Abstract
Cadherin junctions arise from the integrated action of cell adhesion, signaling, and the cytoskeleton. At the zonula adherens (ZA), a WAVE2-Arp2/3 actin nucleation apparatus is necessary for junctional tension and integrity. But how this is coordinated with cadherin adhesion is not known. We now identify cortactin as a key scaffold for actin regulation at the ZA, which localizes to the ZA through influences from both E-cadherin and N-WASP. Using cell-free protein expression and fluorescent single molecule coincidence assays, we demonstrate that cortactin binds directly to the cadherin cytoplasmic tail. However, its concentration with cadherin at the apical ZA also requires N-WASP. Cortactin is known to bind Arp2/3 directly (Weed, S. A., Karginov, A. V., Schafer, D. A., Weaver, A. M., Kinley, A. W., Cooper, J. A., and Parsons, J. T. (2000) J. Cell Biol. 151, 29-40). We further show that cortactin can directly bind WAVE2, as well as Arp2/3, and both these interactions are necessary for actin assembly at the ZA. We propose that cortactin serves as a platform that integrates regulators of junctional actin assembly at the ZA.
Highlights
Productive epithelial interactions require actin filament assembly at E-cadherin adhesions
Cortactin Recruits Arp2/3 to Regulate Actin Dynamics at the zonula adherens (ZA)—We used Caco-2 cells, which assemble prominent zonulae adherentes within their cell-cell contacts [25, 26], as a model in which to analyze how cortactin might influence Arp2/3 at junctions
As Arp2/3 is essentially inactive in isolation, it must be localized to interact with upstream-activating proteins, notably WAVE2, a major nucleation promotor at the ZA [6]
Summary
Productive epithelial interactions require actin filament assembly at E-cadherin adhesions. Results: Cortactin localizes to the zonula adherens through interactions with E-cadherin and N-WASP; there it recruits Arp2/3 and WAVE2 by separate mechanisms to support actin nucleation. At the zonula adherens (ZA), a WAVE2-Arp2/3 actin nucleation apparatus is necessary for junctional tension and integrity. How this is coordinated with cadherin adhesion is not known. We demonstrate that cortactin integrates inputs from E-cadherin and N-WASP to localize selectively to the ZA, where it promotes actin nucleation by scaffolding both Arp2/3 and WAVE2 to the ZA cortex, through distinct binding interactions
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