* 607128

TANKYRASE 2; TNKS2


Alternative titles; symbols

TRF1-INTERACTING ANKYRIN-RELATED ADP-RIBOSE POLYMERASE 2
TANK2
TNKL


HGNC Approved Gene Symbol: TNKS2

Cytogenetic location: 10q23.32     Genomic coordinates (GRCh38): 10:91,798,426-91,865,475 (from NCBI)


TEXT

Cloning and Expression

Using the adaptor protein GRB14 (601524) in a yeast 2-hybrid screen, Lyons et al. (2001) identified a partial TNKS2 clone within a human liver cDNA library. They generated the full-length sequence by isolation of a series of overlapping clones. The deduced 1,166-amino acid protein has a calculated molecular mass of 130 kD. It shares approximately 83% sequence identity with tankyrase-1 (TNKS; 603303), differing mainly in the absence of a histidine/proline/serine-rich (HPS) domain. Both proteins possess 24 ankyrin-type repeats, a sterile alpha motif, and a C-terminal poly(ADP-ribose) polymerase (PARP) homology domain. Critical residues required for NAD+ binding and catalysis are entirely conserved. Northern blot analysis detected strong expression of a 7-kb transcript in skeletal muscle and placenta and moderate expression in leukocytes, small intestine, ovary, testis, prostate, thymus, spleen, and pancreas. Western blot analysis of prostate carcinoma cells revealed a protein with an apparent molecular mass of 130 kD. Fractionation of a fibroblast cell line followed by Western blot analysis revealed both TNKS2 and TNKS in the low density microsome fraction. Confocal microscopy demonstrated both diffuse and punctate cytoplasmic staining for TNKS2, with some overlap with GRB14.

Using the telomeric repeat-binding factor-1 (TRF1; 600951) as probe, Kaminker et al. (2001) isolated a partial TNKS2 cDNA in a yeast 2-hybrid screen of a fibroblast library and attained the full-length clone by 5-prime RACE. The human and mouse TNKS2 proteins share 96% sequence identity. In place of the HPS domain in TNKS, human TNKS2 contains a unique 25-amino acid N-terminal domain. Northern blot analysis detected ubiquitous expression of a 6.6-kb transcript, at varying levels. TNKS2 was found in an insoluble fraction when cells were extracted under nondenaturing conditions, suggesting that the protein associates with insoluble nuclear or cytoskeletal matrices. In mitotic cells, TNKS2 localized to the pericentriolar matrix.


Gene Function

Using deletion analysis with a yeast 2-hybrid binding assay, Lyons et al. (2001) determined that the N-terminal set of ankyrin repeats in TNKS2 interacts with the N terminus of GRB14. By coimmunoprecipitation experiments, they confirmed interaction between TNKS2 and GRB14 in transfected HEK293 cells.

By coimmunoprecipitation and binding studies of in vitro translated protein, Kaminker et al. (2001) verified TRF1/TNKS2 interaction and localized the site of interaction to a 52-amino acid N-terminal domain of TRF1. They also found that overexpression of TNKS2 is cytotoxic, causing loss of mitochondrial membrane potential within 7 hours of transfection. Addition of a PARP inhibitor partially protected cells from TNKS2 toxicity.

In an immunoscreen of novel antigens associated with meningioma, Monz et al. (2001) found that sera of patients with the most common types of meningioma recognized TNKS2. Northern blot analysis demonstrated expression of TNKS2 in 2 common-type meningiomas from patients with immune response, but Monz et al. (2001) were unable to correlate expression of TNKS2 to the immune response.

To investigate a role for TNKS2 at telomeres, Cook et al. (2002) subjected TNKS2 to an in vitro PARP assay. TNKS2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of TNKS2 in the nucleus released endogenous TRF1 from telomeres. These findings established TNKS2 as a bona fide PARP, with itself and TRF1 as acceptors of ADP-ribosylation, and suggested the possibility of a role for TNKS2 at telomeres. Using Northern blot analysis, Cook et al. (2002) detected TNKS2 expression nearly ubiquitously in human adult and fetal tissues, in HeLa cells, and in primary fibroblasts.

Sbodio et al. (2002) showed that tankyrase-2 contains intrinsic PARP activity and, like tankyrase-1, binds to both TRF1 and IRAP (151300). Intrinsic PARP activity of tankyrase-2 depends critically on the met1054 residue. Sequence analysis suggested that the ANK domain of tankyrases comprises 5 subdomains, each consisting of 4 ANK repeats and demarcated from its adjacent subdomain by an LLEAAR-containing insert, that provide redundant binding sites for IRAP. Moreover, tankyrase-2 associates and colocalizes with tankyrase-1, suggesting that both tankyrases might function as a complex. Taken together, the findings of Sbodio et al. (2002) indicated that tankyrase-1 and tankyrase-2 interact with the same set of proteins and probably mediate overlapping functions, both at telomeres and in vesicular compartments.

