α-catenin phosphorylation promotes intercellular adhesion through a dual-kinase mechanism

Escobar, David; Desai, Ridhdhi; Ishiyama, Noboru; Folmsbee, Stephen Sai; Novak, Megan N.; Flozak, Annette S.; Daugherty, Rebecca L.; Mo, Rigen; Nanavati, Dhaval; Sarpal, Ritu; Leckband, Deborah; Ikura, Mitsuhiko; Tepaß, Ulrich; Gottardi, Cara J.

doi:10.1242/jcs.163824

Cited by 46 publications

(34 citation statements)

References 66 publications

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“…Therefore, the key observations regarding the mechanical regulation of a-catenin reported here should be relevant for other cell lines as well. The mechanism of stabilization of a-catenin in the active conformation may involve a posttranslational modification (57) or an interaction with another protein (5). The final inactivation of a-catenin may require the disengagement of E-cadherin, either by simple unbinding or by proteolytic cleavage (58), at the site of adhesion, and cellular recycling processes such as endocytosis (59).…”

Section: Discussionmentioning

confidence: 99%

Sustained α -catenin Activation at E-cadherin Junctions in the Absence of Mechanical Force

Biswas

Hartman

Zaidel-Bar

et al. 2016

Biophysical Journal

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Mechanotransduction at E-cadherin junctions has been postulated to be mediated in part by a force-dependent conformational activation of a-catenin. Activation of a-catenin allows it to interact with vinculin in addition to F-actin, resulting in a strengthening of junctions. Here, using E-cadherin adhesions reconstituted on synthetic, nanopatterned membranes, we show that activation of a-catenin is dependent on E-cadherin clustering, and is sustained in the absence of mechanical force or association with F-actin or vinculin. Adhesions were formed by filopodia-mediated nucleation and micron-scale assembly of E-cadherin clusters, which could be distinguished as either peripheral or central assemblies depending on their relative location at the cell-bilayer adhesion. Whereas F-actin, vinculin, and phosphorylated myosin light chain associated only with the peripheral assemblies, activated a-catenin was present in both peripheral and central assemblies, and persisted in the central assemblies in the absence of actomyosin tension. Impeding filopodia-mediated nucleation and micron-scale assembly of E-cadherin adhesion complexes by confining the movement of bilayer-bound E-cadherin on nanopatterned substrates reduced the levels of activated a-catenin. Taken together, these results indicate that although the initial activation of a-catenin requires micron-scale clustering that may allow the development of mechanical forces, sustained force is not required for maintaining a-catenin in the active state.

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Section: Discussionmentioning

confidence: 99%

Sustained α -catenin Activation at E-cadherin Junctions in the Absence of Mechanical Force

Biswas

Hartman

Zaidel-Bar

et al. 2016

Biophysical Journal

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“…Nonetheless, at least one residue in HMP-1 that we showed is phosphorylated in vivo (serine 649) is conserved in mammalian αE-catenin and has been identified as being phosphorylated in multiple global proteomic analyses in a variety of human cell lines (see http://www.phosphosite.org). Thus, a functional role for α-catenin phosphorylation may be conserved through evolution, and recent findings highlight its potential importance for strong cell–cell adhesion in vivo [45]. …”

Section: Discussionmentioning

confidence: 99%

Phosphoregulation of the C. elegans cadherin–catenin complex

Callaci

Morrison

Shao

et al. 2015

Biochemical Journal

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Adherens junctions play key roles in mediating cell–cell contacts during tissue development. In Caenorhabditis elegans embryos, the cadherin–catenin complex (CCC), composed of the classical cadherin HMR-1 and members of three catenin families, HMP-1, HMP-2 and JAC-1, is necessary for normal blastomere adhesion, gastrulation, ventral enclosure of the epidermis and embryo elongation. Disruption of CCC assembly or function results in embryonic lethality. Previous work suggests that components of the CCC are subject to phosphorylation. However, the identity of phosphorylated residues in CCC components and their contributions to CCC stability and function in a living organism remain speculative. Using mass spectrometry, we systematically identify phosphorylated residues in the essential CCC subunits HMR-1, HMP-1 and HMP-2 in vivo. We demonstrate that HMR-1/cadherin phosphorylation occurs on three sites within its β-catenin binding domain that each contributes to CCC assembly on lipid bilayers. In contrast, phosphorylation of HMP-2/β-catenin inhibits its association with HMR-1/cadherin in vitro, suggesting a role in CCC disassembly. Although HMP-1/α-catenin is also phosphorylated in vivo, phosphomimetic mutations do not affect its ability to associate with other CCC components or interact with actin in vitro. Collectively, our findings support a model in which distinct phosphorylation events contribute to rapid CCC assembly and disassembly, both of which are essential for morphogenetic rearrangements during development.

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“…172 In addition, creatine kinase phosphorylates and facilitates TJ occludin assembly, thereby contributing to TJ remodeling and barrier regulation. 173 In keratinocytes, creatine kinase has been reported to phosphorylate α -catenin and E-cadherin, 174 thereby strengthening intercellular adhesion. 175 As another example, production of IL23 during intestinal inflammation has been reported to induce production of IL17A and IL22, which in turn promote recruitment of innate and adaptive immune cells, host defense, and mucosal homeostasis.…”

Section: Inflammation and Restoration Of Mucosal Barrier Functionmentioning

confidence: 99%

Inflammation and the Intestinal Barrier: Leukocyte–Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair

2016

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The intestinal tract is lined by a single layer of columnar epithelial cells that forms a dynamic, permeable barrier allowing for selective absorption of nutrients, while restricting access to pathogens and food-borne antigens. Precise regulation of epithelial barrier function is therefore required for maintaining mucosal homeostasis and depends, in part, on barrier-forming elements within the epithelium and a balance between pro- and anti-inflammatory factors in the mucosa. Pathologic states, such as inflammatory bowel disease, are associated with a leaky epithelial barrier, resulting in excessive exposure to microbial antigens, recruitment of leukocytes, release of soluble mediators, and ultimately mucosal damage. An inflammatory microenvironment affects epithelial barrier properties and mucosal homeostasis by altering the structure and function of epithelial intercellular junctions through direct and indirect mechanisms. We review our current understanding of complex interactions between the intestinal epithelium and immune cells, with a focus on pathologic mucosal inflammation and mechanisms of epithelial repair. We discuss leukocyte–epithelial interactions, as well as inflammatory mediators that affect the epithelial barrier and mucosal repair. Increased knowledge of communication networks between the epithelium and immune system will lead to tissue-specific strategies for treating pathologic intestinal inflammation.

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α-catenin phosphorylation promotes intercellular adhesion through a dual-kinase mechanism

Cited by 46 publications

References 66 publications

Sustained α -catenin Activation at E-cadherin Junctions in the Absence of Mechanical Force

Sustained α -catenin Activation at E-cadherin Junctions in the Absence of Mechanical Force

Phosphoregulation of the C. elegans cadherin–catenin complex

Inflammation and the Intestinal Barrier: Leukocyte–Epithelial Cell Interactions, Cell Junction Remodeling, and Mucosal Repair

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