TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase)

2011-06-01 Yury Shebzukhov , Sergei Nedospasov Affiliation

German Rheumatism Research Center, a Leibniz Institute, Berlin, Germany (YS, SN); Engelhardt Institute of Molecular Biology, Russian Academy of Sciences, Moscow, Russia (SN)

Identity

HGNC

TNKS

LOCATION

8p23.1

LOCUSID

8658

ALIAS

ARTD5,PARP-5a,PARP5A,PARPL,TIN1,TINF1,TNKS1,pART5

FUSION GENES

Show Gene Fusions

DNA/RNA

Description

Spans 226410 bp, 27 exons.

Transcription

9599 bp long mRNA, containing 3984 bp long ORF.

Proteins

TNKS protein. HPS: region containing homopolymeric runs of His, Pro, and Ser; ANK: ankyrin domain; SAM: multimerization domain homologous to the sterile alpha motif; PARP: PARP catalytic domain.

Description

Isoform 1 (1327 amino acids) contains region with homopolymeric runs of His, Pro, and Ser (HPS domain, aa 1-181), 15 ankyrin repeats (ANK 1 to 15, aa 215-934), multimerization domain homologous to the sterile alpha motif (SAM domain, aa 1030-1089) and PARP catalytic domain (aa 1112-1317). Isoform 2 (643 amino acids) contains only HPS domain and 9 ANK repeats.

Expression

Ubiquitous, high expression in brain and ganglions, skin and cardiac tissue.

Localisation

Nuclear and cytoplasmic.

Function

Poly(ADP-ribosyl)ation (PARsylation) of target proteins: TNKS itself, TNKS2/TNKL, TRF1, IRAP, TAB182/TNKS1BP1, EBNA-1, Mcl-1L, Mcl-1S, NuMA, AXIN1, AXIN2.
TNKS PARsylates TRF1 (telomeric repeat-binding factor 1), a negative regulator of telomere length maintenance. PARsylated TRF1 dissociates from telomeres, enhancing telomerase-mediated telomere elongation (Smith and de Lange, 2000; Cook et al., 2002).
PARsylation of NuMA (nuclear mitotic apparatus protein) by TNKS contributes to mitotic spindle pole assembly (Sbodio and Chi, 2002).
TNKS can PARsylate Mcl-1L and Mcl-1S and inhibit their anti- and pro-apoptotic function correspondingly (Bae et al., 2003).
TNKS inhibits Epstein-Barr virus OriP function by binding and modifying Epstein-Barr nuclear antigen 1 (EBNA1) (Deng et al., 2002; Deng et al., 2005).
PARsylation activity of TNKS increases after phosphorilation by mitogen-activated protein kinase (MAPK) upon insulin stimulation (Chi and Lodish, 2000).
TNKS together with its partner IRAP enhances insulin-stimulated exocytosis of GLUT4 (Yeh et al., 2007).
TNKS PARsylates AXIN1 and AXIN2 components of beta-catenin (the Wnt pathway transcription factor) destruction complex (Huang et al., 2009).
TNKS is a target of the FANCD2, the key protein involved in development of Fanconi anemia. FANCD binds tankyrase-1 and inhibits its PARsylation at telomeres (Lyakhovich et al., 2011).

Homology

With TNKS2/TNKL.

Mutations

Somatic

Frameshift mutations are found in exons 9 and 10 in gastric and colorectal malignant tumors (Kim et al., 2011).

Implicated in

Entity name

Cancer

Note

TNKS is considered as a potential target for anticancer treatment.
Inhibition of PARP activities of TNKS blocks Wnt/beta-catenin pathway and increases efficiency of telomerase inhibitors (Seimiya et al., 2005; Huang et al., 2009; Zhang et al., 2010).

Disease

TNKS expression increased in some tumors (compared to adjacent normal tissues), including breast, bladder and gastric cancer (Gelmini et al., 2004; Gelmini et al., 2007; Poonepalli et al., 2008; Gao et al., 2011), but in other tumors, e.g. malignant glioma and colorectal cancer TNKS expression might be downregulated (Shervington et al., 2007; Shebzukhov et al., 2008), Fanconi anemia (Lyakhovich et al., 2011).

Bibliography

Pubmed ID	Last Year	Title	Authors
12475993	2003	Tankyrase 1 interacts with Mcl-1 proteins and inhibits their regulation of apoptosis.	Bae J et al
10988299	2000	Tankyrase is a golgi-associated mitogen-activated protein kinase substrate that interacts with IRAP in GLUT4 vesicles.	Chi NW et al
11739745	2002	Role for the related poly(ADP-Ribose) polymerases tankyrase 1 and 2 at human telomeres.	Cook BD et al
15795250	2005	Inhibition of Epstein-Barr virus OriP function by tankyrase, a telomere-associated poly-ADP ribose polymerase that binds and modifies EBNA1.	Deng Z et al
11931758	2002	Telomeric proteins regulate episomal maintenance of Epstein-Barr virus origin of plasmid replication.	Deng Z et al
21455637	2011	Expression of tankyrase 1 in gastric cancer and its correlation with telomerase activity.	Gao J et al
15500951	2004	Tankyrase, a positive regulator of telomere elongation, is over expressed in human breast cancer.	Gelmini S et al
17617028	2007	Tankyrase-1 mRNA expression in bladder cancer and paired urine sediment: preliminary experience.	Gelmini S et al
19759537	2009	Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling.	Huang SM et al
21333322	2011	Frameshift mutations of poly(adenosine diphosphate-ribose) polymerase genes in gastric and colorectal cancers with microsatellite instability.	Kim MS et al
21314979	2011	Fanconi anemia protein FANCD2 inhibits TRF1 polyADP-ribosylation through tankyrase1-dependent manner.	Lyakhovich A et al
18720522	2008	Telomere-mediated genomic instability and the clinico-pathological parameters in breast cancer.	Poonepalli A et al
12080061	2002	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.	Sbodio JI et al
15652747	2005	Tankyrase 1 as a target for telomere-directed molecular cancer therapeutics.	Seimiya H et al
18026951	2008	Human tankyrases are aberrantly expressed in colon tumors and contain multiple epitopes that induce humoral and cellular immune responses in cancer patients.	Shebzukhov YV et al
17196947	2007	Telomerase subunits expression variation between biopsy samples and cell lines derived from malignant glioma.	Shervington A et al
11069113	2000	Tankyrase promotes telomere elongation in human cells.	Smith S et al
17059388	2007	Insulin-stimulated exocytosis of GLUT4 is enhanced by IRAP and its partner tankyrase.	Yeh TY et al
20811689	2010	Inhibition of tankyrase 1 in human gastric cancer cells enhances telomere shortening by telomerase inhibitors.	Zhang H et al

