Tankyrase 1 and 2 (TNKS1/2)

Tankyrase 1 (TNKS1) and Tankyrase 2 (TNKS2) are closely related enzymes belonging to the poly(ADP-ribose) polymerase (PARP) family that play a pivotal role in regulating cellular homeostasis through poly(ADP-ribosyl)ation (PARylation) [1, 5]. They function as positive regulators of the Wnt/beta-catenin signaling pathway by PARylating AXIN, a key component of the beta-catenin destruction complex, which triggers its ubiquitination by RNF146 and subsequent proteasomal degradation [2, 12]. Beyond Wnt signaling, tankyrases are essential for telomere length maintenance by regulating the DNA-binding activity of TRF1 and are involved in mitotic spindle assembly and GLUT4 vesicle trafficking [3, 11]. Due to their ability to modulate hyperactive Wnt signaling, TNKS1/2 are attractive therapeutic targets for various cancers, particularly colorectal cancer [8, 10]. However, the clinical development of tankyrase inhibitors has been complicated by dose-limiting gastrointestinal toxicities and the observation that they often require combination with other targeted therapies, such as MEK or CDK4/6 inhibitors, to achieve robust antitumor effects [7, 8].

Other names

TNKSTNKS1TNKS2PARP5APARP5BARTD5ARTD6Poly [ADP-ribose] polymerase 5APoly [ADP-ribose] polymerase 5BTRF1-interacting ankyrin-related ADP-ribose polymerase

Inhibition of poly-ADP-ribosyltransferase activity, leading to the stabilization of AXIN1/2 proteins, which enhances the degradation of beta-catenin and suppresses oncogenic Wnt signaling [1, 5, 8].