Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities

Abstract

Tankyrase 1 (TNKS1) and tankyrase 2 (TNKS2) are two homologous proteins that are gaining increasing importance due to their implication in multiple pathways and diseases such as cancer. TNKS1/2 interact with a large variety of substrates through the ankyrin (ANK) domain, which recognizes a sequence present in all the substrates of tankyrase, called Tankyrase Binding Motif (TBM). One of the main functions of tankyrases is the regulation of protein stability through the process of PARylation-dependent ubiquitination (PARdU). Nonetheless, there are other functions less studied that are also essential in order to understand the role of tankyrases in many pathways. In this review, we concentrate in different tankyrase substrates and we analyze in depth the biological consequences derived of their interaction with TNKS1/2. We also examine the concept of both canonical and non-canonical TBMs and finally, we focus on the information about the role of TNKS1/2 in different tumor context, along with the benefits and limitations of the current TNKS inhibitors targeting the catalytic PARP domain and the novel strategies to develop inhibitors against the ankyrin domain. Available data indicates the need for further deepening in the knowledge of tankyrases to elucidate and improve the current view of the role of these PARP family members and get inhibitors with a better therapeutic and safety profile.

Adp-Ribosylation as Post-Translational Modification of Proteins: Use of Inhibitors in Cancer Control

“…RNF146/Iduna ubiquitin ligase associates with tankyrase, involved in PARylation-dependent ubiquitylation (PARdU) reactions: tankyrases PARylate their substrate proteins and then RNF146 recognizes PAR portion of PARylated proteins by its WWE domain and is allosterically activated to ubiquitylate them for proteasomal degradation [27][28][29][30]. Several tankyrase binding motifs (TBM) act in concert to allow interaction between RNF146 and the ankyrin repeat clusters (ARC) of tankyrases [31]. Oligonucleotide/oligosaccharide-binding (OB) fold is present in single strand-DNA binding protein 1 (hSSB1), which relocates to sites of DNA damage by recognition of PAR polymers, promoting the DDR [32].…”

“…High levels of TNKS1 and/or TNKS2 expression have been observed mainly in colon, lung, brain, breast, ovarian and liver cancers [31]. Several mutations may occur altering PARylation activity, depending on large deletions or to point mutations.…”

“…Several mutations may occur altering PARylation activity, depending on large deletions or to point mutations. The stability of many proteins is regulated via PARdU: Axin1/2, PTEN, 3BP2, TRF1, are processed and degraded by PARdU, as well as the actors of this activity, TNKS1/2 and RNF146 [31]. Tankyrases modify the tumor suppressors phosphatase and tensin homolog (PTEN), and axin 1/2, which regulate the levels of phosphatidylinositol 3,4,5 triphosphate and βcatenin, negatively regulating Akt/PI3K pathway (PTEN) and Wnt signaling (axin).…”

“…Wnt-driven cancers such as CRC, HCC and lung cancers may benefit from Tankyrase inhibitors [31,95,96]. In lung cancer, most often showing TNKS overexpression, tumors possess abnormal Wnt activity, due to APC and β-catenin mutations, as well as to deregulation of upstream Wnt signaling effectors, such as Dishevelled 3 (Dvl-3), or downregulation of Wnt antagonists as Wnt-inhibitory factor 1 (WIF 1).…”

“…Tankyrases PARylate AXIN, and recruit the E3 ubiquitin ligase RNF146 containing the PAR-binding WWE domain, which ubiquitylates AXIN, destining it for proteasomal degradation. In this optic, tankyrase promotes Wnt signaling, while TNKS inhibitors are useful in treatment of Wnt-driven cancers [31,98]. G007-LK is a selective tankyrases inhibitor [99]: the treatment with this inhibitor induced loss of expression of MYC and impaired cell growth, with accumulation of βcatenin degradasomes.…”