Other search tools

About this data

The publication data currently available has been vetted by Vanderbilt faculty, staff, administrators and trainees. The data itself is retrieved directly from NCBI's PubMed and is automatically updated on a weekly basis to ensure accuracy and completeness.

If you have any questions or comments, please contact us.

Results: 1 to 10 of 15

Publication Record

Connections

A Shared Pattern of β-Catenin Activation in Bronchopulmonary Dysplasia and Idiopathic Pulmonary Fibrosis.
Sucre JMS, Deutsch GH, Jetter CS, Ambalavanan N, Benjamin JT, Gleaves LA, Millis BA, Young LR, Blackwell TS, Kropski JA, Guttentag SH
(2018) Am J Pathol 188: 853-862
MeSH Terms: A549 Cells, Adult, Animals, Animals, Newborn, Axin Protein, Bronchopulmonary Dysplasia, Cell Nucleus, Epithelial Cells, Female, Fetus, Humans, Idiopathic Pulmonary Fibrosis, Lung, Mice, Inbred C57BL, Phosphorylation, Pregnancy, Pregnancy Trimester, Second, Protein Processing, Post-Translational, Signal Transduction, Tyrosine, beta Catenin
Show Abstract · Added March 21, 2018
Wnt/β-catenin signaling is necessary for normal lung development, and abnormal Wnt signaling contributes to the pathogenesis of both bronchopulmonary dysplasia (BPD) and idiopathic pulmonary fibrosis (IPF), fibrotic lung diseases that occur during infancy and aging, respectively. Using a library of human normal and diseased human lung samples, we identified a distinct signature of nuclear accumulation of β-catenin phosphorylated at tyrosine 489 and epithelial cell cytosolic localization of β-catenin phosphorylated at tyrosine 654 in early normal lung development and fibrotic lung diseases BPD and IPF. Furthermore, this signature was recapitulated in murine models of BPD and IPF. Image analysis of immunofluorescence colocalization demonstrated a consistent pattern of elevated nuclear phosphorylated β-catenin in the lung epithelium and surrounding mesenchyme in BPD and IPF, closely resembling the pattern observed in 18-week fetal lung. Nuclear β-catenin phosphorylated at tyrosine 489 associated with an increased expression of Wnt target gene AXIN2, suggesting that the observed β-catenin signature is of functional significance during normal development and injury repair. The association of specific modifications of β-catenin during normal lung development and again in response to lung injury supports the widely held concept that repair of lung injury involves the recapitulation of developmental programs. Furthermore, these observations suggest that β-catenin phosphorylation has potential as a therapeutic target for the treatment and prevention of both BPD and IPF.
Copyright © 2018 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.
0 Communities
2 Members
0 Resources
21 MeSH Terms
Loss of Axin2 Causes Ocular Defects During Mouse Eye Development.
Alldredge A, Fuhrmann S
(2016) Invest Ophthalmol Vis Sci 57: 5253-5262
MeSH Terms: Alleles, Animals, Axin Protein, Disease Models, Animal, Eye, Eye Diseases, Gene Expression Regulation, Developmental, Immunohistochemistry, Mice, Mice, Inbred C57BL, Mice, Knockout, Organogenesis, Polymerase Chain Reaction, Wnt Signaling Pathway
Show Abstract · Added April 18, 2017
Purpose - The scaffold protein Axin2 is an antagonist and universal target of the Wnt/β-catenin pathway. Disruption of Axin2 may lead to developmental eye defects; however, this has not been examined. The purpose of this study was to investigate the role of Axin2 during ocular and extraocular development in mouse.
Methods - Animals heterozygous and homozygous for a Axin2lacZ knock-in allele were analyzed at different developmental stages for reporter expression, morphology as well as for the presence of ocular and extraocular markers using histologic and immunohistochemical techniques.
Results - During early eye development, the Axin2lacZ reporter was expressed in the periocular mesenchyme, RPE, and optic stalk. In the developing retina, Axin2lacZ reporter expression was initiated in ganglion cells at late embryonic stages and robustly expressed in subpopulations of amacrine and horizontal cells postnatally. Activation of the Axin2lacZ reporter overlapped with labeling of POU4F1, PAX6, and Calbindin. Germline deletion of Axin2 led to variable ocular phenotypes ranging from normal to severely defective eyes exhibiting microphthalmia, coloboma, lens defects, and expanded ciliary margin. These defects were correlated with abnormal tissue patterning in individual affected tissues, such as the optic fissure margins in the ventral optic cup and in the expanded ciliary margin.
