Regulation of Adherens Junction Dynamics by Phosphorylation Switches

Abstract

Adherens junctions connect the actin cytoskeleton of neighboring cells through transmembrane cadherin receptors and a network of adaptor proteins. The interactions between these adaptors and cadherin as well as the activity of actin regulators localized to adherens junctions are tightly controlled to facilitate cell junction assembly or disassembly in response to changes in external or internal forces and/or signaling. Phosphorylation of tyrosine, serine, or threonine residues acts as a switch on the majority of adherens junction proteins, turning “on” or “off” their interactions with other proteins and/or their enzymatic activity. Here, we provide an overview of the kinases and phosphatases regulating phosphorylation of adherens junction proteins and bring examples of phosphorylation events leading to the assembly or disassembly of adherens junctions, highlighting the important role of phosphorylation switches in regulating their dynamics.

Spatial integration of E-cadherin adhesion, signalling and the epithelial cytoskeleton

“…nectins [17], growth factors receptors and integrins). In spite of extensive progress in the identification of cytoskeletal proteins found at junctions [18,19], the precise F-actin organization and the specific actin remodelling functions at cadherin contacts lack in-depth understanding. A pool of G-actin at junctions [20] has unknown functions, but may provide a local pool of monomers for filament remodelling.…”

Flotillins in intercellular adhesion – from cellular physiology to human diseases

“…Possible role of flotillins in Src-family-kinase-dependent regulation of cadherin complexes Phosphorylation is also important for the regulation of adherens junction dynamics, although the exact events are still not very well known (Bertocchi et al, 2012;Pust et al, 2013). Src family kinases, which are recruited to cell-cell junctions upon cadherin binding, are regulators of cadherin-mediated adhesion and also affect flotillin function (Babuke et al, 2009;Bertocchi et al, 2012;NeumannGiesen et al, 2007;Riento et al, 2009).…”

“…Src family kinases, which are recruited to cell-cell junctions upon cadherin binding, are regulators of cadherin-mediated adhesion and also affect flotillin function (Babuke et al, 2009;Bertocchi et al, 2012;NeumannGiesen et al, 2007;Riento et al, 2009). In particular, Src coimmunoprecipitates with flotillin 2 in HeLa cells (Neumann-Giesen et al, 2007), and phosphorylation of flotillins by Fyn induces their endocytosis (Riento et al, 2009).…”

Quantitative phosphoproteomics unveils temporal dynamics of thrombin signaling in human endothelial cells

“…This analysis led us to the following observations: (1) the majority of the phosphoproteins within each pathway have at least one phosphosite regulated upon thrombin stimulation, which highlights that phosphorylation is a prominent component of thrombin signaling and that cellular responses to stimuli are the result of the combined effect of phosphorylations on many proteins rather than a single phosphorylation event. For example, we report dynamically regulated phosphosites on proteins within the different layers of the cell-cell junctions 48 ( Figures 4 and 5) and on a large number of proteins involved in Weibel-Palade body secretion, including some involved in vesicle transport, tethering, docking, priming, and fusion ( Figure 7); and (2) several proteins contain multiple regulated phosphosites with distinct temporal profiles, suggesting that it is not a single but rather a combination of phosphorylation and dephosphorylation events that regulate protein function. It is tempting to speculate that these highly regulated proteins might be key hubs of the thrombin-induced signaling and therefore the most promising candidates to be investigated further.…”