Tankyrase Explained

Tankyrase, also known as tankyrase 1, is an enzyme that in humans is encoded by the TNKS gene.^{[1] [2] [3]} It inhibits the binding of TERF1 to telomeric DNA.^[4] Tankyrase attracts substantial interest in cancer research through its interaction with AXIN1 and AXIN2, which are negative regulators of pro-oncogenic β-catenin signaling. Importantly, activity in the β-catenin destruction complex can be increased by tankyrase inhibitors and thus such inhibitors are a potential therapeutic option to reduce the growth of β-catenin-dependent cancers.^[5]

Description^[6]

Tankyrase-1 is a poly-ADP-ribosyltransferase involved in various processes such as Wnt signaling pathway, telomere length and vesicle trafficking. Acts as an activator of the Wnt signaling pathway by mediating poly-ADP-ribosylation (PARylation) of AXIN1 and AXIN2, 2 key components of the beta-catenin destruction complex: poly-ADP-ribosylated target proteins are recognized by RNF146, which mediates their ubiquitination and subsequent degradation. Also mediates PARsylation of BLZF1 and CASC3, followed by recruitment of RNF146 and subsequent ubiquitination. Mediates PARsylation of TERF1, thereby contributing to the regulation of telomere length. Involved in centrosome maturation during prometaphase by mediating PARsylation of HEPACAM2/MIKI. May also regulate vesicle trafficking and modulate the subcellular distribution of SLC2A4/GLUT4-vesicles. May be involved in spindle pole assembly through PARsylation of NUMA1. Stimulates 26S proteasome activity.^[7]

Protein interactions

TNKS has been shown to interact with:

• FNBP1,^[8]
• MCL1,^[9]
• TERF1,^{[10] [11]} and
• TNKS1BP1.^{[12] [13]}

Further reading

• Andersson B, Wentland MA, Ricafrente JY, Liu W, Gibbs RA . A "double adaptor" method for improved shotgun library construction . Anal. Biochem. . 236 . 1 . 107–13 . 1996 . 8619474 . 10.1006/abio.1996.0138 .
• Yu W, Andersson B, Worley KC, Muzny DM, Ding Y, Liu W, Ricafrente JY, Wentland MA, Lennon G, Gibbs RA . Large-scale concatenation cDNA sequencing . Genome Res. . 7 . 4 . 353–8 . 1997 . 9110174 . 139146 . 10.1101/gr.7.4.353 .
• Smith S, de Lange T . Cell cycle dependent localization of the telomeric PARP, tankyrase, to nuclear pore complexes and centrosomes . J. Cell Sci. . 112 . 21 . 3649–56 . 1999 . 10.1242/jcs.112.21.3649 . 10523501 .
• Chi NW, Lodish HF . Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles . J. Biol. Chem. . 275 . 49 . 38437–44 . 2001 . 10988299 . 10.1074/jbc.M007635200 . free .
• Lyons RJ, Deane R, Lynch DK, Ye ZS, Sanderson GM, Eyre HJ, Sutherland GR, Daly RJ . Grant Robert Sutherland . Identification of a novel human tankyrase through its interaction with the adaptor protein Grb14 . J. Biol. Chem. . 276 . 20 . 17172–80 . 2001 . 11278563 . 10.1074/jbc.M009756200 . free .
• Kim BY, Krämer H, Yamamoto A, Kominami E, Kohsaka S, Akazawa C . Molecular characterization of mammalian homologues of class C Vps proteins that interact with syntaxin-7 . J. Biol. Chem. . 276 . 31 . 29393–402 . 2001 . 11382755 . 10.1074/jbc.M101778200 . free .
• Cook BD, Dynek JN, Chang W, Shostak G, Smith S . Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres . Mol. Cell. Biol. . 22 . 1 . 332–42 . 2002 . 11739745 . 134233 . 10.1128/MCB.22.1.332-342.2002 .
• Sbodio JI, Lodish HF, Chi NW . Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase) . Biochem. J. . 361 . Pt 3 . 451–9 . 2002 . 11802774 . 1222327 . 10.1042/0264-6021:3610451 .
• Seimiya H, Smith S . The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182) . J. Biol. Chem. . 277 . 16 . 14116–26 . 2002 . 11854288 . 10.1074/jbc.M112266200 . free .
• Sbodio JI, Chi NW . Identification of a tankyrase-binding motif shared by IRAP, TAB182, and human TRF1 but not mouse TRF1. NuMA contains this RXXPDG motif and is a novel tankyrase partner . J. Biol. Chem. . 277 . 35 . 31887–92 . 2002 . 12080061 . 10.1074/jbc.M203916200 . free .
• Rippmann JF, Damm K, Schnapp A . Functional characterization of the poly(ADP-ribose) polymerase activity of tankyrase 1, a potential regulator of telomere length . J. Mol. Biol. . 323 . 2 . 217–24 . 2002 . 12381316 . 10.1016/S0022-2836(02)00946-4 .
• Bae J, Donigian JR, Hsueh AJ . Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis . J. Biol. Chem. . 278 . 7 . 5195–204 . 2003 . 12475993 . 10.1074/jbc.M201988200 . free .
• Loayza D, De Lange T . POT1 as a terminal transducer of TRF1 telomere length control . Nature . 423 . 6943 . 1013–8 . 2003 . 12768206 . 10.1038/nature01688 . 2003Natur.423.1013L . 4370276 .
• Fuchs U, Rehkamp GF, Slany R, Follo M, Borkhardt A . The formin-binding protein 17, FBP17, binds via a TNKS binding motif to tankyrase, a protein involved in telomere maintenance . FEBS Lett. . 554 . 1–2 . 10–6 . 2003 . 14596906 . 10.1016/S0014-5793(03)01063-9 . 19552309 .
• Seimiya H, Muramatsu Y, Smith S, Tsuruo T . Functional subdomain in the ankyrin domain of tankyrase 1 required for poly(ADP-ribosyl)ation of TRF1 and telomere elongation . Mol. Cell. Biol. . 24 . 5 . 1944–55 . 2004 . 14966275 . 350561 . 10.1128/MCB.24.5.1944-1955.2004 .
• Dynek JN, Smith S . Resolution of sister telomere association is required for progression through mitosis . Science . 304 . 5667 . 97–100 . 2004 . 15064417 . 10.1126/science.1094754 . 2004Sci...304...97D . 38793700 .
• Ye JZ, de Lange T . TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex . Nat. Genet. . 36 . 6 . 618–23 . 2004 . 15133513 . 10.1038/ng1360 . free .