Conclusions - Our results reveal a critical role for Axin2 during ocular development, likely by restricting the activity of the Wnt/β-catenin pathway.
0 Communities
1 Members
0 Resources
14 MeSH Terms
Wnt pathway activation by ADP-ribosylation.
Yang E, Tacchelly-Benites O, Wang Z, Randall MP, Tian A, Benchabane H, Freemantle S, Pikielny C, Tolwinski NS, Lee E, Ahmed Y
(2016) Nat Commun 7: 11430
MeSH Terms: Adenosine Diphosphate Ribose, Amino Acid Sequence, Animals, Animals, Genetically Modified, Axin Protein, Cell Line, Tumor, Drosophila Proteins, Drosophila melanogaster, Embryo, Nonmammalian, Gene Expression Regulation, Developmental, HEK293 Cells, Humans, Low Density Lipoprotein Receptor-Related Protein-6, Lymphocytes, Molecular Sequence Data, Proteolysis, Sequence Alignment, Tankyrases, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin
Show Abstract · Added February 13, 2017
Wnt/β-catenin signalling directs fundamental processes during metazoan development and can be aberrantly activated in cancer. Wnt stimulation induces the recruitment of the scaffold protein Axin from an inhibitory destruction complex to a stimulatory signalosome. Here we analyse the early effects of Wnt on Axin and find that the ADP-ribose polymerase Tankyrase (Tnks)--known to target Axin for proteolysis-regulates Axin's rapid transition following Wnt stimulation. We demonstrate that the pool of ADP-ribosylated Axin, which is degraded under basal conditions, increases immediately following Wnt stimulation in both Drosophila and human cells. ADP-ribosylation of Axin enhances its interaction with the Wnt co-receptor LRP6, an essential step in signalosome assembly. We suggest that in addition to controlling Axin levels, Tnks-dependent ADP-ribosylation promotes the reprogramming of Axin following Wnt stimulation; and propose that Tnks inhibition blocks Wnt signalling not only by increasing destruction complex activity, but also by impeding signalosome assembly.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Wnt/Wingless Pathway Activation Is Promoted by a Critical Threshold of Axin Maintained by the Tumor Suppressor APC and the ADP-Ribose Polymerase Tankyrase.
Wang Z, Tacchelly-Benites O, Yang E, Thorne CA, Nojima H, Lee E, Ahmed Y
(2016) Genetics 203: 269-81
MeSH Terms: Adenomatous Polyposis Coli Protein, Animals, Axin Protein, Drosophila, Genotype, Mitosis, Protein Interaction Domains and Motifs, Protein Stability, Tankyrases, Wnt Proteins, Wnt Signaling Pathway, Xenopus
Show Abstract · Added February 13, 2017
Wnt/β-catenin signal transduction directs metazoan development and is deregulated in numerous human congenital disorders and cancers. In the absence of Wnt stimulation, a multiprotein "destruction complex," assembled by the scaffold protein Axin, targets the key transcriptional activator β-catenin for proteolysis. Axin is maintained at very low levels that limit destruction complex activity, a property that is currently being exploited in the development of novel therapeutics for Wnt-driven cancers. Here, we use an in vivo approach in Drosophila to determine how tightly basal Axin levels must be controlled for Wnt/Wingless pathway activation, and how Axin stability is regulated. We find that for nearly all Wingless-driven developmental processes, a three- to fourfold increase in Axin is insufficient to inhibit signaling, setting a lower-limit for the threshold level of Axin in the majority of in vivo contexts. Further, we find that both the tumor suppressor adenomatous polyposis coli (APC) and the ADP-ribose polymerase Tankyrase (Tnks) have evolutionarily conserved roles in maintaining basal Axin levels below this in vivo threshold, and we define separable domains in Axin that are important for APC- or Tnks-dependent destabilization. Together, these findings reveal that both APC and Tnks maintain basal Axin levels below a critical in vivo threshold to promote robust pathway activation following Wnt stimulation.
