Dataset Information

?-catenin cytomechanics--role in cadherin-dependent adhesion and mechanotransduction.

ABSTRACT: The findings presented here demonstrate the role of ?-catenin in cadherin-based adhesion and mechanotransduction in different mechanical contexts. Bead-twisting measurements in conjunction with imaging, and the use of different cell lines and ?-catenin mutants reveal that the acute local mechanical manipulation of cadherin bonds triggers vinculin and actin recruitment to cadherin adhesions in an actin- and ?-catenin-dependent manner. The modest effect of ?-catenin on the two-dimensional binding affinities of cell surface cadherins further suggests that force-activated adhesion strengthening is due to enhanced cadherin-cytoskeletal interactions rather than to ?-catenin-dependent affinity modulation. Complementary investigations of cadherin-based rigidity sensing also suggest that, although ?-catenin alters traction force generation, it is not the sole regulator of cell contractility on compliant cadherin-coated substrata.

SUBMITTER: Barry AK

PROVIDER: S-EPMC3986676 | biostudies-literature | 2014 Apr

REPOSITORIES: biostudies-literature

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α-catenin cytomechanics--role in cadherin-dependent adhesion and mechanotransduction.

Barry Adrienne K AK Tabdili Hamid H Muhamed Ismaeel I Wu Jun J Shashikanth Nitesh N Gomez Guillermo A GA Yap Alpha S AS Gottardi Cara J CJ de Rooij Johan J Wang Ning N Leckband Deborah E DE

Journal of cell science 20140212 Pt 8

The findings presented here demonstrate the role of α-catenin in cadherin-based adhesion and mechanotransduction in different mechanical contexts. Bead-twisting measurements in conjunction with imaging, and the use of different cell lines and α-catenin mutants reveal that the acute local mechanical manipulation of cadherin bonds triggers vinculin and actin recruitment to cadherin adhesions in an actin- and α-catenin-dependent manner. The modest effect of α-catenin on the two-dimensional binding ...[more]

PMID: 24522187

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Project description:The cellular network composed of the evolutionarily conserved metabolic pathways of protein N-glycosylation, Wnt/?-catenin signaling pathway, and E-cadherin-mediated cell-cell adhesion plays pivotal roles in determining the balance between cell proliferation and intercellular adhesion during development and in maintaining homeostasis in differentiated tissues. These pathways share a highly conserved regulatory molecule, ?-catenin, which functions as both a structural component of E-cadherin junctions and as a co-transcriptional activator of the Wnt/?-catenin signaling pathway, whose target is the N-glycosylation-regulating gene, DPAGT1. Whereas these pathways have been studied independently, little is known about the dynamics of their interaction. Here we present the first numerical model of this network in MDCK cells. Since the network comprises a large number of molecules with varying cell context and time-dependent levels of expression, it can give rise to a wide range of plausible cellular states that are difficult to track. Using known kinetic parameters for individual reactions in the component pathways, we have developed a theoretical framework and gained new insights into cellular regulation of the network. Specifically, we developed a mathematical model to quantify the fold-change in concentration of any molecule included in the mathematical representation of the network in response to a simulated activation of the Wnt/ ?-catenin pathway with Wnt3a under different conditions. We quantified the importance of protein N-glycosylation and synthesis of the DPAGT1 encoded enzyme, GPT, in determining the abundance of cytoplasmic ?-catenin. We confirmed the role of axin in ?-catenin degradation. Finally, our data suggest that cell-cell adhesion is insensitive to E-cadherin recycling in the cell. We validate the model by inhibiting ?-catenin-mediated activation of DPAGT1 expression and predicting changes in cytoplasmic ?-catenin concentration and stability of E-cadherin junctions in response to DPAGT1 inhibition. We show the impact of pathway dysregulation through measurements of cell migration in scratch-wound assays. Collectively, our results highlight the importance of numerical analyses of cellular networks dynamics to gain insights into physiological processes and potential design of therapeutic strategies to prevent epithelial cell invasion in cancer.

Dataset Information

?-catenin cytomechanics--role in cadherin-dependent adhesion and mechanotransduction.

Publications

α-catenin cytomechanics--role in cadherin-dependent adhesion and mechanotransduction.

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