scholarly journals The Wnt pathway scaffold protein Axin promotes signaling specificity by suppressing competing kinase reactions

2019 ◽  
Author(s):  
Maire Gavagan ◽  
Erin Fagnan ◽  
Elizabeth B. Speltz ◽  
Jesse G. Zalatan
Keyword(s):  
Wnt Signaling ◽  
Wnt Pathway ◽  
Rate Increase ◽  
Reaction Rates ◽  
Scaffold Protein ◽  
Protein Targets ◽  
Signaling Specificity ◽  
Inactive State ◽  
Multiple Substrates ◽  
Reconstituted System

AbstractGSK3β is a multifunctional kinase that phosphorylates β-catenin in the Wnt signaling network and also acts on other protein targets in response to distinct cellular signals. To test the long-standing hypothesis that the scaffold protein Axin specifically accelerates β-catenin phosphorylation, we measured GSK3β reaction rates with multiple substrates in a minimal, biochemically-reconstituted system. We observed an unexpectedly small, ~2-fold Axin-mediated rate increase for the β-catenin reaction. The much larger effects reported previously may have arisen because Axin can rescue GSK3β from an inactive state that occurs only under highly specific conditions. Surprisingly, Axin significantly slows the reaction of GSK3β with CREB, a non-Wnt pathway substrate. When both β-catenin and CREB are present, Axin accelerates the β-catenin reaction by preventing competition with CREB. Thus, while Axin alone does not markedly accelerate the β-catenin reaction, in physiological settings where multiple GSK3β substrates are present, Axin can promote signaling specificity by suppressing interactions with competing, non-Wnt pathway targets.

scholarly journals Development of small molecules targeting the Wnt pathway for the treatment of colon cancer: a high-throughput screening approach

2010 ◽  
Vol 299 (2) ◽  
pp. G293-G300 ◽  
Author(s):  
Wei Chen ◽  
Minyong Chen ◽  
Larry S. Barak
Keyword(s):  
Colon Cancer ◽  
Drug Discovery ◽  
Wnt Signaling ◽  
Small Molecule ◽  
High Throughput ◽  
High Throughput Screening ◽  
Wnt Pathway ◽  
Protein Targets ◽  
Wnt Proteins ◽  
Development And Differentiation

Wnt proteins play major roles in development and differentiation, and abnormalities in their regulation are believed to contribute to the formation of many cancers, including colorectal malignancies. As a result, there has been an interest in identifying small molecule inhibitors of Wnt signaling as tool compounds for research or as precursors to new generations of anticancer drugs. Advancements in robotic technology along with reductions in the costs of equipment, chemical libraries, and information handling have made high-throughput drug discovery programs possible in an academic setting. In this minireview we discuss the most plausible protein targets for inhibiting Wnt signaling in colon cancer therapy, list small molecule Wnt inhibitors that have been identified through recent drug discovery efforts, and provide our laboratory's strategy for identifying novel Wnt signaling antagonists using high-throughput screening. In particular, we summarize the results of a screen of over 1,200 drug and druglike compounds we recently completed in which niclosamide was identified as a Wnt pathway antagonist.

scholarly journals The Scaffold Protein Axin Promotes Signaling Specificity within the Wnt Pathway by Suppressing Competing Kinase Reactions

Cell Systems ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 515-525.e5
Author(s):  
Maire Gavagan ◽  
Erin Fagnan ◽  
Elizabeth B. Speltz ◽  
Jesse G. Zalatan
Keyword(s):  
Wnt Pathway ◽  
Scaffold Protein ◽  
Signaling Specificity

scholarly journals Regulation of Wnt Signaling by FOX Transcription Factors in Cancer

Cancers ◽  
2021 ◽  
Vol 13 (14) ◽  
pp. 3446
Author(s):  
Stefan Koch
Keyword(s):  
Transcription Factors ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Treatment Options ◽  
Wnt Signaling Pathway ◽  
Tissue Homeostasis ◽  
Fine Tuning ◽  
Dependent Manner ◽  
Forkhead Box ◽  
Signaling Activity

Aberrant activation of the oncogenic Wnt signaling pathway is a hallmark of numerous types of cancer. However, in many cases, it is unclear how a chronically high Wnt signaling tone is maintained in the absence of activating pathway mutations. Forkhead box (FOX) family transcription factors are key regulators of embryonic development and tissue homeostasis, and there is mounting evidence that they act in part by fine-tuning the Wnt signaling output in a tissue-specific and context-dependent manner. Here, I review the diverse ways in which FOX transcription factors interact with the Wnt pathway, and how the ectopic reactivation of FOX proteins may affect Wnt signaling activity in various types of cancer. Many FOX transcription factors are partially functionally redundant and exhibit a highly restricted expression pattern, especially in adults. Thus, precision targeting of individual FOX proteins may lead to safe treatment options for Wnt-dependent cancers.