Other Information

Locus ID:

NCBI: 8658
MIM: 603303
HGNC: 11941
Ensembl: ENSG00000173273

Variants:

dbSNP: 8658
ClinVar: 8658
TCGA: ENSG00000173273
COSMIC: TNKS

RNA/Proteins

Gene ID	Transcript ID	Uniprot
ENSG00000173273	ENST00000310430	O95271
ENSG00000173273	ENST00000517770	H0YAW5
ENSG00000173273	ENST00000518281	E7EQ52
ENSG00000173273	ENST00000518635	A0A0C4DGE3
ENSG00000173273	ENST00000520408	E7EWY6
ENSG00000173273	ENST00000522110	E5RHD2

Expression (GTEx)

Adipose - Subcutaneous

Adipose - Visceral

Adrenal Gland

Artery - Aorta

Artery - Tibial

Bladder

Brain - Amygdala

Brain - Anterior cingulate cortex

Brain - Caudate

Brain - Cerebellar Hemisphere

Brain - Cerebellum

Brain - Cortex

Brain - Frontal Cortex

Brain - Hippocampus

Brain - Hypothalamus

Brain - Nucleus accumbens

Brain - Putamen

Brain - Spinal cord

Brain - Substantia nigra

Breast - Mammary Tissue

Cells - Cultured fibroblasts

Cells - EBV - transformed lymphocytes

Cervix - Ectocervix

Cervix - Endocervix

Colon - Sigmoid

Colon - Transverse

Esophagus - Gastroesophageal Junction

Esophagus - Mucosa

Esophagus - Muscularis

Fallopian Tube

Heart - Atrial Appendage

Heart - Left Ventricle

Kidney - Cortex

Kidney - Medulla

Liver

Lung

Minor Salivary Gland

Muscle - Skeletal

Nerve - Tibial

Ovary

Pancreas

Pituitary

Prostate

Skin - Not Sun Exposed

Skin - Sun Exposed

Small Intestine - Terminal Ileum

Spleen

Stomach

Testis

Thyroid

Uterus

Vagina

Whole Blood

Pathways

Pathway	Source	External ID
Metabolism of proteins	REACTOME	R-HSA-392499
Post-translational protein modification	REACTOME	R-HSA-597592
Disease	REACTOME	R-HSA-1643685
Diseases of signal transduction	REACTOME	R-HSA-5663202
Signaling by WNT in cancer	REACTOME	R-HSA-4791275
XAV939 inhibits tankyrase, stabilizing AXIN	REACTOME	R-HSA-5545619
Signal Transduction	REACTOME	R-HSA-162582
Signaling by Wnt	REACTOME	R-HSA-195721
TCF dependent signaling in response to WNT	REACTOME	R-HSA-201681
Degradation of AXIN	REACTOME	R-HSA-4641257
Deubiquitination	REACTOME	R-HSA-5688426
Ub-specific processing proteases	REACTOME	R-HSA-5689880

Protein levels (Protein atlas)

Not detected

Low

Medium

High

References

Pubmed ID	Year	Title	Citations
20421936	2010	Two new Loci for body-weight regulation identified in a joint analysis of genome-wide association studies for early-onset extreme obesity in French and german study groups.	125
15064417	2004	Resolution of sister telomere association is required for progression through mitosis.	95
21799911	2011	Ubiquitin ligase RNF146 regulates tankyrase and Axin to promote Wnt signaling.	82
15133513	2004	TIN2 is a tankyrase 1 PARP modulator in the TRF1 telomere length control complex.	68
20379614	2010	Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.	62
12080061	2002	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.	54
11854288	2002	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).	53
16076287	2005	NuMA is a major acceptor of poly(ADP-ribosyl)ation by tankyrase 1 in mitosis.	53
24419084	2014	LEF1 and B9L shield β-catenin from inactivation by Axin, desensitizing colorectal cancer cells to tankyrase inhibitors.	36
19759176	2009	Interaction between Poly(ADP-ribose) and NuMA contributes to mitotic spindle pole assembly.	34

Citation

Yury Shebzukhov ; Sergei Nedospasov

TNKS (tankyrase, TRF1-interacting ankyrin-related ADP-ribose polymerase)

Atlas Genet Cytogenet Oncol Haematol. 2011-06-01

Online version: http://atlasgeneticsoncology.org/gene/43534/tnks-(tankyrase-trf1-interacting-ankyrin-related-adp-ribose-polymerase)