Axin: An emerging key scaffold at the synapse

Chen, Yu; Fu, Amy Kit Yu; Ip, Nancy Y.

doi:10.1002/iub.1184

Cited by 15 publications

(14 citation statements)

References 56 publications

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“…9 597 and 521-663 in ZIP6 and ZIP10, respectively). Similar to known docking sites of GSK3 on axin 1 (AXIN1) and 2 (AXIN2)3334, these cytoplasmic loop segments within the two ZIP transporters are enriched in charged residues and C-terminally flanked by a histidine-rich segment. It has long been known that NCAM1 can be phosphorylated within its intracellular domain by casein kinase 1 (CK1) and GSK3 but in these early studies the phospho-acceptor site was not determined35.…”

Section: Discussionmentioning

confidence: 83%

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

Dylan

Mehrabian

Williams

et al. 2017

Sci Rep

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The prion protein (PrP) evolved from the subbranch of ZIP metal ion transporters comprising ZIPs 5, 6 and 10, raising the prospect that the study of these ZIPs may reveal insights relevant for understanding the function of PrP. Building on data which suggested PrP and ZIP6 are critical during epithelial-to-mesenchymal transition (EMT), we investigated ZIP6 in an EMT paradigm using ZIP6 knockout cells, mass spectrometry and bioinformatic methods. Reminiscent of PrP, ZIP6 levels are five-fold upregulated during EMT and the protein forms a complex with NCAM1. ZIP6 also interacts with ZIP10 and the two ZIP transporters exhibit interdependency during their expression. ZIP6 contributes to the integration of NCAM1 in focal adhesion complexes but, unlike cells lacking PrP, ZIP6 deficiency does not abolish polysialylation of NCAM1. Instead, ZIP6 mediates phosphorylation of NCAM1 on a cluster of cytosolic acceptor sites. Substrate consensus motif features and in vitro phosphorylation data point toward GSK3 as the kinase responsible, and interface mapping experiments identified histidine-rich cytoplasmic loops within the ZIP6/ZIP10 heteromer as a novel scaffold for GSK3 binding. Our data suggests that PrP and ZIP6 inherited the ability to interact with NCAM1 from their common ZIP ancestors but have since diverged to control distinct posttranslational modifications of NCAM1.

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Section: Discussionmentioning

confidence: 83%

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

Dylan

Mehrabian

Williams

et al. 2017

Sci Rep

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“…In a separate study, it was demonstrated that Axin inhibition in a neuroblastoma cell line, through the application of Li (lithium) and a GSK-3β inhibitor, promoted neurite outgrowth, whereas ectopic Axin expression caused an opposite phenotype [43]. Subsequently, several reports have shown Axin's role in neuronal proliferation and differentiation, axon formation, dendritic spine morphology, and synapse formation [44][45][46][47][48].…”

Section: Vertebrate Modelsmentioning

confidence: 99%

Axin Family of Scaffolding Proteins in Development: Lessons from C. elegans

Mallick

Taylor

Ranawade

et al. 2019

JDB

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Scaffold proteins serve important roles in cellular signaling by integrating inputs from multiple signaling molecules to regulate downstream effectors that, in turn, carry out specific biological functions. One such protein, Axin, represents a major evolutionarily conserved scaffold protein in metazoans that participates in the WNT pathway and other pathways to regulate diverse cellular processes. This review summarizes the vast amount of literature on the regulation and functions of the Axin family of genes in eukaryotes, with a specific focus on Caenorhabditis elegans development. By combining early studies with recent findings, the review is aimed to serve as an updated reference for the roles of Axin in C. elegans and other model systems.

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“…(A) Intracellular protein Axin functions as a major scaffold for components of synapses, which include interactive glutamate receptors of the NMDA and AMPA types, bidirectional signaling by ephrin-B, and adhesive interactions through N-cadherin, the latter of which modulates gene transcription through β-catenin. Based on Wei et al (2010) and Chen et al (2013). (B) Expected crosstalk of Laminin (Ln)-induced signals, transferred to the intracellular milieu through PrP C -scaffolded mGluR1/5-, NCAM- and L1-mediated pathways.…”

Section: The Prion Protein As a Cell Surface Scaffold Proteinmentioning

confidence: 99%

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

Linden

2017

Front. Mol. Neurosci.

111

104

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The prion glycoprotein (PrPC) is mostly located at the cell surface, tethered to the plasma membrane through a glycosyl-phosphatydil inositol (GPI) anchor. Misfolding of PrPC is associated with the transmissible spongiform encephalopathies (TSEs), whereas its normal conformer serves as a receptor for oligomers of the β-amyloid peptide, which play a major role in the pathogenesis of Alzheimer’s Disease (AD). PrPC is highly expressed in both the nervous and immune systems, as well as in other organs, but its functions are controversial. Extensive experimental work disclosed multiple physiological roles of PrPC at the molecular, cellular and systemic levels, affecting the homeostasis of copper, neuroprotection, stem cell renewal and memory mechanisms, among others. Often each such process has been heralded as the bona fide function of PrPC, despite restricted attention paid to a selected phenotypic trait, associated with either modulation of gene expression or to the engagement of PrPC with a single ligand. In contrast, the GPI-anchored prion protein was shown to bind several extracellular and transmembrane ligands, which are required to endow that protein with the ability to play various roles in transmembrane signal transduction. In addition, differing sets of those ligands are available in cell type- and context-dependent scenarios. To account for such properties, we proposed that PrPC serves as a dynamic platform for the assembly of signaling modules at the cell surface, with widespread consequences for both physiology and behavior. The current review advances the hypothesis that the biological function of the prion protein is that of a cell surface scaffold protein, based on the striking similarities of its functional properties with those of scaffold proteins involved in the organization of intracellular signal transduction pathways. Those properties are: the ability to recruit spatially restricted sets of binding molecules involved in specific signaling; mediation of the crosstalk of signaling pathways; reciprocal allosteric regulation with binding partners; compartmentalized responses; dependence of signaling properties upon posttranslational modification; and stoichiometric requirements and/or oligomerization-dependent impact on signaling. The scaffold concept may contribute to novel approaches to the development of effective treatments to hitherto incurable neurodegenerative diseases, through informed modulation of prion protein-ligand interactions.

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Axin: An emerging key scaffold at the synapse

Cited by 15 publications

References 56 publications

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

A ZIP6-ZIP10 heteromer controls NCAM1 phosphorylation and integration into focal adhesion complexes during epithelial-to-mesenchymal transition

Axin Family of Scaffolding Proteins in Development: Lessons from C. elegans

The Biological Function of the Prion Protein: A Cell Surface Scaffold of Signaling Modules

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