A Wnt signaling pathway controls hox gene expression and neuroblast migration in C. elegans

Development ◽  
1999 ◽  
Vol 126 (1) ◽  
pp. 37-49 ◽  
Author(s):  
J.N. Maloof ◽  
J. Whangbo ◽  
J.M. Harris ◽  
G.D. Jongeward ◽  
C. Kenyon
Keyword(s):  
Gene Expression ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Hox Genes ◽  
Wnt Signaling Pathway ◽  
Beta Catenin ◽  
Hox Gene ◽  
C Elegans ◽  
Neuroblast Migration ◽  
Pathway Gene

The specification of body pattern along the anteroposterior (A/P) body axis is achieved largely by the actions of conserved clusters of Hox genes. Limiting expression of these genes to localized regional domains and controlling the precise patterns of expression within those domains is critically important for normal patterning. Here we report that egl-20, a C. elegans gene required to activate expression of the Hox gene mab-5 in the migratory neuroblast QL, encodes a member of the Wnt family of secreted glycoproteins. We have found that a second Wnt pathway gene, bar-1, which encodes a beta-catenin/Armadillo-like protein, is also required for activation of mab-5 expression in QL. In addition, we describe the gene pry-1, which is required to limit expression of the Hox genes lin-39, mab-5 and egl-5 to their correct local domains. We find that egl-20, pry-1 and bar-1 all function in a linear genetic pathway with conserved Wnt signaling components, suggesting that a conserved Wnt pathway activates expression of mab-5 in the migratory neuroblast QL. Moreover, we find that members of this Wnt signaling system play a major role in both the general and fine-scale control of Hox gene expression in other cell types along the A/P axis.

A transcriptional and post-transcriptional dysregulation of Dishevelled 1 and 2 underlies the Wnt signaling impairment in type I Gaucher disease experimental models

2019 ◽  
Vol 29 (2) ◽  
pp. 274-285 ◽  
Author(s):  
Roberto Costa ◽  
Stefania Bellesso ◽  
Susanna Lualdi ◽  
Rosa Manzoli ◽  
Valeria Pistorio ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Gaucher Disease ◽  
Wnt Pathway ◽  
Experimental Models ◽  
Type I ◽  
Loss Of Function ◽  
Single Nucleotide Variants ◽  
Bone Differentiation

Abstract Bone differentiation defects have been recently tied to Wnt signaling alterations occurring in vitro and in vivo Gaucher disease (GD) models. In this work, we provide evidence that the Wnt signaling multi-domain intracellular transducers Dishevelled 1 and 2 (DVL1 and DVL2) may be potential upstream targets of impaired beta glucosidase (GBA1) activity by showing their misexpression in different type 1 GD in vitro models. We also show that in Gba mutant fish a miR-221 upregulation is associated with reduced dvl2 expression levels and that in type I Gaucher patients single-nucleotide variants in the DVL2 3′ untranslated region are related to variable canonical Wnt pathway activity. Thus, we strengthen the recently outlined relation between bone differentiation defects and Wnt/β-catenin dysregulation in type I GD and further propose novel mechanistic insights of the Wnt pathway impairment caused by glucocerebrosidase loss of function.

scholarly journals A Context-Dependent Role for the RNF146 Ubiquitin Ligase in Wingless/Wnt Signaling in Drosophila

Genetics ◽  
2018 ◽  
Vol 211 (3) ◽  
pp. 913-923 ◽  
Author(s):  
Zhenghan Wang ◽  
Ofelia Tacchelly-Benites ◽  
Geoffrey P. Noble ◽  
Megan K. Johnson ◽  
Jean-Philippe Gagné ◽  
...  
Keyword(s):  
Wnt Signaling ◽  
Ubiquitin Ligase ◽  
Wnt Pathway ◽  
Gene Activation ◽  
Negative Regulator ◽  
Compensatory Mechanisms ◽  
E3 Ligases ◽  
Pathway Activation ◽  
Wingless Signaling

