How do posttranslational modifications of cell-cell adhesions impact their stability?2018-06-11T15:23:48+00:00

How do posttranslational modifications of cell-cell adhesions impact their stability?

Posttranslational modification of adhesion complex components is one of the most complicated aspects in the regulation of cell-cell adhesions. It involves an array of protein enzymes and despite a growing body of knowledge on the topic, many of the specific mechanisms, from recruitment of regulators, to the consequence each modification has on adhesion stability and function has yet to be described.

Phosphorylation events are the most prominent posttranslational modification to play a role in the regulation of cell-cell adhesions. These are mediated by phosphatases and kinases, of which at least 34 are known to localize to AJs alone [1]. In many cases the method by which phosphatases/kinases are recruited to the adhesion site has yet to be established, however, in most cases direct binding with either core components or scaffolding proteins is likely to be involved. Indeed this has been established in some specific cases; for example CSK and VE-PTP bind directly to VE-cadherin [2], MET and PTPRF to β-catenin [3][4] and ROCK1 to p120-catenin [12].


hosphorylation of cell-cell adhesion components can affect the adhesions’ stabilisation, (a) Normal adherens junction, (b) Tyrosine phosphorylation of VE-cadherin is induced, which can lead to (c) cleavage of VE-cadherin and weakening of the adherens junction

Addition or removal of a phosphate molecule may not only alter the targets binding affinity to other components, but may activate or deactivate enzymatic properties to produce either positive (stabilizing), or negative (destabilizing) consequences. Furthermore, the activity of kinases/phosphatases is often correlated to the action of the cell-cell adhesion complex, with mechanical cues from neighboring cells triggering the enzymatic activity of the protein. This was observed, for example, when the H-Ras/Raf/MEK/ERK signaling cascade was induced following the attachment of invasive breast cancer cells to endothelial cells in vitro. Here, tyrosine phosphorylation of VE-cadherin was induced, and subsequently, the dissociation of β-catenin from the complex observed [5].

Similarly, attachment of neutrophils and lymphocytes to endothelial cells activated by TNF-α lead to the rapid dissociation of the tyrosine phosphatase VE-PTP from VE-cadherin [2]. VE-PTP had previously been found to bind to, and reduce the phosphorylation of VE-cadherin, but not β-catenin [6], which effectively stabilized the adhesion complex. Leukocyte mediated dissociation of VE-PTP from VE-cadherin was associated with increased phosphorylation of VE-cadherin as well as β-catenin and plakoglobin. Importantly, it was the plakoglobin that was found to be essential in VE-PTP stabilization VE-cadherin [2].

As mentioned, leukocyte mediated dissociation of VE-PTP was only observed in cells that had been activated by the inflammatory cytokine, TNF-α, highlighting that regulators themselves may be activated only under specific cellular conditions. This was again reflected when the tyrosine phosphatase SHP2 was found to dissociate from β-catenin as a result of thrombin stimulation [7]. Later studies noted that dissociation of SHP2 promoted catenin phosphorylation [8], confirming it to be a substrate of SHP2 [9], and revealed, through silencing or inhibition of SHP2 its role in promoting the mobility of E-cadherin, and hence, the integrity of adhesion complexes [21]).

Similarly, posttranslational modification of scaffolding proteins such as p120-catenin may be equally influential to the stability of the adhesion complex. This was demonstrated when it was found that PKCa mediated phosphorylation of p120-catenin at Serine 879 which initiated dissociation of p120-catenin from the AJ, and subsequently promoted its disassembly [10].

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