Notes and References

1. Smith S, Giriat I, Schmitt A, de Lange T . Tankyrase, a poly(ADP-ribose) polymerase at human telomeres . Science . 282 . 5393 . 1484–7 . Dec 1998 . 9822378 . 10.1126/science.282.5393.1484 . 10.1.1.466.9024 .
2. Zhu L, Smith S, de Lange T, Seldin MF . Chromosomal mapping of the tankyrase gene in human and mouse . Genomics . 57 . 2 . 320–1 . May 1999 . 10198177 . 10.1006/geno.1999.5771 .
3. Web site: Entrez Gene: TNKS tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase.
4. Cook . B. D. . Dynek . J. N. . Chang . W. . Shostak . G. . Smith . S. . Role for the Related Poly(ADP-Ribose) Polymerases Tankyrase 1 and 2 at Human Telomeres . Molecular and Cellular Biology . 1 January 2002 . 22 . 1 . 332–342 . 10.1128/MCB.22.1.332-342.2002. 11739745 . 134233 . free .
5. Wang W, Liu P, Lavrijsen M, Li S, Zhang R, Li S, van de Geer WS, van de Werken HJ, Peppelenbosch MP, Smits R. Evaluation of AXIN1 and AXIN2 as targets of tankyrase inhibition in hepatocellular carcinoma cell lines . Scientific Reports . 11 . 7470 . April 2021 . 1 . 33811251 . 8018973 . 10.1038/s41598-021-87091-4 . 2021NatSR..11.7470W .
6. Web site: TNKS - Poly [ADP-ribose] polymerase tankyrase-1 - Homo sapiens (Human) - TNKS gene & protein.
7. 10872471 . 10.1146/annurev.biochem.68.1.1015 . 68 . The 26S proteasome: a molecular machine designed for controlled proteolysis . 1999 . Annu. Rev. Biochem. . 1015–68 . Voges D, Zwickl P, Baumeister W.
8. Fuchs U, Rehkamp GF, Slany R, Follo M, Borkhardt A . The formin-binding protein 17, FBP17, binds via a TNKS binding motif to tankyrase, a protein involved in telomere maintenance . FEBS Lett. . 554 . 1–2 . 10–6 . Nov 2003 . 14596906 . 10.1016/s0014-5793(03)01063-9. 19552309 .
9. Bae J, Donigian JR, Hsueh AJ . Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis . J. Biol. Chem. . 278 . 7 . 5195–204 . Feb 2003 . 12475993 . 10.1074/jbc.M201988200 . free .
10. Cook BD, Dynek JN, Chang W, Shostak G, Smith S . Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres . Mol. Cell. Biol. . 22 . 1 . 332–42 . Jan 2002 . 11739745 . 134233 . 10.1128/mcb.22.1.332-342.2002.
11. Sbodio JI, Lodish HF, Chi NW . Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase) . Biochem. J. . 361 . Pt 3 . 451–9 . Feb 2002 . 11802774 . 1222327 . 10.1042/0264-6021:3610451.
12. Seimiya H, Smith S . The telomeric poly(ADP-ribose) polymerase, tankyrase 1, contains multiple binding sites for telomeric repeat binding factor 1 (TRF1) and a novel acceptor, 182-kDa tankyrase-binding protein (TAB182) . J. Biol. Chem. . 277 . 16 . 14116–26 . Apr 2002 . 11854288 . 10.1074/jbc.M112266200 . free .
13. Sbodio JI, Chi NW . Identification of a tankyrase-binding motif shared by IRAP, TAB182, and human TRF1 but not mouse TRF1. NuMA contains this RXXPDG motif and is a novel tankyrase partner . J. Biol. Chem. . 277 . 35 . 31887–92 . Aug 2002 . 12080061 . 10.1074/jbc.M203916200 . free .