Abstract
Desmosomes have a central role in mediating extracellular adhesion between cells, but they also coordinate other biological processes such as proliferation, differentiation, apoptosis and migration. In particular, several lines of evidence have implicated desmosomal proteins in regulating the actin cytoskeleton and attachment to the extracellular matrix, indicating signaling crosstalk between cell–cell junctions and cell–matrix adhesions. In our study, we found that cells lacking the desmosomal cadherin Desmoglein-2 (Dsg2) displayed a significant increase in spreading area on both fibronectin and collagen, compared to control A431 cells. Intriguingly, this effect was observed in single spreading cells, indicating that Dsg2 can exert its effects on cell spreading independent of cell–cell adhesion. We hypothesized that Dsg2 may mediate cell–matrix adhesion via control of Rap1 GTPase, which is well known as a central regulator of cell spreading dynamics. We show that Rap1 activity is elevated in Dsg2 knockout cells, and that Dsg2 harnesses Rap1 and downstream TGFβ signaling to influence both cell spreading and focal adhesion protein phosphorylation. Further analysis implicated the Rap GEF PDZ-GEF2 in mediating Dsg2-dependent cell spreading. These data have identified a novel role for Dsg2 in controlling cell spreading, providing insight into the mechanisms via which cadherins exert non-canonical junction-independent effects.
Highlights
Desmosomes have a central role in mediating extracellular adhesion between cells, but they coordinate other biological processes such as proliferation, differentiation, apoptosis and migration
As desmosomal cadherins are central players in mediating cell–cell attachment, we investigated whether loss of Desmoglein-2 (Dsg2) in A431 epidermal cells would have an effect on the attachment and spreading of single cells on extracellular matrix (ECM)
Like other members of the desmosome, desmosomal cadherins have been shown to control actin cytoskeletal rearrangements[21], which are necessary for the dynamic cell shape changes involved in processes such as cell–matrix adhesion, spreading and migration[22]
Summary
Desmosomes have a central role in mediating extracellular adhesion between cells, but they coordinate other biological processes such as proliferation, differentiation, apoptosis and migration. Myocardium and epidermis that are exposed to significant and frequent levels of mechanical stress[7] Considering this critical role for desmosomes in mediating tissue integrity, it is not surprising that mutations in desmosomal cadherins (and other desmosome components) have been linked to a variety of different epidermal disorders (related to skin fragility/blistering, loss of hair, etc.) and arrhythmogenic cardiomyopathy, which is characterized by loss of cell–cell adhesion and gap junction defects in c ardiomyocytes[8,9]. We observed a significant increase in spreading area for individual Dsg[2] knockout cells (Dsg2KO) compared to control A431 cells (A431CT), suggesting that even when Dsg[2] is not part of a stable cell–cell junction (i.e., in single spreading cells), it can still exerts signaling effects involved in crosstalk with cell–matrix adhesions. Differences in focal adhesion protein phosphorylation were lost in confluent monolayers of A431CT and Dsg2KO cells, indicating that the prominent effects of Dsg[2] on cell spreading may be masked by other junctional proteins when widespread and uniform cell–cell adhesion is present
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