The Cadherin Cytoplasmic Domain Is Unstructured in the Absence of β-Catenin

Huber, Andrew H.; Stewart, Daniel B.; Laurents, Douglas V.; Nelson, W. James; Weis, William I.

doi:10.1074/jbc.m010377200

Cited by 236 publications

(190 citation statements)

References 70 publications

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“…This suggests that both residues must be phosphorylated to compromise E-cadherin adhesion, whereas a recent study indicated phosphorylation of either of these residues compromised Ncadherin adhesion (15). Phosphorylation of ␤-catenin Y489 reduces binding affinity between ␤-catenin and N-cadherin ϳ4-fold whereas phosphorylation of ␤-catenin Y654 reduces binding affinity between ␤-catenin and E-cadherin 6-to 10-fold (9,10,13,15). It is possible that the fourfold reduction in affinity does not itself disrupt E-cadherin binding to ␤-catenin but facilitates the phosphorylation of Y654 that then in combination with phosphorylation of Y489 compromises binding of ␤-catenin and cadherin.…”

Section: Discussionmentioning

confidence: 88%

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Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

Winter

Shasby²,

Shasby³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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vation of the type 1 histamine (H1) or the type 2 protease-activated (PAR-2) G protein-coupled receptors interrupts E-cadherin adhesion and decreases the transepithelial resistance (TER) of epithelium. Several reports suggest that cadherin adhesive function depends on the association of cadherin with ␤-catenin and that this association is regulated by phosphorylation of tyrosines in ␤-catenin. We tested the hypothesis that loss of cadherin adhesion and compromise of TER on activation of the H1 or PAR-2 receptor is due to phosphorylation of tyrosines in ␤-catenin. L cells were stably transfected to express E-cadherin (L-E-cad cells) and H1 (L-H1-E-cad cells). L cells and Madin-Darby canine kidney (MDCK) cells constitutively express PAR-2. Stably transfected L-E-cad, L-H1-E-cad, and MDCK cells were also stably transfected with FLAG-tagged wild-type (WT) or mutant ␤-catenin, converting tyrosine 142, 489, or 654 to the nonphosphorylatable mimetic, phenylalanine (WT, Y142F, Y489F, or Y654F). Activation of H1 or PAR-2 interrupted adhesion to an immobilized E-cadherin-Fc fusion protein of L-H1-E-cad, L-E-cad, and MDCK cells expressing WT or Y142F ␤-catenin but did not interrupt adhesion of L-H1-E-cad, L-E-cad, and MDCK cells expressing the Y489F or Y654F mutant ␤-catenins. PAR-2 activation decreased the TER of monolayers of MDCK cells expressing WT or Y142F ␤-catenin 40 -45%. However, PAR-2 activation did not decrease the TER of monolayers of MDCK cells expressing Y489F or Y654F ␤-catenin. The protein tyrosine phosphatase PTP1B binds to the cadherin cytoplasmic domain and dephosphorylates ␤-catenin. Inhibition of PTP1B interrupted adhesion to E-cadherin-Fc of MDCK cells expressing WT ␤-catenin but did not affect the adhesion of MDCK cells expressing Y489F or Y654F ␤-catenin. Similarly, inhibition of PTP1B compromised the TER of MDCK cells expressing WT ␤-catenin but did not affect the TER of MDCK cells expressing Y489F or Y654F ␤-catenin. We conclude that phosphorylation of tyrosines 489 and 654 in ␤-catenin is a necessary step in the process by which G protein-coupled H1 and PAR-2 receptors interrupt Ecadherin adhesion. We also conclude that activation of PAR-2 has no effect on the TER without first interrupting E-cadherin adhesion.AIRWAY EPITHELIA CREATE an important barrier between the tissues of the lung and the environment. This barrier is dependent on molecules that bind the epithelial cells to each other and to molecules of the tight junction that act as resistors to paracellular molecular traffic. E-cadherin mediates calciumdependent homotypic cell-cell adhesion in epithelia. We (24, 27) previously reported that activation of the type 1 histamine (H1) or the type 2 protease-activated receptor (PAR-2) decreased the transepithelial resistance (TER) of airway epithelium by interrupting E-cadherin adhesion. In these reports, activation of the H1 or PAR-2 receptor interrupted E-cadherindependent adhesion of E-cadherin expressing L cells and of primary airway epithelium to immobilized E-cadherin. Activation of H1 or ...

