Activation of β-catenin Signaling Pathways by Classical G-Protein-Coupled Receptors: Mechanisms and Consequences in Cycling and Non-cycling Cells

Shevtsov, Sergey P.; Haq, Syed; Force, Thomas

doi:10.4161/cc.5.20.3357

Cited by 48 publications

(43 citation statements)

References 48 publications

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“…When Wnt signal is initiated, this destruction complex is disassembled, and the degradation of ␤-catenin is inhibited, facilitating its entry to the nucleus. Most of the previous studies have shown that the cross-talk of the signal transduction pathways between Wnt and classic GPCR occurs at GSK3 level (Shevtsov et al, 2006;Force et al, 2007). Results from this study show that the interaction between certain GPCRs and ␤-catenin could also control the canonical Wnt signaling pathway independently of the destruction complex.…”

Section: Discussionmentioning

confidence: 48%

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Min¹,

Cho²,

Kwon³

et al. 2011

Molecular Pharmacology

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Classical G protein-coupled receptors (GPCRs) and canonical Wnt pathways were believed to use distinct signaling pathways. However, recent studies have shown that these two pathways interact each other by sharing several intermediate signaling components. Recent in vivo studies showed that antipsychotic drugs, which block dopamine D2-like receptors, increase the cellular levels of downstream signaling components of canonical Wnt pathways, such as dishevelled (Dvl), glycogen synthase kinase 3␤ (GSK3␤), and ␤-catenin. These results suggest that some functional interactions might exist between Wnt pathway and D2-like receptors. In this study, we show that among five different dopamine receptor subtypes, D 2 receptor (D 2 R) selectively inhibited the Wnt signaling, which was measured by lymphoid enhancing factor-1 (LEF-1)-dependent transcriptional activities. D 2 R-mediated inhibition of Wnt signaling was agonist-and G protein-independent and did not require receptor phosphorylation or endocytosis. D 2 R inhibited the LEF-1-dependent transcriptional activities, and this inhibitory activity was not affected by the inhibition of GSK-3␤, suggesting that D 2 R inhibited the Wnt signaling by acting on the downstream of GSK3␤. D 2 R directly interacted with ␤-catenin through the second and third loops, leading to a reduction of ␤-catenin distribution in the nucleus, resulting in an inhibition of LEF-1-dependent transcription. This is a novel mechanism for the regulation of canonical Wnt signaling by GPCRs, in which receptor proteins recruit ␤-catenin from cytosol to the plasma membrane, resulting in the decrement of the ␤-catenin/LEF-1-dependent transcription in the nucleus.

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Section: Discussionmentioning

confidence: 48%

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Min¹,

Cho²,

Kwon³

et al. 2011

Molecular Pharmacology

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“…The role of b-catenin signalling in fully differentiated cells, such as cardiomyocytes, is less clear, although current data suggest it is Wntindependent. In this cell type GSK3b is inactivated by PKB/ Akt, which in turn leads to the stabilisation of b-catenin and subsequent increase in TCF/LEF reporter gene expression [47,62]. Our results also link the emerin-b-catenin complex to GSK3b activity on both components, although further studies are required to ascertain its precise role.…”

Section: Emerin Can Occur In Non-nuclear Membranesmentioning

confidence: 59%

Identification of an emerin–β-catenin complex in the heart important for intercalated disc architecture and β-catenin localisation

Wheeler

Warley

Roberts

et al. 2009

Cell. Mol. Life Sci.

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How mutations in the protein emerin lead to the cardiomyopathy associated with X-linked Emery-Dreifuss muscular dystrophy (X-EDMD) is unclear. We identified emerin at the adherens junction of the intercalated disc, where it co-localised with the catenin family of proteins. Emerin bound to wild type beta-catenin both in vivo and in vitro. Mutating the GSK3beta phosphorylation sites on beta-catenin abolished this binding. Wild type but not mutant forms of emerin associated with X-EDMD were able to reduce beta-catenin protein levels. Cardiomyocytes from emerin-null mice hearts exhibited erroneous beta-catenin distribution and intercalated disc architecture. Treatment of wild type cardiomyocytes with phenylephrine, which inactivates GSK3beta, redistributed emerin and beta-catenin. Emerin was identified as a direct target of GSK3beta activity since exogenous expression of GSK3beta reduced emerin levels at the nuclear envelope. We propose that perturbation to or total loss of the emerin-beta-catenin complex compromises both intercalated disc function and beta-catenin signalling in cardiomyocytes.