Copyright © 2016 by the Genetics Society of America.
0 Communities
1 Members
0 Resources
12 MeSH Terms
Toggling a conformational switch in Wnt/β-catenin signaling: regulation of Axin phosphorylation. The phosphorylation state of Axin controls its scaffold function in two Wnt pathway protein complexes.
Tacchelly-Benites O, Wang Z, Yang E, Lee E, Ahmed Y
(2013) Bioessays 35: 1063-70
MeSH Terms: Animals, Axin Protein, Humans, Phosphorylation, Protein Binding, Signal Transduction, Wnt Signaling Pathway, beta Catenin
Show Abstract · Added March 5, 2014
The precise orchestration of two opposing protein complexes - one in the cytoplasm (β-catenin destruction complex) and the other at the plasma membrane (LRP6 signaling complex) - is critical for controlling levels of the transcriptional co-factor β-catenin, and subsequent activation of the Wnt/β-catenin signal transduction pathway. The Wnt pathway component Axin acts as an essential scaffold for the assembly of both complexes. How the β-catenin destruction and LRP6 signaling complexes are modulated following Wnt stimulation remains controversial. A recent study in Science by He and coworkers reveals an underlying logic for Wnt pathway control in which Axin phosphorylation toggles a switch between the active and inactive states. This mini-review focuses on this and two other recent studies that provide insight into the initial signaling events triggered by Wnt exposure. We emphasize regulation of the β-catenin destruction and LRP6 signaling complexes and propose a framework for future work in this area.
© 2013 WILEY Periodicals, Inc.
0 Communities
1 Members
0 Resources
8 MeSH Terms
Receptor tyrosine kinase-like orphan receptor 2 (Ror2) expression creates a poised state of Wnt signaling in renal cancer.
Rasmussen NR, Wright TM, Brooks SA, Hacker KE, Debebe Z, Sendor AB, Walker MP, Major MB, Green J, Wahl GM, Rathmell WK
(2013) J Biol Chem 288: 26301-10
MeSH Terms: Axin Protein, Carcinoma, Renal Cell, Cell Line, Tumor, Gene Expression Regulation, Enzymologic, Gene Expression Regulation, Neoplastic, Humans, Kidney Neoplasms, Low Density Lipoprotein Receptor-Related Protein-6, Neoplasm Proteins, Receptor Tyrosine Kinase-like Orphan Receptors, Wnt Signaling Pathway, Wnt3A Protein, beta Catenin
Show Abstract · Added October 17, 2015
Expression of the receptor tyrosine kinase-like orphan receptor 2 (Ror2) has been identified in an increasing array of tumor types and is known to play a role as an important mediator of Wnt signaling cascades. In this study, we aimed to clarify Ror2 interactions with the Wnt pathways within the context of renal cell carcinoma (RCC). An examination of Ror2 expression in primary human RCC tumors showed a significant correlation with several Wnt signaling genes, including the classical feedback target gene Axin2. We provide evidence that Ror2 expression results in a partially activated state for canonical Wnt signaling through an increased signaling pool of β-catenin, leading to an enhancement of downstream target genes following Wnt3a stimulation in both renal and renal carcinoma-derived cells. Additionally, inhibition of low-density lipoprotein receptor-related protein 6 (LRP6) with either siRNA or dickkopf decreased the response to Wnt3a stimulation, but no change was seen in the increased β-catenin pool associated with Ror2 expression, suggesting that LRP6 cofactor recruitment is necessary for a Wnt3a-induced signal but that it does not participate in the Ror2 effect on β-catenin signaling. These results highlight a new role for Ror2 in conveying a tonic signal to stabilize soluble β-catenin and create a poised state of enhanced responsiveness to Wnt3a exogenous signals in RCC.
0 Communities
1 Members
0 Resources
13 MeSH Terms
A biochemical screen for identification of small-molecule regulators of the Wnt pathway using Xenopus egg extracts.
