Novel function of GCN2 in directional migration

Abstract

GCN2 is a protein kinase, which is implicated in several diseases, including cancer. The only well-characterized role of GCN2 is a translational reprogramming of cells when challenged by several types of stress. Since cancer cells are often in a hostile microenvironment, this alone has put GCN2 in the limelight as a potential therapeutic target. In order to understand the roles GCN2 plays in cancer development, our group analysed patient-derived transcriptome data and identified correlations between GCN2 and genes associated with potential novel functions. These studies identified cell migration as a correlating pathway. In the current study, we were able to demonstrate through in-vitro transwell migration assay and live-cell imaging that GCN2 has a function in directional migration. An effective rescue of the migration defect in a cell-line carrying siRNA-resistant GCN2 further supported this finding. We also investigated the requirement of known molecular functions of GCN2 in directional migration, which revealed that these molecular functions are required for the function in directional migration. Preliminary observations also suggest that protein levels of several actin-binding proteins are altered in cells expressing different levels of GCN2. These observations strongly highlight the relevance of GCN2 in directional migration. The ability of cells to sense and directionally migrate towards various chemical cues has been implicated in various steps of cancer metastasis. The novel finding that GCN2 is important in directional migration highlights the importance of GCN2 in cancer in a different perspective. This knowledge can be exploited in targeting GCN2 in cancer, which is already thought to be valuable strategy owing to its involvement in the stress responses.