Perspective SHEDding light on the role of Pragmin pseudo-kinases in cancer

The human kinome comprises more than 50 pseudo-kinases with unclear biological function due to the absence of apparent catalytic activity, and therefore, with presumably little interest for cancer drug discovery. However, it is now acknowledged that several of them, such as Pragmin family members, play roles as important as those of active kinases in human cancer. How these pseudo-kinases promote tumor formation is largely unknown. Recently, independent structural analyses of three Pragmin pseudo-kinases (Pragmin, SGK223, and SGK269/ PEAK1) revealed a split helical dimerization (SHED)-based mechanism of action. Additional sequence-structure analysis identified C19orf35 as a new member of the Pragmin family. Based on the results of these molecular studies, we present a unified model on how Pragmin pseudo-kinases may regulate oncogenic signaling, and suggest potential therapeutic strategies to block their tumor activity.