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

Abstract

The desmosome (DSM) is a cell‐cell adhesion complex required for the mechanical stability of tissues and regulation of other biological processes, such as proliferation and migration. Proteins from three families make up the complex: Transmembrane cadherins connect adjacent cells, plaque proteins stabilize attachment on the intracellular face, and the plakin protein desmoplakin (DSP) anchors the DSM complex to the intermediate filament cytoskeleton. Many studies have reported diverse mechanisms by which cancer progression alters DSM gene expression, but the signaling pathways that govern the expression and localization of DSM constituent proteins remain elusive. Recent work has identified the transcription factor serum response factor (SRF) as a regulator of mRNA levels and localization of DSM proteins such as the cadherin Desmoglein‐1. Here, we treated several cancer cell lines with siRNA and a pharmacological inhibitor (CCG‐1423) of SRF and its cofactor, MAL, to broadly investigate the role of these transcription factors in regulating DSM gene expression and protein localization. Our results demonstrate that abrogation of MAL/SRF signaling through both siRNA and pharmacological inhibition results in a decrease in mRNA levels of DSP. In addition, localization of DSP to borders is also reduced upon inhibition of MAL/SRF signaling. We observed similar changes for the plaque proteins Plakophilin‐2 and Plakoglobin, but not for desmosomal cadherins. As DSP is required to maintain the strength of DSM attachments, we also investigated the role of MAL/SRF signaling on the adhesion strength between cells. Our data highlight a novel link between MAL/SRF signaling and DSP expression, and contribute to a growing understanding of the variety of signaling pathways involved in mediating DSM gene expression.Support or Funding InformationThis project was funded by an NIH South Carolina IDeA Networks of Biomedical Research Excellence (SC INBRE) grant #5P20GM103499‐17 which provided a Developmental Research Project (DRP) sub‐award #22050‐ZA14 to AD.This abstract is from the Experimental Biology 2019 Meeting. There is no full text article associated with this abstract published in The FASEB Journal.