Tankyrases: structure, function and therapeutic implications in cancer.

Abstract

Several cellular signaling pathways are regulated by ADP-ribosylation, a posttranslational modification catalyzed by members of the ARTD superfamily. Tankyrases are distinguishable from the rest of this family by their unique domain organization, notably the sterile alpha motif responsible for oligomerization and ankyrin repeats mediating protein-protein interactions. Tankyrases are involved in various cellular functions, such as telomere homeostasis, Wnt/β-catenin signaling, glucose metabolism, and cell cycle progression. In these processes, Tankyrases regulate the interactions and stability of target proteins by poly (ADP-ribosyl)ation. Modified proteins are subsequently recognized by the E3 ubiquitin ligase RNF146, poly-ubiquitinated and predominantly guided to 26S proteasomal degradation. Several small molecule inhibitors have been described for Tankyrases; they compete with the co-substrate NAD(+) for binding to the ARTD catalytic domain. The recent, highly potent and selective inhibitors possess several properties of lead compounds and can be used for proof-of-concept studies in cancer and other Tankyrase linked diseases.