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Section: Discussionmentioning

confidence: 88%

“…␤-Catenin binds to E-cadherin in the endoplasmic reticulum. In the absence of ␤-catenin binding, the cadherin cytoplasmic domain lacks structure, PEST sites are exposed, and cadherin is rapidly proteolyzed (9,10). Peptides that compete with ␤-catenin for binding to cadherin also interrupt cadherin adhesion (1).…”

mentioning

confidence: 99%

Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

Winter

Shasby²,

Shasby³

2008

American Journal of Physiology-Lung Cellular and Molecular Phys

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“…A major regulator of cadherin stability is its intracellular binding partner β-catenin (9). In vitro evidence demonstrates that β-catenin/cadherin interactions are dynamically regulated in response to activity (10,11), allowing β-catenin to modify cadherin stability during different forms of synaptic plasticity.…”

mentioning

confidence: 99%

Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

Mills¹,

Bartlett²,

Dissing-Olesen

et al. 2014

Proc. Natl. Acad. Sci. U.S.A.

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Significance Complex learning and memory are believed to require the weakening or elimination of synapses in the brain, a process mediated by adhesion molecules, which maintain synapse strength and stability. In the present study, we examine in vivo the effects of stabilization of β-catenin, an intracellular protein that is a component of the cadherin adhesion complex. We find that stabilization of β-catenin in the brain prevents normal activity-dependent downscaling of synapse strength, resulting in a striking impairment in cognitive flexibility. These results demonstrate that β-catenin plays an important role in learning and memory and that aberrant increases in synaptic adhesion can have detrimental effects on cognitive function.

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“…When bound to β-catenin, classical cadherins on neighboring cells interact homophilically and, thereby, promote cell-cell adhesion (16). When not bound to β-catenin, classical cadherins are rapidly degraded (17,18). The regulation of classical cadherin function by β-catenin thereby forms the foundation of adherens junctions and is crucial for cell adhesion in all studied bilaterian tissues, including epithelia, neurons, muscles, and bones (3,19).…”

mentioning

confidence: 99%

Origin of metazoan cadherin diversity and the antiquity of the classical cadherin/β-catenin complex

Nichols

Roberts

Richter

et al. 2012

Proc. Natl. Acad. Sci. U.S.A.

170

196

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The evolution of cadherins, which are essential for metazoan multicellularity and restricted to metazoans and their closest relatives, has special relevance for understanding metazoan origins. To reconstruct the ancestry and evolution of cadherin gene families, we analyzed the genomes of the choanoflagellate Salpingoeca rosetta, the unicellular outgroup of choanoflagellates and metazoans Capsaspora owczarzaki, and a draft genome assembly from the homoscleromorph sponge Oscarella carmela. Our finding of a cadherin gene in C. owczarzaki reveals that cadherins predate the divergence of the C. owczarzaki, choanoflagellate, and metazoan lineages. Data from these analyses also suggest that the last common ancestor of metazoans and choanoflagellates contained representatives of at least three cadherin families, lefftyrin, coherin, and hedgling. Additionally, we find that an O. carmela classical cadherin has predicted structural features that, in bilaterian classical cadherins, facilitate binding to the cytoplasmic protein β-catenin and, thereby, promote cadherin-mediated cell adhesion. In contrast with premetazoan cadherin families (i.e., those conserved between choanoflagellates and metazoans), the later appearance of classical cadherins coincides with metazoan origins.

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The Cadherin Cytoplasmic Domain Is Unstructured in the Absence of β-Catenin

Cited by 236 publications

References 70 publications

Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

Compromised E-cadherin adhesion and epithelial barrier function with activation of G protein-coupled receptors is rescued by Y-to-F mutations in β-catenin

Cognitive flexibility and long-term depression (LTD) are impaired following β-catenin stabilization in vivo

Origin of metazoan cadherin diversity and the antiquity of the classical cadherin/β-catenin complex

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