To examine whether tumors overexpress tankyrase-2, Sidorova et al. (2006) raised anti-TNKL antibodies that did not cross-react with tankyrase-1. Of 18 breast tumor sections, 2 were positive for TNKL. Others were negative or contained barely detectable protein. Surrounding normal tissues were negative. Immunostaining with anti-TNKL antibody revealed expression of TNKL protein in epithelial cells of a limited number of normal renal tubules, whereas other renal tubules were negative. These data suggested that TNKL is not expressed ubiquitously in human tissues. To determine whether the upregulation of TNKL is associated with tissue regeneration and cell proliferation, Sidorova et al. (2006) compared the activity and concentration of the enzyme in a model HEK293 cell line arrested by serum deprivation and restimulated with serum. The serum-starved quiescent cell culture exhibited detectable protein as did the proliferating cells; enzyme activity dramatically increased in the latter. Sidorova et al. (2006) concluded that pathologic overexpression of TNKL in some tumors may be the result of the cancer-related adaptation of the malignant cells dependent on tankyrase activity. Under normal conditions, the protein might be upregulated during cell differentiation and also posttranslationally in proliferating cells.

Huang et al. (2009) used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin (116806)-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin (603816), the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, Huang et al. (2009) found that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase-1 (603303) and tankyrase-2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.


Gene Structure

Kaminker et al. (2001) determined that the TNKS2 gene contains 27 exons and spans about 66 kb.


Mapping

By FISH, Lyons et al. (2001) mapped the TNKS2 gene to chromosome 10q23.2. Kaminker et al. (2001) mapped the TNKS2 gene to chromosome 10q23-q24 by FISH and refined the localization to 10q23.3 by radiation hybrid analysis.


REFERENCES

  1. 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. Molec. Cell. Biol. 22: 332-342, 2002. [PubMed: 11739745, images, related citations] [Full Text]

  2. Huang, S.-M. A., Mishina, Y. M., Liu, S., Cheung, A., Stegmeier, F., Michaud, G. A., Charlat, O., Wiellette, E., Zhang, Y., Wiessner, S., Hild, M., Shi, X., and 24 others. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461: 614-620, 2009. [PubMed: 19759537, related citations] [Full Text]

  3. Kaminker, P. G., Kim, S.-H., Taylor, R. D., Zebarjadian, Y., Funk, W. D., Morin, G. B., Yaswen, P., Campisi, J. TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression. J. Biol. Chem. 276: 35891-35899, 2001. [PubMed: 11454873, related citations] [Full Text]

  4. Lyons, R. J., Deane, R., Lynch, D. K., Ye, Z.-S., Sanderson, G. M., Eyre, H. J., Sutherland, G. R., Daly, R. J. Identification of a novel human tankyrase through its interaction with the adaptor protein Grb14. J. Biol. Chem. 276: 17172-17180, 2001. [PubMed: 11278563, related citations] [Full Text]

  5. Monz, D., Munnia, A., Comtesse, N., Fischer, U., Steudel, W.-I., Feiden, W., Glass, B., Meese, E. U. Novel tankyrase-related gene detected with meningioma-specific sera. Clin. Cancer Res. 7: 113-119, 2001. [PubMed: 11205898, related citations]

  6. Sbodio, J. I., Lodish, H. F., Chi, N.-W. Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase). Biochem. J. 361: 451-459, 2002. [PubMed: 11802774, related citations] [Full Text]

  7. Sidorova, N., Zavalishina, L., Kurchashova, S., Korsakova, N., Nazhimov, V., Frank, G., Kuimov, A. Immunohistochemical detection of tankyrase 2 in human breast tumors and normal renal tissue. Cell Tissue Res. 323: 137-145, 2006. [PubMed: 16151859, related citations] [Full Text]


Ada Hamosh - updated : 11/13/2009
Anne M. Stumpf - updated : 5/11/2006
Creation Date:
Patricia A. Hartz : 7/30/2002
mgross : 08/25/2021
terry : 09/09/2010
alopez : 11/18/2009
terry : 11/13/2009
alopez : 5/11/2006
alopez : 5/29/2003
carol : 8/1/2002
carol : 7/31/2002

* 607128

TANKYRASE 2; TNKS2


Alternative titles; symbols

TRF1-INTERACTING ANKYRIN-RELATED ADP-RIBOSE POLYMERASE 2
TANK2
TNKL


HGNC Approved Gene Symbol: TNKS2

Cytogenetic location: 10q23.32     Genomic coordinates (GRCh38): 10:91,798,426-91,865,475 (from NCBI)