Aberrant activation of the Wnt signal transduction pathway triggers the development of colorectal cancer. The ADP-ribose polymerase Tankyrase (TNKS) mediates proteolysis of Axin—a negative regulator of Wnt signaling—and provides a promising therapeutic target for Wnt-driven diseases. Proteolysis of TNKS substrates is mediated through their ubiquitination by the poly-ADP-ribose (pADPr)-dependent RING-domain E3 ubiquitin ligase RNF146/Iduna. Like TNKS, RNF146 promotes Axin proteolysis and Wnt pathway activation in some cultured cell lines, but in contrast with TNKS, RNF146 is dispensable for Axin degradation in colorectal carcinoma cells. Thus, the contexts in which RNF146 is essential for TNKS-mediated Axin destabilization and Wnt signaling remain uncertain. Herein, we tested the requirement for RNF146 in TNKS-mediated Axin proteolysis and Wnt pathway activation in a range of in vivo settings. Using null mutants in Drosophila, we provide genetic and biochemical evidence that Rnf146 and Tnks function in the same proteolysis pathway in vivo. Furthermore, like Tnks, Drosophila Rnf146 promotes Wingless signaling in multiple developmental contexts by buffering Axin levels to ensure they remain below the threshold at which Wingless signaling is inhibited. However, in contrast with Tnks, Rnf146 is dispensable for Wingless target gene activation and the Wingless-dependent control of intestinal stem cell proliferation in the adult midgut during homeostasis. Together, these findings demonstrate that the requirement for Rnf146 in Tnks-mediated Axin proteolysis and Wingless pathway activation is dependent on physiological context, and suggest that, in some cell types, functionally redundant pADPr-dependent E3 ligases or other compensatory mechanisms promote the Tnks-dependent proteolysis of Axin in both mammalian and Drosophila cells.

scholarly journals Fine-Tuning of Sequence Specificity by Near Attack Conformations in Enzyme-Catalyzed Peptide Hydrolysis

Catalysts ◽  
2020 ◽  
Vol 10 (6) ◽  
pp. 684
Author(s):  
S. Kashif Sadiq
Keyword(s):  
Cleavage Site ◽  
Catalytic Effect ◽  
Reaction Rates ◽  
Fine Tuning ◽  
Sequence Specificity ◽  
Peptide Hydrolysis ◽  
Multiple Substrates ◽  
Uncatalyzed Reaction ◽  
Hiv 1

The catalytic role of near attack conformations (NACs), molecular states that lie on the pathway between the ground state (GS) and transition state (TS) of a chemical reaction, is not understood completely. Using a computational approach that combines Bürgi–Dunitz theory with all-atom molecular dynamics simulations, the role of NACs in catalyzing the first stages of HIV-1 protease peptide hydrolysis was previously investigated using a substrate that represents the recognized SP1-NC cleavage site of the HIV-1 Gag polyprotein. NACs were found to confer no catalytic effect over the uncatalyzed reaction there ( Δ Δ G N ‡ ∼ 0 kcal/mol). Here, using the same approach, the role of NACs across multiple substrates that each represent a further recognized cleavage site is investigated. Overall rate enhancement varies by | Δ Δ G ‡ | ∼ 12–15 kcal/mol across this set, and although NACs contribute a small and approximately constant barrier to the uncatalyzed reaction (< Δ G N ‡ u > = 4.3 ± 0.3 kcal/mol), they are found to contribute little significant catalytic effect ( | Δ Δ G N ‡ | ∼ 0–2 kcal/mol). Furthermore, no correlation is exhibited between NAC contributions and the overall energy barrier ( R 2 = 0.01). However, these small differences in catalyzed NAC contributions enable rates to match those required for the kinetic order of processing. Therefore, NACs may offer an alternative and subtle mode compared to non-NAC contributions for fine-tuning reaction rates during complex evolutionary sequence selection processes—in this case across cleavable polyproteins whose constituents exhibit multiple functions during the virus life-cycle.

scholarly journals Wnt Pathway: An Integral Hub for Developmental and Oncogenic Signaling Networks

2020 ◽  
Vol 21 (21) ◽  
pp. 8018 ◽  
Author(s):  
Monica Sharma ◽  
Kevin Pruitt
Keyword(s):  
Stem Cell ◽  
Wnt Signaling ◽  
Wnt Pathway ◽  
Cell Movement ◽  
Signaling Cascades ◽  
Cell Renewal ◽  
Oncogenic Signaling ◽  
Stem Cell Renewal ◽  
Development Processes ◽  
Cell Niche

The Wnt pathway is an integral cell-to-cell signaling hub which regulates crucial development processes and maintenance of tissue homeostasis by coordinating cell proliferation, differentiation, cell polarity, cell movement, and stem cell renewal. When dysregulated, it is associated with various developmental diseases, fibrosis, and tumorigenesis. We now better appreciate the complexity and crosstalk of the Wnt pathway with other signaling cascades. Emerging roles of the Wnt signaling in the cancer stem cell niche and drug resistance have led to development of therapeutics specifically targeting various Wnt components, with some agents currently in clinical trials. This review highlights historical and recent findings on key mediators of Wnt signaling and how they impact antitumor immunity and maintenance of cancer stem cells. This review also examines current therapeutics being developed that modulate Wnt signaling in cancer and discusses potential shortcomings associated with available therapeutics.

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