Wnt Signaling to β-Catenin Involves Two Interactive Components

Chen, Ruihong; Ding, Wenwen; McCormick, Frank

doi:10.1074/jbc.m905336199

Cited by 202 publications

(70 citation statements)

References 69 publications

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“…Hepatocyte growth factor reduces GSK-3 activity and induces nuclear translocation of ␤-catenin and Lef/Tcf-dependent transcription in mammary epithelial cells (48). Epidermal growth factor reduces GSK-3 activity but does not induce ␤-catenin accumulation and transcriptional activity of Lef/Tcf in mammary epithelial cells (49). FGF-1 reduces in GSK-3 activity in neuronal cells, but consequences on ␤-catenin signaling are unknown (50).…”

Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-2 Induces Lef/Tcf-dependent Transcription in Human Endothelial Cells

Holnthoner

Pillinger

Gröger

et al. 2002

Journal of Biological Chemistry

114

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Section: Discussionmentioning

confidence: 99%

Fibroblast Growth Factor-2 Induces Lef/Tcf-dependent Transcription in Human Endothelial Cells

Holnthoner

Pillinger

Gröger

et al. 2002

Journal of Biological Chemistry

114

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“…Certain isoforms of PKC are able to phosphorylate GSK3␤ in vitro (45). Nevertheless, PKC may not be the sole signaling molecule since inhibitors of PKC do not completely block Wnt effects (46). Integrin-linked kinase is another kinase that was able to induce nuclear ␤-catenin accumulation (47), activate PKB in vivo and phosphorylate GSK3␤ in vitro (48).…”

Section: Figmentioning

confidence: 99%

Differential Regulation of Glycogen Synthase Kinase 3β by Insulin and Wnt Signaling

Ding

Chen²,

McCormick

2000

Journal of Biological Chemistry

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407

346

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Glycogen synthase kinase 3␤ (GSK3␤) is a key component in many biological processes including insulin and Wnt signaling. Since the activation of each signaling pathway results in a decrease in GSK3␤ activity, we examined the specificity of their downstream effects in the same cell type. Insulin induces an increased activity of glycogen synthase but has no influence on the protein level of ␤-catenin. In contrast, Wnt increases the cytosolic pool of ␤-catenin but not glycogen synthase activity. We found that, unlike insulin, neither the phosphorylation status of the serine9 residue of GSK3␤ nor the activity of protein kinase B is regulated by Wnt. Although the decrease in GSK3␤ activity is required, GSK3␤ may not be the limiting component for Wnt signaling in the cells that we examined. Our results suggest that the axin-conductin complexed GSK3␤ may be dedicated to Wnt rather than insulin signaling. Insulin and Wnt pathways regulate GSK3␤ through different mechanisms, and therefore lead to distinct downstream events.

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“…␤-Catenin Stabilization-Regulation of ␤-catenin stability is a crucial control point in Wnt signaling pathways (40). GSK-3␤ induces the phosphorylation of ␤-catenin and triggers its degradation through the ubiquitin-proteasome pathway (44,58).…”

Section: Trolox and E 2 Modulate Activation Of The Neuronal Wnt Signamentioning

confidence: 99%

“…Wnt proteins inhibit GSK-3␤, disrupting a multiprotein complex comprising GSK-3␤ and its substrates in the Wnt signaling pathway, which, unlike other growth factors, do not require a priming phosphate (29). Wnt signaling also inactivates GSK-3␤ via activation of the protein kinase C (PKC) enzyme (40,41), which is decreased in the cortex of AD patients (42); besides, PKC activation is an important step in the estrogen protection mechanism against A␤ neurotoxicity (43). In the absence of a Wnt ligand, GSK-3␤ phosphorylates ␤-catenin for ubiquitin-proteasome mediated degradation (44).…”

mentioning

confidence: 99%

Trolox and 17β-Estradiol Protect against Amyloid β-Peptide Neurotoxicity by a Mechanism That Involves Modulation of the Wnt Signaling Pathway

