Protein Arginine Methyltransferase 5 May Interact with KRAS through PPP2CA

Abstract

Despite decades of research and its status as one of the most mutated oncoproteins in colorectal cancer (CRC), targeted therapies are yet to have been developed for the KRAS protein. To this extent, a previous study by our group found that, in CRC, KRAS may interact with another oncoprotein, called Protein Arginine Methyltransferase 5 (PRMT5). PRMT5 is an epigenetic regulator in multiple cellular processes and is overexpressed in 75% of CRC patient tumor samples while being negatively correlated with CRC patient survival. Therefore, our previous findings suggest that it might be possible to target the prominent oncoprotein KRAS through its potential interactions with the oncoprotein PRMT5. Here, we look more closely at the KRAS-PRMT5 interaction and suggest that PRMT5 may interact with KRAS through PPP2CA. We first show that PRMT5 may interact with KRAS through PPP2CA using the STRING database. We next show that PPP2CA is over expressed in CRC patient datasets. We then show that PPP2CA expression is strongly correlated with PRMT5 and KRAS expression in CRC patient datasets. We next model these protein-protein interactions and show that PPP2CA expression is correlated with patient survival in CRC patient datasets. Finally, we propose a mechanism through which PRMT5 may interact with KRAS by inhibiting PPP2CA.