Desmoplakin promotes cell migration via coordinated control of p38 MAPK and Rho GTPase signaling.

PAC Gym

Desmosomes are cell-cell adhesion complexes crucial for maintaining the integrity of tissues, especially those under high mechanical stress. One of the key components of desmosomes is desmoplakin (DSP), an obligate component of desmosomal cell-cell junctions which links the adhesion plaque to the cytoskeletal intermediate filament network. Due to the vital nature of this connection for mechanical stability of the desmosome, DSP has a been a frequent protein of interest for studying the stability of cell-cell adhesion. While a central role for DP in maintaining the structure and stability of the desmosome is well established, recent work has indicated that DP’s functions may extend beyond cell-cell adhesion.In our study, we show that loss of DP results in a significant increase in cellular migration, as measured by scratch wound assays, transwell migration assays and invasion assays. Loss of DP causes dramatic changes in actin cytoskeleton morphology, including enhanced protrusiveness and an increase in filopodia length and number. Interestingly, these changes are also observed in single cells, indicating that control of actin morphology is a cell-cell adhesion-independent function of DP. An investigation of cellular signaling pathways uncovered aberrant Rac and p38 MAPK activity in DP knockdown cells, restoration of which is sufficient to rescue DP-dependent changes in both cell migration and actin cytoskeleton morphology. Taken together, these data highlight a previously uncharacterized role for the desmosomal cytolinker DP in coordinating cellular migration via p38 MAPK and Rac signaling.