TEXT

Cloning and Expression

Using the adaptor protein GRB14 (601524) in a yeast 2-hybrid screen, Lyons et al. (2001) identified a partial TNKS2 clone within a human liver cDNA library. They generated the full-length sequence by isolation of a series of overlapping clones. The deduced 1,166-amino acid protein has a calculated molecular mass of 130 kD. It shares approximately 83% sequence identity with tankyrase-1 (TNKS; 603303), differing mainly in the absence of a histidine/proline/serine-rich (HPS) domain. Both proteins possess 24 ankyrin-type repeats, a sterile alpha motif, and a C-terminal poly(ADP-ribose) polymerase (PARP) homology domain. Critical residues required for NAD+ binding and catalysis are entirely conserved. Northern blot analysis detected strong expression of a 7-kb transcript in skeletal muscle and placenta and moderate expression in leukocytes, small intestine, ovary, testis, prostate, thymus, spleen, and pancreas. Western blot analysis of prostate carcinoma cells revealed a protein with an apparent molecular mass of 130 kD. Fractionation of a fibroblast cell line followed by Western blot analysis revealed both TNKS2 and TNKS in the low density microsome fraction. Confocal microscopy demonstrated both diffuse and punctate cytoplasmic staining for TNKS2, with some overlap with GRB14.

Using the telomeric repeat-binding factor-1 (TRF1; 600951) as probe, Kaminker et al. (2001) isolated a partial TNKS2 cDNA in a yeast 2-hybrid screen of a fibroblast library and attained the full-length clone by 5-prime RACE. The human and mouse TNKS2 proteins share 96% sequence identity. In place of the HPS domain in TNKS, human TNKS2 contains a unique 25-amino acid N-terminal domain. Northern blot analysis detected ubiquitous expression of a 6.6-kb transcript, at varying levels. TNKS2 was found in an insoluble fraction when cells were extracted under nondenaturing conditions, suggesting that the protein associates with insoluble nuclear or cytoskeletal matrices. In mitotic cells, TNKS2 localized to the pericentriolar matrix.


Gene Function

Using deletion analysis with a yeast 2-hybrid binding assay, Lyons et al. (2001) determined that the N-terminal set of ankyrin repeats in TNKS2 interacts with the N terminus of GRB14. By coimmunoprecipitation experiments, they confirmed interaction between TNKS2 and GRB14 in transfected HEK293 cells.

By coimmunoprecipitation and binding studies of in vitro translated protein, Kaminker et al. (2001) verified TRF1/TNKS2 interaction and localized the site of interaction to a 52-amino acid N-terminal domain of TRF1. They also found that overexpression of TNKS2 is cytotoxic, causing loss of mitochondrial membrane potential within 7 hours of transfection. Addition of a PARP inhibitor partially protected cells from TNKS2 toxicity.

In an immunoscreen of novel antigens associated with meningioma, Monz et al. (2001) found that sera of patients with the most common types of meningioma recognized TNKS2. Northern blot analysis demonstrated expression of TNKS2 in 2 common-type meningiomas from patients with immune response, but Monz et al. (2001) were unable to correlate expression of TNKS2 to the immune response.

To investigate a role for TNKS2 at telomeres, Cook et al. (2002) subjected TNKS2 to an in vitro PARP assay. TNKS2 poly(ADP-ribosyl)ated itself and TRF1. Overexpression of TNKS2 in the nucleus released endogenous TRF1 from telomeres. These findings established TNKS2 as a bona fide PARP, with itself and TRF1 as acceptors of ADP-ribosylation, and suggested the possibility of a role for TNKS2 at telomeres. Using Northern blot analysis, Cook et al. (2002) detected TNKS2 expression nearly ubiquitously in human adult and fetal tissues, in HeLa cells, and in primary fibroblasts.

Sbodio et al. (2002) showed that tankyrase-2 contains intrinsic PARP activity and, like tankyrase-1, binds to both TRF1 and IRAP (151300). Intrinsic PARP activity of tankyrase-2 depends critically on the met1054 residue. Sequence analysis suggested that the ANK domain of tankyrases comprises 5 subdomains, each consisting of 4 ANK repeats and demarcated from its adjacent subdomain by an LLEAAR-containing insert, that provide redundant binding sites for IRAP. Moreover, tankyrase-2 associates and colocalizes with tankyrase-1, suggesting that both tankyrases might function as a complex. Taken together, the findings of Sbodio et al. (2002) indicated that tankyrase-1 and tankyrase-2 interact with the same set of proteins and probably mediate overlapping functions, both at telomeres and in vesicular compartments.

