respectively. Tau protein was phosphorylated as a result of two nonredundant mechanisms: (1) inhibition of the canonical Wnt (wingless-type MMTV integration site family) pathway, with ensuing activation of glycogen synthase kinase-3beta; and (2) activation of type-5 cyclin-dependent kinase (Cdk5). MDMA induced the expression of the Wnt antagonist, Dickkopf-1, and the expression of the Cdk5-activating protein, p25. In addition, the increase in tau phosphorylation was attenuated by strategies that rescued the Wnt pathway or inhibited Cdk5. Finally, an impairment in hippocampus-dependent spatial learning was induced by doses of MDMA that increased tau phosphorylation, although the impairment outlasted this biochemical event. We conclude that tau hyperphosphorylation in the hippocampus may contribute to the impairment of learning and memory associated with MDMA abuse.
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PMID:Enhanced tau phosphorylation in the hippocampus of mice treated with 3,4-methylenedioxymethamphetamine ("Ecstasy"). 1835 27

Wnts are secreted glycoproteins that control diverse biological processes, such as proliferation, differentiation, and apoptosis. We here found that Wnt5a inhibited apoptosis induced by serum deprivation in primary-cultured human dermal fibroblasts. Anti-apoptotic activity of Wnt5a was not inhibited by a dickkopf-1 (DKK), which blocks the canonical Wnt pathway. On the other hand, loss of function of protein kinase A (PKA), induced by treatment with PKA inhibitors, siRNA-mediated knocking down of endogenous PKA catalytic subunits, or enforced expression of dominant-negative PKA inhibited the Wnt5a anti-apoptotic activity, indicating the involvement of PKA in the Wnt5a anti-apoptotic activity. In agreement, phosphorylation levels of a cAMP response element binding protein (CREB), a representative downstream effector of PKA, the activation of which is known to lead to the pro-survival effects, was elevated by Wnt5a. In addition, Wnt5a increased the nuclear beta-catenin level and treatment with imatinib or ionomycin, either of which blocks the beta-catenin pathway, reduced the anti-apoptotic activity of Wnt5a, together suggesting the simultaneous involvement of the beta-catenin-mediated pathway in the Wnt5a anti-apoptotic activity. Based on another finding indicating that Wnt5a upregulated PKA-mediated phosphorylation of glycogen synthase kinase-3beta (GSK-3beta) at serine 9 that caused inactivation of GSK-3beta and subsequently resulted in activation of the beta-catenin pathway, we have speculated that the Wnt5a anti-apoptotic activity may be partially mediated by PKA-mediated phosphorylation of GSK-3beta and subsequent activation of the beta-catenin pathway.
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PMID:Anti-apoptotic action of Wnt5a in dermal fibroblasts is mediated by the PKA signaling pathways. 1840 62

This study investigates involvement of beta-catenin signalling in regulation of p-glycoprotein (p-gp) expression in endothelial cells derived from brain vasculature. Pharmacological interventions that enhance or that block beta-catenin signalling were applied to primary rat brain endothelial cells and to immortalized human brain endothelial cells, hCMEC/D3, nuclear translocation of beta-catenin being determined by immunocytochemistry and by western blot analysis to confirm effectiveness of the manipulations. Using the specific glycogen synthase kinase-3 (GSK-3) inhibitor 6-bromoindirubin-3'-oxime enhanced beta-catenin and increased p-gp expression including activating the MDR1 promoter. These increases were accompanied by increases in p-gp-mediated efflux capability as observed from alterations in intracellular fluorescent calcein accumulation detected by flow cytometry. Similar increases in p-gp expression were noted with other GSK-3 inhibitors, i.e. 1-azakenpaullone or LiCl. Application of Wnt agonist [2-amino-4-(3,4-(methylenedioxy) benzylamino)-6-(3-methoxyphenyl)pyrimidine] also enhanced beta-catenin and increased transcript and protein levels of p-gp. By contrast, down-regulating the pathway using Dickkopf-1 or quercetin decreased p-gp expression. Similar changes were observed with multidrug resistance protein 4 and breast cancer resistance protein, both known to be present at the blood-brain barrier. These results suggest that regulation of p-gp and other multidrug efflux transporters in brain vasculature can be influenced by beta-catenin signalling.
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PMID:Activation of beta-catenin signalling by GSK-3 inhibition increases p-glycoprotein expression in brain endothelial cells. 1862 6

17beta-Estradiol (E2) has been implicated to be neuroprotective in a variety of neurodegenerative disorders, although the mechanism remains poorly understood. The current study sheds light on this issue by demonstrating that low physiological levels of E2 protects the hippocampus CA1 against global cerebral ischemia by preventing elevation of dickkopf-1 (Dkk1), an antagonist of the Wnt/beta-catenin signaling pathway, which is a principal mediator of neurodegeneration in cerebral ischemia and Alzheimer's disease. E2 inhibition of Dkk1 elevation correlated with a reduction of phospho-beta-catenin and elevation of nuclear beta-catenin levels, as well as enhancement of Wnt-3, suggesting E2 activation of the Wnt/beta-catenin signaling pathway. In agreement, the beta-catenin downstream prosurvival factor, survivin, was induced by E2 at 24 and 48 h after cerebral ischemia, an effect observed only in surviving neurons because degenerating neurons lacked survivin expression. E2 suppression of Dkk1 elevation was found to be caused by attenuation of upstream c-Jun N-terminal protein kinase (JNK)/c-Jun signaling, as E2 attenuation of JNK/c-Jun activation and a JNK inhibitor significantly blocked Dkk1 induction. Tau hyperphosphorylation has been implicated to have a prodeath role in Alzheimer's disease and cerebral ischemia, and E2 attenuates tau hyperphosphorylation. Our study demonstrates that tau hyperphosphorylation is strongly induced after global cerebral ischemia, and that E2 inhibits tau hyperphosphorylation by suppressing activation of the JNK/c-Jun/Dkk1 signaling pathway. Finally, exogenous Dkk1 replacement via intracerebroventricular administration completely reversed E2-induced neuroprotection, nuclear beta-catenin induction, and phospho-tau attenuation, further suggesting that E2 inhibition of Dkk1 is a critical mechanism underlying its neuroprotective and phospho-tau regulatory effects after cerebral ischemia.
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PMID:Role of Dickkopf-1, an antagonist of the Wnt/beta-catenin signaling pathway, in estrogen-induced neuroprotection and attenuation of tau phosphorylation. 1871 1

