The MAL/SRF Pathway Regulates Desmosome Protein Expression and Localization in Cancer Cells.

PAC Gym

The desmosome (DSM) is a cell-cell adhesion complex whose localization to the plasma membrane facilitates the mechanical stability of tissues and cell-cell communication, as well as behaviors such as migration and proliferation. DSM function depends upon a tripartite organizational structure wherein transmembrane cadherins link adjacent cells, plaque proteins stabilize arrays of DSMs on the intracellular face, and desmoplakin (DP) anchors DSMs to the intermediate filament cytoskeleton. DSMs are proteins of interest in cancer progression, a process which hinges upon the mis-regulation of many biological functions in which DSMs are involved. Diverse mechanisms for the disruption of DSM dynamics in cancer have been reported, but the specific signaling pathways regulating the expression and localization of DSM proteins remain elusive. Recent work has implicated the transcription factor serum response factor (SRF) and its coactivator, Myocardin-Related Transcription Factor A (MRTF-A), in the transcription and localization of DSM proteins. Here, we have targeted MRTF-A/SRF signaling in several cancer cells lines to investigate their role in regulating DSM gene expression and protein localization. Our results demonstrate that abrogation of MRTF-A/SRF signaling attenuates mRNA levels of several DSM genes, and impinges upon the ability of those DSMs to localize to the plasma membrane. Interestingly, this effect appears to occur independently of corresponding depletion of DSM protein levels, and does not disrupt adhesive strength among cells. Our results therefore provide critical insights into the regulation of DSMs, while at the same time underscoring its complexity and the need for continued inquiry along these lines.