To examine whether tumors overexpress tankyrase-2, Sidorova et al. (2006) raised anti-TNKL antibodies that did not cross-react with tankyrase-1. Of 18 breast tumor sections, 2 were positive for TNKL. Others were negative or contained barely detectable protein. Surrounding normal tissues were negative. Immunostaining with anti-TNKL antibody revealed expression of TNKL protein in epithelial cells of a limited number of normal renal tubules, whereas other renal tubules were negative. These data suggested that TNKL is not expressed ubiquitously in human tissues. To determine whether the upregulation of TNKL is associated with tissue regeneration and cell proliferation, Sidorova et al. (2006) compared the activity and concentration of the enzyme in a model HEK293 cell line arrested by serum deprivation and restimulated with serum. The serum-starved quiescent cell culture exhibited detectable protein as did the proliferating cells; enzyme activity dramatically increased in the latter. Sidorova et al. (2006) concluded that pathologic overexpression of TNKL in some tumors may be the result of the cancer-related adaptation of the malignant cells dependent on tankyrase activity. Under normal conditions, the protein might be upregulated during cell differentiation and also posttranslationally in proliferating cells.

Huang et al. (2009) used a chemical genetic screen to identify a small molecule, XAV939, which selectively inhibits beta-catenin (116806)-mediated transcription. XAV939 stimulates beta-catenin degradation by stabilizing axin (603816), the concentration-limiting component of the destruction complex. Using a quantitative chemical proteomic approach, Huang et al. (2009) found that XAV939 stabilizes axin by inhibiting the poly-ADP-ribosylating enzymes tankyrase-1 (603303) and tankyrase-2. Both tankyrase isoforms interact with a highly conserved domain of axin and stimulate its degradation through the ubiquitin-proteasome pathway.


Gene Structure

Kaminker et al. (2001) determined that the TNKS2 gene contains 27 exons and spans about 66 kb.


Mapping

By FISH, Lyons et al. (2001) mapped the TNKS2 gene to chromosome 10q23.2. Kaminker et al. (2001) mapped the TNKS2 gene to chromosome 10q23-q24 by FISH and refined the localization to 10q23.3 by radiation hybrid analysis.


REFERENCES

  1. 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. Molec. Cell. Biol. 22: 332-342, 2002. [PubMed: 11739745] [Full Text: https://doi.org/10.1128/MCB.22.1.332-342.2002]

  2. Huang, S.-M. A., Mishina, Y. M., Liu, S., Cheung, A., Stegmeier, F., Michaud, G. A., Charlat, O., Wiellette, E., Zhang, Y., Wiessner, S., Hild, M., Shi, X., and 24 others. Tankyrase inhibition stabilizes axin and antagonizes Wnt signalling. Nature 461: 614-620, 2009. [PubMed: 19759537] [Full Text: https://doi.org/10.1038/nature08356]

  3. Kaminker, P. G., Kim, S.-H., Taylor, R. D., Zebarjadian, Y., Funk, W. D., Morin, G. B., Yaswen, P., Campisi, J. TANK2, a new TRF1-associated poly(ADP-ribose) polymerase, causes rapid induction of cell death upon overexpression. J. Biol. Chem. 276: 35891-35899, 2001. [PubMed: 11454873] [Full Text: https://doi.org/10.1074/jbc.M105968200]

  4. Lyons, R. J., Deane, R., Lynch, D. K., Ye, Z.-S., Sanderson, G. M., Eyre, H. J., Sutherland, G. R., Daly, R. J. Identification of a novel human tankyrase through its interaction with the adaptor protein Grb14. J. Biol. Chem. 276: 17172-17180, 2001. [PubMed: 11278563] [Full Text: https://doi.org/10.1074/jbc.M009756200]

  5. Monz, D., Munnia, A., Comtesse, N., Fischer, U., Steudel, W.-I., Feiden, W., Glass, B., Meese, E. U. Novel tankyrase-related gene detected with meningioma-specific sera. Clin. Cancer Res. 7: 113-119, 2001. [PubMed: 11205898]

  6. Sbodio, J. I., Lodish, H. F., Chi, N.-W. Tankyrase-2 oligomerizes with tankyrase-1 and binds to both TRF1 (telomere-repeat-binding factor 1) and IRAP (insulin-responsive aminopeptidase). Biochem. J. 361: 451-459, 2002. [PubMed: 11802774] [Full Text: https://doi.org/10.1042/0264-6021:3610451]

  7. Sidorova, N., Zavalishina, L., Kurchashova, S., Korsakova, N., Nazhimov, V., Frank, G., Kuimov, A. Immunohistochemical detection of tankyrase 2 in human breast tumors and normal renal tissue. Cell Tissue Res. 323: 137-145, 2006. [PubMed: 16151859] [Full Text: https://doi.org/10.1007/s00441-005-0053-8]


Contributors:
Ada Hamosh - updated : 11/13/2009
Anne M. Stumpf - updated : 5/11/2006

Creation Date:
Patricia A. Hartz : 7/30/2002

Edit History:
mgross : 08/25/2021
terry : 09/09/2010
alopez : 11/18/2009
terry : 11/13/2009
alopez : 5/11/2006
alopez : 5/29/2003
carol : 8/1/2002
carol : 7/31/2002