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“…A number of previous studies demonstrated that GPCR activation regulates ␤-catenin function and localization, but the mechanism(s) involved remained incompletely defined (50). PKD1, a major downstream element in GPCR signaling, plays a critical role in mediating migration and proliferation of intestinal epithelial cells (54,79).…”

Section: Discussionmentioning

confidence: 99%

Positive cross talk between protein kinase D and β-catenin in intestinal epithelial cells: impact on β-catenin nuclear localization and phosphorylation at Ser⁵⁵²

Wang

Han

Sinnett‐Smith

et al. 2016

American Journal of Physiology-Cell Physiology

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Given the fundamental role of β-catenin signaling in intestinal epithelial cell proliferation and the growth-promoting function of protein kinase D1 (PKD1) in these cells, we hypothesized that PKDs mediate cross talk with β-catenin signaling. The results presented here provide several lines of evidence supporting this hypothesis. We found that stimulation of intestinal epithelial IEC-18 cells with the G protein-coupled receptor (GPCR) agonist angiotensin II (ANG II), a potent inducer of PKD activation, promoted endogenous β-catenin nuclear localization in a time-dependent manner. A significant increase was evident within 1 h of ANG II stimulation (P< 0.01), peaked at 4 h (P< 0.001), and declined afterwards. GPCR stimulation also induced a marked increase in β-catenin-regulated genes and phosphorylation at Ser(552) in intestinal epithelial cells. Exposure to preferential inhibitors of the PKD family (CRT006610 or kb NB 142-70) or knockdown of the isoforms of the PKD family prevented the increase in β-catenin nuclear localization and phosphorylation at Ser(552) in response to ANG II. GPCR stimulation also induced the formation of a complex between PKD1 and β-catenin, as shown by coimmunoprecipitation that depended on PKD1 catalytic activation, as it was abrogated by cell treatment with PKD family inhibitors. Using transgenic mice that express elevated PKD1 protein in the intestinal epithelium, we detected a marked increase in the localization of β-catenin in the nucleus of crypt epithelial cells in the ileum of PKD1 transgenic mice, compared with nontransgenic littermates. Collectively, our results identify a novel cross talk between PKD and β-catenin in intestinal epithelial cells, both in vitro and in vivo.

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Activation of β-catenin Signaling Pathways by Classical G-Protein-Coupled Receptors: Mechanisms and Consequences in Cycling and Non-cycling Cells

Cited by 48 publications

References 48 publications

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Identification of an emerin–β-catenin complex in the heart important for intercalated disc architecture and β-catenin localisation

Positive cross talk between protein kinase D and β-catenin in intestinal epithelial cells: impact on β-catenin nuclear localization and phosphorylation at Ser⁵⁵²

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Activation of β-catenin Signaling Pathways by Classical G-Protein-Coupled Receptors: Mechanisms and Consequences in Cycling and Non-cycling Cells

Cited by 48 publications

References 48 publications

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Novel Regulatory Mechanism of Canonical Wnt Signaling by Dopamine D2 Receptor through Direct Interaction with β-Catenin

Identification of an emerin–β-catenin complex in the heart important for intercalated disc architecture and β-catenin localisation

Positive cross talk between protein kinase D and β-catenin in intestinal epithelial cells: impact on β-catenin nuclear localization and phosphorylation at Ser552

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Positive cross talk between protein kinase D and β-catenin in intestinal epithelial cells: impact on β-catenin nuclear localization and phosphorylation at Ser⁵⁵²