Thorne CA, Lafleur B, Lewis M, Hanson AJ, Jernigan KK, Weaver DC, Huppert KA, Chen TW, Wichaidit C, Cselenyi CS, Tahinci E, Meyers KC, Waskow E, Orton D, Salic A, Lee LA, Robbins DJ, Huppert SS, Lee E
(2011) J Biomol Screen 16: 995-1006
MeSH Terms: Animals, Axin Protein, Enzyme Assays, Flavones, HEK293 Cells, HeLa Cells, High-Throughput Screening Assays, Humans, Luciferases, Reproducibility of Results, Small Molecule Libraries, Wnt Signaling Pathway, Xenopus laevis, beta Catenin
Show Abstract · Added October 3, 2011
Misregulation of the Wnt pathway has been shown to be responsible for a variety of human diseases, most notably cancers. Screens for inhibitors of this pathway have been performed almost exclusively using cultured mammalian cells or with purified proteins. We have previously developed a biochemical assay using Xenopus egg extracts to recapitulate key cytoplasmic events in the Wnt pathway. Using this biochemical system, we show that a recombinant form of the Wnt coreceptor, LRP6, regulates the stability of two key components of the Wnt pathway (β-catenin and Axin) in opposing fashion. We have now fused β-catenin and Axin to firefly and Renilla luciferase, respectively, and demonstrate that the fusion proteins behave similarly as their wild-type counterparts. Using this dual luciferase readout, we adapted the Xenopus extracts system for high-throughput screening. Results from these screens demonstrate signal distribution curves that reflect the complexity of the library screened. Of several compounds identified as cytoplasmic modulators of the Wnt pathway, one was further validated as a bona fide inhibitor of the Wnt pathway in cultured mammalian cells and Xenopus embryos. We show that other embryonic pathways may be amendable to screening for inhibitors/modulators in Xenopus egg extracts.
2 Communities
3 Members
0 Resources
14 MeSH Terms
Role of STRAP in regulating GSK3β function and Notch3 stabilization.
Kashikar ND, Zhang W, Massion PP, Gonzalez AL, Datta PK
(2011) Cell Cycle 10: 1639-54
MeSH Terms: Adaptor Proteins, Signal Transducing, Amino Acid Sequence, Ankyrins, Axin Protein, Cell Line, Tumor, Glycogen Synthase Kinase 3, Glycogen Synthase Kinase 3 beta, Humans, Lithium Chloride, Molecular Sequence Data, Neoplasm Proteins, Phosphorylation, Protein Binding, Protein Structure, Tertiary, RNA Interference, RNA, Small Interfering, Receptor, Notch3, Receptors, Notch, Repressor Proteins, Sequence Alignment, Ubiquitination
Show Abstract · Added March 5, 2014
Glycogen synthase kinase 3β (GSK3β) can regulate a broad range of cellular processes in a variety of cell types and tissues through its ability to phosphorylate its substrates in a cell- and time-specific manner. Although it is known that Axin and presenilin help to recruit β-catenin/Smad3 and tau protein to GSK3β, respectively, it is not clear how many of the other GSK3β substrates are recruited to it. Here, we have established the binding of GSK3β with a novel scaffold protein, STRAP, through its WD40 domains. In a new finding, we have observed that STRAP, GSK3β and Axin form a ternary complex together. We show for the first time that intracellular fragment of Notch3 (ICN3) binds with GSK3β through the ankyrin repeat domain. This binding between STRAP and GSK3β is reduced by small-molecule inhibitors of GSK3β. Further studies revealed that STRAP also binds ICN3 through the ankyrin repeat region, and this binding is enhanced in a proteasomal inhibition-dependent manner. In vivo ubiquitination studies indicate that STRAP reduces ubiquitination of ICN3, suggesting a role of STRAP in stabilizing ICN3. This is supported by the fact that STRAP and Notch3 are co-upregulated and co-localized in 59% of non-small cell lung cancers, as observed in an immunohistochemical staining of tissue microarrays. These results provide a potential mechanism by which STRAP regulates GSK3β function and Notch3 stabilization and further support the oncogenic functions of STRAP.
0 Communities
1 Members
0 Resources
21 MeSH Terms
Pyrvinium, a potent small molecule Wnt inhibitor, promotes wound repair and post-MI cardiac remodeling.
