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Plakophilin 4 (PKP4, also called p0071) is a unique armadillo family protein localized at adherens junctions that acts as a scaffold protein capable of clustering cadherins. PKP4 also regulates cadherin recycling which is vital to enable junction dynamics. In addition, PKP4 controls the mechanical properties of cells by regulating actin filament organization through small Rho-GTPases. In this setting, PKP4 controls the localization and activity of specific guanine exchange factors (GEFs) and of their opponents, the GTPase activating proteins (GAPs). Through the formation of multiprotein complexes with Rho-GTPases, their regulators and their effectors, PKP4 controls the spatio-temporal activity of Rho signaling to regulate cell adhesion and cell mechanics. In keratinocytes, PKP4 prevents differentiation and at the same time dampens proliferation. This is, in part achieved through an interaction with the Hippo pathway, which controls the activity of the transcriptional co-factors YAP and TAZ. In a feedback loop, YAP/TAZ modulate PKP4 localization and function. Here, we review the various functions of PKP4 in cell signaling, cell mechanics, cell adhesion and growth control. We discuss how these functions converge in the regulation of cell adhesion dynamics to allow cells to adapt to their changing environment and enable proliferation, delamination but, at the same time, guarantee cell barrier function.

Desmosomes are intercellular junctions, which preserve tissue integrity during homeostatic and stress conditions. These functions rely on their unique structural properties, which enable them to respond to context-dependent signals and transmit them to change cell behavior. Desmosome composition and size vary depending on tissue specific expression and differentiation state. Their constituent proteins are highly regulated by posttranslational modifications that control their function in the desmosome itself and in addition regulate a multitude of desmosome-independent functions. This review will summarize our current knowledge how signaling pathways that control epithelial shape, polarity and function regulate desmosomes and how desmosomal proteins transduce these signals to modulate cell behavior.

Background Cancer metastases are the main cause of lethality. The five-year survival rate for patients diagnosed with advanced stage oral cancer is 30%. Hence, the identification of novel therapeutic targets is an urgent need. However, tumors are comprised of a heterogeneous collection of cells with distinct genetic and molecular profiles that can differentially promote metastasis making therapy development a challenging task. Here, we leveraged intratumoral heterogeneity in order to identify drivers of cancer cell motility that might be druggable targets for anti-metastasis therapy. Methods We used 2D migration and 3D matrigel-based invasion assays to characterize the invasive heterogeneity among and within four human oral cancer cell lines in vitro. Subsequently, we applied mRNA-sequencing to map the transcriptomes of poorly and strongly invasive subclones as well as primary tumors and matched metastasis. Results We identified SAS cells as a highly invasive oral cancer cell line. Clonal analysis of SAS yielded a panel of 20 subclones with different invasive capacities. Integrative gene expression analysis identified the Lymphocyte cell-specific protein-tyrosine kinase (LCK) as a druggable target gene associated with cancer cell invasion and metastasis. Inhibition of LCK using A-770041 or dasatinib blocked invasion of highly aggressive SAS cells. Interestingly, reduction of LCK activity increased the formation of adherens junctions and induced cell differentiation. Conclusion Analysis of invasive heterogeneity led to the discovery of LCK as an important regulator of motility in oral cancer cells. Hence, small molecule mediated inhibition of LCK could be a promising anti-metastasis therapy option for oral cancer patients.

The mature mammalian myocardium contains composite junctions ( areae compositae ) that comprise proteins of adherens junctions as well as desmosomes. Mutations or deficiency of many of these proteins are linked to heart failure and/or arrhythmogenic cardiomyopathy in patients. We firstly wanted to address the question whether the expression of these proteins shows an age-dependent alteration in the atrium of the human heart. Right atrial biopsies, obtained from patients undergoing routine bypass surgery for coronary heart disease were subjected to immunohistology and/or western blotting for the plaque proteins plakoglobin (γ-catenin) and plakophilin 2. Moreover, the Z-band protein cypher 1 (Cypher/ZASP) and calcium handling proteins of the sarcoplasmic reticulum (SR) like phospholamban, SERCA and calsequestrin were analyzed. We noted expression of plakoglobin, plakophilin 2 and Cypher/ZASP in these atrial preparations on western blotting and/or immunohistochemistry. There was an increase of Cypher/ZASP expression with age. The present data extend our knowledge on the expression of anchoring proteins and SR regulatory proteins in the atrium of the human heart and indicate an age-dependent variation in protein expression. It is tempting to speculate that increased expression of Cypher/ZASP may contribute to mechanical changes in the aging human myocardium.

