Biology subjects

Troyanovsky, S. M.

Publications and source records attributed to Troyanovsky, S. M..

4 recordsLinked to original sources

bioRxiv2026

δ-Catenins couple cadherin adhesions to phospholipid-rich membrane domains

{delta}-Catenins interact with both classical and desmosomal cadherins and play essential, yet incompletely understood, role in adherens junctions (AJs) and desmosomes. According to the prevailing model, {delta}-catenins are recruited to these junctions exclusively through direct binding to the cadherin juxtamembrane domain (JMD). Here, we show that plakophilin 4 (Pkp4), one of the AJ-associated {delta}-catenins, is recruited into AJs through two distinct and independent mechanisms. The first is the conventional pathway based on direct interaction with the cadherin JMD. The second is a previously unrecognized mechanism that targets Pkp4 specifically to lateral AJs, submicron-sized, exceptionally stable junctions located along the mid-lateral region of epithelial cell-cell contacts. This targeting occurs independently of the cadherin JMD but requires an interaction with phospholipid-rich plasma membrane domains. We identify the conserved insert between ARM repeats 5 and 6 as the phospholipid-binding module of Pkp4. Because both membrane-binding determinants within this insert, a palmitoylated cysteine residue and a polybasic motif, are highly conserved throughout the {delta}-catenin family, our findings suggest that recognition of specialized plasma membrane domains is a general property of {delta}-catenins. We propose that the interplay between cadherin- and phospholipid-dependent targeting mechanisms enables individual {delta}-catenins to selectively stabilize distinct cadherin-based cell-cell junctions, thereby contributing to the overall architecture of the cell-cell adhesion system.

cell biology↗

bioRxiv2025

Two δ-Catenins, Plakophilin 4 and p120, Promote Formation of Distinct Types of Adherens Junctions

Classic cadherins are instrumental for joining cells into tissues by producing cell-cell adhesions known as adherens junctions (AJs). These morphologically diverse structures are tailored to the specific cell sites, type of cells, and particular functions. The mechanism of AJ diversification remains unknown. Here we show that two members of the {delta}-catenin protein family, p120 and plakophilin 4 (pkp4), which interact with the juxtamembrane intracellular region of classic cadherins, promote distinct types of cadherin clustering thereby contributing to AJ specialization. The type controlled by p120 is driven by interactions between cadherin-associated protein, -catenin, and actin filaments. This "canonical" clustering mechanism results in formation of AJs that play a major role in overall cell-cell adhesion. The type promoted by pkp4 is driven by an -catenin-independent cadherin-F-actin interaction. It generates the so-called lateral spot AJs, which apparently function in processes other than cell-cell adhesion. Collectively, our study shows how {delta}-catenins regulate a balance between different types of AJs in epithelial cells.

cell biology↗

bioRxiv2024

Characterization of early and late events of adherens junction assembly

Cadherins are transmembrane adhesion receptors. Cadherin ectodomains form adhesive 2D clusters through cooperative trans and cis interactions, whereas its intracellular region interacts with specific cytosolic proteins, termed catenins, to anchor the cadherin-catenin complex (CCC) to the actin cytoskeleton. How these two types of interactions are coordinated in the formation of specialized cell-cell adhesions, adherens junctions (AJ), remains unclear. We focus here on the role of the actin-binding domain of -catenin (ABD) by showing that the interaction of ABD with actin generates actin-bound CCC oligomers (CCC/actin strands) incorporating up to six CCCs. The strands are primarily formed on the actin-rich cell protrusions. Once in cell-cell interface, the strands become involved in cadherin ectodomain clustering. Such combination of the extracellular and intracellular oligomerizations gives rise to the composite oligomers, trans CCC/actin clusters. To mature, these clusters then rearrange their actin filaments using several redundant pathways, two of which are characterized here: one depends on the -catenin-associated protein, vinculin and the second one depends on the unstructured C-terminus of ABD. Thus, AJ assembly proceeds through spontaneous formation of trans CCC/actin clusters and their successive reorganization.

cell biology↗

bioRxiv2023

MARCH family E3 ubiquitin ligases selectively target and degrade cadherin family proteins

Cadherin family proteins play a central role in epithelial and endothelial cell-cell adhesion. The dynamic regulation of cell adhesion is achieved in part through endocytic membrane trafficking pathways that modulate cadherin cell surface levels. Here, we define the role for various MARCH family ubiquitin ligases in the regulation of cadherin degradation. We find that MARCH2 selectively downregulates VE-cadherin, resulting in loss of adherens junction proteins at cell borders and a loss of endothelial barrier function. Interestingly, N-cadherin is refractory to MARCH ligase expression, demonstrating that different classical cadherin family proteins are differentially regulated by MARCH family ligases. Using chimeric cadherins, we find that the specificity of different MARCH family ligases for different cadherins is conferred by the cadherin transmembrane domain. Further, juxta-membrane lysine residues are required for cadherin degradation by MARCH proteins. These findings expand our understanding of cadherin regulation and highlight a new role for mammalian MARCH family ubiquitin ligases in differentially regulating cadherin turnover.

cell biology↗