How is the cytoskeleton linked to adherens junctions?2017-12-26T13:01:10+08:30

How is the cytoskeleton linked to adherens junctions?

Early biochemical studies exploring the structural link between the cytoskeleton and cadherins in adherens junctions (AJs) concluded that it comprised direct interactions in the following order; cadherin tails bind β-catenin, β-catenin binds the VH1 domain of α-catenin [1], the VH3 domain of α-catenin binds actin [1].

Indeed, the importance of α-catenin in this link was highlighted after chimeric cadherin-αE-catenin fusion proteins were introduced into fibroblasts lacking cadherin, and a rescue of cadherin function was observed. This was noted to be dependent on the inclusion of the αE-catenin C-terminus [2]. α-catenin’s importance was again highlighted in vivo when a similar study was performed using Drosophila. In this case the DE-cadherin-α-catenin fusion protein was found to rescue adhesion defects independently of β-catenin [3].

Despite the clear evidence that α-catenin is essential in this link, it is also clear that a more complex arrangement of proteins localize to the AJ plaque region. This was proposed by the Weis and Nelson groups after in vitro biochemical experiments showed that α-catenin-β-catenin heterodimers have a low affinity for actin [4][5]. α-catenin binds more readily to actin as a homodimer, yet due to the β-catenin binding site overlapping with heterodimer interface, α-catenin can only bind to the AJ as a monomer [5]. Recently, this was attributed to β-catenin disrupting interactions that exist between four α-helix bundles of α-catenin and confer its asymmetric homodimer arrangement. These findings were determined through crystallization of a near-complete human α-catenin dimer [6]. Furthermore, in an earlier study a novel assay using isolated cadherin-containing membrane patches to which β-catenin was added also showed that although α-catenin could bind the cadherin-β-catenin complex, subsequent addition of G- or F-actin failed to bind to this new complex of cadherin-β-catenin-α-catenin [4]. Similarly, although the cadherin-β-catenin-α-catenin complex has successfully been isolated from cells, this has not yet been achieved with actin also bound. It is important to note, however, that both of these are basically negative results.

Additional biochemical and in vitro studies by the Weis and Nelson groups further indicate that a direct link between the cytoskeleton and α-catenin is unlikely to occur in vivo, and instead, is likely mediated by additional adaptor proteins. For example, observations from FRAP experiments revealed contrasting dynamics of actin and α-catenin at cell-cell contact sites. Here, α-catenin was seen to exhibit a significantly slower depletion rate when compared to actin, which underwent rapid exchange with a cytoplasmic pool of actin [4][5]. The dynamics of actin and α-catenin were also explored using Drosophila epithelial cells and two separate populations of actin were identified, each with different rates of turnover. Whilst the majority of actin was highly dynamic, and was proposed to serve in preventing the lateral movement of homophilic E-cadherin clusters within the membrane, a smaller pool of actin was highly stable and this was correlated to adhesion stability. Interestingly α-catenin was found to be essential for tethering the cadherin clusters to the dynamic actin filament network but was not required for complex stability [7]. It was concluded in this study that unidentified adaptor proteins likely ensure stability in mobile AJs.

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  2. Imamura Y, Itoh M, Maeno Y, Tsukita S, and Nagafuchi A. Functional domains of alpha-catenin required for the strong state of cadherin-based cell adhesion. J. Cell Biol. 1999; 144(6):1311-22. [PMID: 10087272]
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