Saraswati S, Alfaro MP, Thorne CA, Atkinson J, Lee E, Young PP
(2010) PLoS One 5: e15521
MeSH Terms: Adaptor Proteins, Signal Transducing, Animals, Axin Protein, Casein Kinase Ialpha, Cell Proliferation, Enzyme Activation, Gene Expression, HEK293 Cells, Heart, Humans, Immunoblotting, Intercellular Signaling Peptides and Proteins, Mice, Myocardial Infarction, Myocardium, Proto-Oncogene Proteins c-myc, Pyrvinium Compounds, Repressor Proteins, Reverse Transcriptase Polymerase Chain Reaction, Signal Transduction, Ventricular Remodeling, Wnt Proteins, Wound Healing, beta Catenin
Show Abstract · Added March 5, 2014
Wnt signaling plays an important role in developmental and stem cell biology. To test the hypothesis that temporary inhibition of Wnt signaling will enhance granulation tissue and promote angiogenesis in tissue repair, we employed a recently characterized small molecule Wnt inhibitor. Pyrvinium is an FDA-approved drug that we identified as a Wnt inhibitor in a chemical screen for small molecules that stabilize β-catenin and inhibit Axin degradation. Our subsequent characterization of pyrvinium has revealed that its critical cellular target in the Wnt pathway is Casein Kinase 1α. Daily administration of pyrvinium directly into polyvinyl alcohol (PVA) sponges implanted subcutaneously in mice generated better organized and vascularized granulation tissue; this compound also increased the proliferative index of the tissue within the sponges. To evaluate its effect in myocardial repair, we induced a myocardial infarction (MI) by coronary artery ligation and administered a single intramyocardial dose of pyrvinium. Mice were evaluated by echocardiography at 7 and 30 days post-MI and treatment; post mortem hearts were evaluated by histology at 30 days. Pyrvinium reduced adverse cardiac remodeling demonstrated by decreased left ventricular internal diameter in diastole (LVIDD) as compared to a control compound. Increased Ki-67+ cells were observed in peri-infarct and distal myocardium of pyrvinium-treated animals. These results need to be further followed-up to determine if therapeutic inhibition of canonical Wnt may avert adverse remodeling after ischemic injury and its impact on myocardial repair and regeneration.
0 Communities
1 Members
0 Resources
24 MeSH Terms
Small-molecule inhibition of Wnt signaling through activation of casein kinase 1α.
Thorne CA, Hanson AJ, Schneider J, Tahinci E, Orton D, Cselenyi CS, Jernigan KK, Meyers KC, Hang BI, Waterson AG, Kim K, Melancon B, Ghidu VP, Sulikowski GA, LaFleur B, Salic A, Lee LA, Miller DM, Lee E
(2010) Nat Chem Biol 6: 829-36
MeSH Terms: Adaptor Proteins, Signal Transducing, Adenomatous Polyposis Coli, Animals, Axin Protein, Casein Kinase I, Casein Kinase Ialpha, Cell Extracts, Cell Line, Tumor, Cell Proliferation, Colonic Neoplasms, Dose-Response Relationship, Drug, Enzyme Activation, Enzyme Inhibitors, Humans, Intracellular Signaling Peptides and Proteins, Oocytes, Pyrvinium Compounds, Repressor Proteins, Signal Transduction, Wnt Proteins, Xenopus Proteins, Xenopus laevis, beta Catenin
Show Abstract · Added February 3, 2014
Wnt/β-catenin signaling is critically involved in metazoan development, stem cell maintenance and human disease. Using Xenopus laevis egg extract to screen for compounds that both stabilize Axin and promote β-catenin turnover, we identified an FDA-approved drug, pyrvinium, as a potent inhibitor of Wnt signaling (EC(50) of ∼10 nM). We show pyrvinium binds all casein kinase 1 (CK1) family members in vitro at low nanomolar concentrations and pyrvinium selectively potentiates casein kinase 1α (CK1α) kinase activity. CK1α knockdown abrogates the effects of pyrvinium on the Wnt pathway. In addition to its effects on Axin and β-catenin levels, pyrvinium promotes degradation of Pygopus, a Wnt transcriptional component. Pyrvinium treatment of colon cancer cells with mutation of the gene for adenomatous polyposis coli (APC) or β-catenin inhibits both Wnt signaling and proliferation. Our findings reveal allosteric activation of CK1α as an effective mechanism to inhibit Wnt signaling and highlight a new strategy for targeted therapeutics directed against the Wnt pathway.
0 Communities
5 Members
0 Resources
23 MeSH Terms