Migration is an important process during cellular activity and embryo development. We recently showed that Dickkopf-1(Dkk-1), an antagonist of Wnt/ beta-catenin signaling pathway, could promote trophoblast cell invasion during murine placentation. However, mechanism of Dkk-1 action on cell migration was not clear. The objective of this study was to further evaluate the effect of Dkk-1 on cell migration and to identify the underlining mechanisms. Functional assays with stable Dkk-1 transfected HEK293 cells revealed that Dkk-1 expression increased cell migration by decreasing cell-cell adhesion, not cell-matrix adhesion. Treatment with LiCl and Genistein (widely used inhibitor of glycogen synthase kinase-3 and tyrosine protein kinase, respectively.) could inhibit the migration effect of Dkk-1, and significantly increased the membrane localization of beta-catenin and E-cadherin in HEK293 cells transfected with Dkk-1. Further data showed that HEK293 cells transfected with Dkk-1 have significantly decreased accumulation of both beta-catenin and E-cadherin at the cell membrane. Together, our data suggest that Dkk-1 stimulates the release of beta-catenin from cell membrane and facilitates cell migration which accompanies degradation of beta-catenin/E-cadherin.
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PMID:Dickkopf-1 enhances migration of HEK293 cell by beta-catenin/E-cadherin degradation. 1927 95

Invasion of human trophoblasts is promoted through activation of wingless (Wnt) signaling, suggesting a role of the pathway in placental development and morphogenesis. However, details on the process such as involvement of canonical and/or noncanonical Wnt signaling cascades as well as their target genes are largely unknown. Hence, signal transduction via canonical Wnt signaling or phosphatidylinositide 3-kinase (PI3K)/AKT and their cross talk as well as trophoblast-specific protease expression were investigated in trophoblastic SGHPL-5 cells and primary extravillous trophoblasts purified from first-trimester placentas. Western blot analyses revealed that the recombinant Wnt ligand Wnt-3A increased phosphorylation of AKT and the downstream kinase glycogen synthase kinase (GSK)-3beta as well as accumulation of activated, nuclear beta-catenin. In accordance, luciferase expression of a canonical Wnt/TCF reporter and cell migration in first-trimester villous explant cultures and of SGHPL-5 cells were stimulated. Chemical inhibition of PI3K abolished Wnt-dependent phosphorylation of AKT and GSK-3beta and trophoblast motility but did not affect appearance of activated beta-catenin or Wnt/TCF reporter activity. In contrast, inhibition of the canonical pathway through soluble Dickkopf-1 did not influence AKT and GSK-3beta phosphorylation but reduced Wnt reporter activity, accumulation of active beta-catenin, and cell migration. Both inhibitors decreased Wnt-3A-induced secretion of pro- and active matrix metalloproteinase-2 from SGHPL-5 cells and pure EVT. The data suggest that Wnt-3A may activate canonical Wnt signaling and PI3K/AKT through distinct receptors. The two signaling cascades act independently in trophoblasts; however, both pathways promote Wnt-dependent migration and the release of matrix metalloproteinase-2, which has been identified as novel Wnt target in invasive trophoblasts.
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PMID:Wingless (Wnt)-3A induces trophoblast migration and matrix metalloproteinase-2 secretion through canonical Wnt signaling and protein kinase B/AKT activation. 1988 70

To investigate the role of the Wnt inhibitor Dickkopf-1 (DKK-1) in the pathophysiology of neurodegenerative diseases, we analysed DKK-1 expression and localization in transgenic mouse models expressing familial Alzheimer's disease mutations and a frontotemporal dementia mutation. A significant increase of DKK-1 expression was found in the diseased brain areas of all transgenic lines, where it co-localized with hyperphosphorylated tau-bearing neurons. In TgCRND8 mice, DKK-1 immunoreactivity was detected in neurons surrounding amyloid deposits and within the choline acetyltransferase-positive neurons of the basal forebrain. Active glycogen synthase kinase-3 (GSK-3) was found to co-localize with DKK-1 and phospho-tau staining. Downstream to GSK-3, a significant reduction in beta-catenin translocation to the nucleus, indicative of impaired Wnt signaling functions, was found as well. Cumulatively, our findings indicate that DKK-1 expression is associated with events that lead to neuronal death in neurodegenerative diseases and support a role for DKK-1 as a key mediator of neurodegeneration with therapeutic potential.
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PMID:Increased Dickkopf-1 expression in transgenic mouse models of neurodegenerative disease. 2005 Sep 68


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