Quintanilla

Muñoz

Metcalfe

et al. 2005

Journal of Biological Chemistry

116

124

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Oxidative stress is a key mechanism in amyloid ␤-peptide (A␤)-mediated neurotoxicity; therefore, the protective roles of 17␤-estradiol (E 2 ) and antioxidants (Trolox and vitamin C) were assayed on hippocampal neurons. Our results show the following: 1) E 2 and Trolox attenuated the neurotoxicity mediated by A␤ and H 2 O 2 as measured by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide reduction assays, quantification of apoptotic cells, and morphological studies of the integrity of the neurite network. 2) Vitamin C failed to protect neurons from A␤ toxicity. 3) A␤-mediated endoperoxide production, reported to induce cell damage, was decreased in the presence of E 2 and Trolox. 4) Two key Wnt signaling components were affected by E 2 and Trolox; in fact, the enzyme glycogen synthase kinase 3␤ was inhibited by both E 2 and Trolox, and both compounds were able to stabilize cytoplasmic ␤-catenin. 5) E 2 activated the expression of the Wnt-5a and Wnt-7a ligands, and at the same time, E 2 , through the ␣-estrogen receptor, was able to prevent the excitotoxic A␤-induced rise in bulk-free Ca 2؉as an alternative pathway to increase cell viability. 6) Finally, the Wnt-7a ligand protected against cytoplasmic calcium disturbances induced by A␤ treatment. Our results suggest that control of oxidative stress, regulation of cytoplasmic calcium, and activation of Wnt signaling may prevent A␤ neurotoxicity. Alzheimer disease (AD)1 is a neurodegenerative disease characterized by neuronal cell death, dystrophic neurites, neurofibrillary tangles, and senile plaques (1). Senile plaques are composed by the amyloid ␤-peptide (A␤), a 40 -42-amino acid peptide that originates from the proteolytic cleavage of the amyloid precursor protein (2). There is also evidence relating the etiopathology of AD with oxidative stress induced by A␤ in the brain of AD patients (3-6). A␤ increases the production of intraneuronal reactive oxygen species (ROS) and stimulates hydrogen peroxide (H 2 O 2 ) levels through metal ion reduction (7,8). Free radicals peroxidize membrane lipids (9) and oxidize proteins (10). In vitro experiments also support the observation that the neurotoxic effect of A␤ is mediated by free radical mechanisms (5, 11, 12) and alteration of Ca 2ϩ homeostasis (13). Furthermore, several studies have reported neuroprotection by antioxidants against A␤-mediated cytotoxicity (14 -16). Also, 17␤-estradiol (E 2 ; estrogen) treatment apparently has beneficial effects on AD (17, 18). In addition, E 2 prevents A␤-induced cell death by activation of the ␣-ER (19) and preserves neuronal viability and function in cortical neurons exposed to glutamate toxicity (20). Also, there is evidence that E 2 prevents morphological neurodegenerative changes in hippocampal neurons caused by A␤ deposits (21).On the other hand, neurofibrillary tangles are intracellular aggregates of paired helical filaments produced by hyperphosphorylation of the microtubule-associated protein tau (23). It has been proposed that glycogen synthase kinase-3␤ (GSK-3␤...

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Wnt Signaling to β-Catenin Involves Two Interactive Components

Cited by 202 publications

References 69 publications

Fibroblast Growth Factor-2 Induces Lef/Tcf-dependent Transcription in Human Endothelial Cells

Fibroblast Growth Factor-2 Induces Lef/Tcf-dependent Transcription in Human Endothelial Cells

Differential Regulation of Glycogen Synthase Kinase 3β by Insulin and Wnt Signaling

Trolox and 17β-Estradiol Protect against Amyloid β-Peptide Neurotoxicity by a Mechanism That Involves Modulation of the Wnt Signaling Pathway

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