Plakophilin 4 (PKP4) is a component of cell–cell junctions that regulates intercellular adhesion and Rho-signaling during cytokinesis with an unknown function during epidermal differentiation. Here we show that keratinocytes lacking PKP4 fail to develop a cortical actin ring, preventing adherens junction maturation and generation of tissue tension. Instead, PKP4-depleted cells display increased stress fibers. PKP4-dependent RhoA localization at AJs was required to activate a RhoA-ROCK2-MLCK-MLC2 axis and organize actin into a cortical ring. AJ-associated PKP4 provided a scaffold for the Rho activator ARHGEF2 and the RhoA effectors MLCK and MLC2, facilitating the spatio-temporal activation of RhoA signaling at cell junctions to allow cortical ring formation and actomyosin contraction. In contrast, association of PKP4 with the Rho suppressor ARHGAP23 reduced ARHGAP23 binding to RhoA which prevented RhoA activation in the cytoplasm and stress fiber formation. These data identify PKP4 as an AJ component that transduces mechanical signals into cytoskeletal organization.

p120 is the prototypic member of the p120 subfamily of armadillo-related proteins that includes p0071, δ -catenin/NPRAP, ARVCF and the more distantly related plakophilins 1–3. Like armadillo, β -catenin and plakoglobin these proteins are involved in mediating cell–cell adhesion. Besides their junctional localization they also reveal a cytoplasmic and nuclear localization. Non-cadherin-associated, cytoplasmic p120 functions in Rho signaling and regulation of cytoskeletal organization and actin dynamics. The nuclear function remains largely unsolved. Some characteristics seem to be shared by the various members of the family but it seems unlikely that p120-related proteins have solely redundant functions and compete for interactions with identical binding partners. Stabilization of cadherins at the membrane seems a common function of p120, p0071, δ -catenin and ARVCF but it is not yet known if and how these proteins confer distinct properties to cellular junctions. Moreover, p0071, NPRAP and ARVCF have a C-terminal PDZ-binding motif that is lacking in p120 pointing to distinct roles of these proteins. PDZ domains are found in a series of proteins involved in establishing cell polarity in epithelial cells. Thus, p120 proteins may not only be master regulators of cadherin abundance and activity but play additional roles in regulating cell polarity. This review focuses on the putative roles of p120 proteins in cell polarity.

Plakophilins are proteins of the desmosomal plaque. Based on the observation that plakophilins localize not only to desmosomes but also to the cytoplasm and nucleus, additional functions in cell signaling have been proposed. In this issue, Sobolik-Delmaire et al. address the nuclear function of Plakophilin-1. The authors show that Plakophilin-1 interacts with ssDNA in vitro and may have a function in protecting cells from DNA damage.

Cell cycle progression is tightly regulated by cyclin-dependent kinases (CDKs). The ankyrin-repeat protein p19INK4d functions as a key regulator of G1/S transition; however, its molecular mode of action is unknown. Here, we combine cell and structural biology methods to unravel the mechanism by which p19INK4d controls cell cycle progression. We delineate how the stepwise phosphorylation of p19INK4d Ser66 and Ser76 by cell cycle-independent (p38) and -dependent protein kinases (CDK1), respectively, leads to local unfolding of the three N-terminal ankyrin repeats of p19INK4d. This dissociates the CDK6–p19INK4d inhibitory complex and, thereby, activates CDK6. CDK6 triggers entry into S-phase, whereas p19INK4d is ubiquitinated and degraded. Our findings reveal how signaling-dependent p19INK4d unfolding contributes to the irreversibility of G1/S transition.