Cell-cell adhesions are critical for the development and maintenance of tissues. Present at sites of cell-cell contact are the adherens junctions and tight junctions. The adherens junctions mediate cell-cell adhesion via the actions of nectins and cadherins. The tight junctions regulate passage of ions and small molecules between cells and establish cell polarity. Historically, the adherens and tight junctions have been thought of as discrete complexes. However, it is now clear that a high level of interdependency exists between the two junctional complexes. The adherens junctions and tight junctions are physically linked, by the zonula occludens proteins, and linked via signaling molecules including several polarity complexes and actin cytoskeletal modifiers. This review will first describe the individual components of both the adherens and tight junctions and then discuss the coupling of the two complexes with an emphasis on the signaling links and physical interactions between the two junctional complexes.

Vinculin is a cytoplasmic actin-binding protein enriched in focal adhesions and adherens junctions that is essential for embryonic development. Much is now known regarding the role of vinculin in governing cell–matrix adhesion. In the past decade that the crystal structure of vinculin and the molecular details for how vinculin regulates adhesion events have emerged. The recent data suggests a critical function for vinculin in regulating integrin clustering, force generation, and strength of adhesion. In addition to an important role in cell– matrix adhesion, vinculin is also emerging as a regulator of apoptosis, Shigella entry into host cells, and cadherin-based cell–cell adhesion. A close inspection of this work reveals that there are similarities between vinculin’s role in focal adhesions and these processes and also some intriguing differences.

Endoplasmic reticulum (ER) stress is a major contributor to liver disease and hepatic fibrosis, but the role it plays varies depending on the cause and progression of the disease. Furthermore, ER stress plays a distinct role in hepatocytes versus hepatic stellate cells (HSCs), which adds to the complexity of understanding ER stress and its downstream signaling through the unfolded protein response (UPR) in liver disease. Here, the authors focus on the current literature of ER stress in nonalcoholic and alcoholic fatty liver diseases, how ER stress impacts hepatocyte injury, and the role of ER stress in HSC activation and hepatic fibrosis. This review provides insight into the complex signaling and regulation of the UPR, parallels and distinctions between different liver diseases, and how ER stress may be targeted as an antisteatotic or antifibrotic therapy to limit the progression of liver disease.

Tissue fibrosis is characterized by uncontrolled deposition and diminished clearance of fibrous connective tissue proteins, ultimately leading to organ scarring. Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) have recently emerged as pivotal drivers of mesenchymal cell activation in human fibrosis. Therapeutic strategies inhibiting YAP and TAZ have been hindered by the critical role that these proteins play in regeneration and homeostasis in different cell types. Here, we find that the Gαs-coupled dopamine receptor D1 (DRD1) is preferentially expressed in lung and liver mesenchymal cells relative to other resident cells of these organs. Agonism of DRD1 selectively inhibits YAP/TAZ function in mesenchymal cells and shifts their phenotype from profibrotic to fibrosis resolving, reversing in vitro extracellular matrix stiffening and in vivo tissue fibrosis in mouse models. Aromatic l-amino acid decarboxylase [DOPA decarboxylase (DDC)], the enzyme responsible for the final step in biosynthesis of dopamine, is decreased in the lungs of subjects with idiopathic pulmonary fibrosis, and its expression inversely correlates with disease severity, consistent with an endogenous protective role for dopamine signaling that is lost in pulmonary fibrosis. Together, these findings establish a pharmacologically tractable and cell-selective approach to targeting YAP/TAZ via DRD1 that reverses fibrosis in mice.