Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities Zamudio Martínez, Esteban Herrera-Campos, Ana Belén Muñoz, Alberto Rodríguez Vargas, José Manuel Oliver, Francisco Javier TNKS1/2 Tankyrase binding motif Proteosomal Degradation The work in the authors’ laboratory is funded by the Agencia Estatal de Investigación SAF2012–40011-C02–01, SAF2015–70520-R, RTI2018–098968-BI00, RTICC RD12/0036/0026 and PID2019-104867RB-I00/AEI/https://doi.org/10. 13039/501100011033), and Instituto de Salud Carlos III—Fondo Europeo de Desarrollo Regional (CIBERONC ISCIII CB16/12/00421 and CB16/12/00273); by Junta de Andalucía, project of Excellence from Junta de Andalucía P10-CTS- 0662, P12-CTS-383 to FJO, CIBER Cáncer to FJO. Fundación Domingo Martínez (call 2019). JMRV is funded through a contract Juan de la Cierva (Reincorporación) from Ministerio de Ciencia e Innovación. 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. 2026-02-12T08:48:52Z 2026-02-12T08:48:52Z 2021-04-28 journal article Zamudio-Martinez E, Herrera-Campos AB, Muñoz A, Rodríguez-Vargas JM, Oliver FJ. (2021). Tankyrases as modulators of pro-tumoral functions: molecular insights and therapeutic opportunities. J Exp Clin Cancer Res. 2021 Apr 28; 40 (1): 144. doi: 10.1186/s13046-021-01950-6 1756-9966 https://hdl.handle.net/10481/110908 10.1186/s13046-021-01950-6 eng http://creativecommons.org/licenses/by-nc-nd/4.0/ open access Attribution-NonCommercial-NoDerivatives 4.0 Internacional Springer Nature