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Gene Review

PTPRN2  -  protein tyrosine phosphatase, receptor...

Homo sapiens

Synonyms: IA-2beta, IAR, ICAAR, Islet cell autoantigen-related protein, KIAA0387, ...
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Disease relevance of PTPRN2


High impact information on PTPRN2

  • Here, we demonstrate colocalization of myosin Va (MyoVa) with insulin in pancreatic beta-cells and show that MyoVa copurifies with insulin in density gradients and with the vesicle marker phogrin-enhanced green fluorescent protein upon fluorescence-activated sorting of vesicles [4].
  • Insulinoma-associated protein (IA)-2beta, also known as phogrin, is an enzymatically inactive member of the transmembrane protein tyrosine phosphatase family and is located in dense-core secretory vesicles [5].
  • Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice [5].
  • In the present study, we determined the genomic structure of IA-2beta and found that both human and mouse IA-2beta consist of 23 exons and span approximately 1,000 and 800 kb, respectively [5].
  • Knockout of the IA-2beta gene in NOD mice, the most widely studied animal model for human type 1 diabetes, failed to prevent the development of cyclophosphamide-induced diabetes [5].

Biological context of PTPRN2

  • Genomic DNA analysis indicates that the 17-amino-acid insert is coded by a separate exon, suggesting that both IA-2beta and PTP-NP-2 are isoforms arising by alternate splicing of the same gene [6].
  • We have localised ICAAR to human chromosome 7q36 [7].
  • A 4.7 kb cDNA of tyrosine phosphatase-like protein, phogrin, was isolated from a human islet cDNA library [8].
  • In the current study, we have examined the overlapping specificities and antigenic epitopes of autoantibodies to ICA512 and phogrin and determined whether intramolecular epitope spreading occurs during the development of diabetic autoimmunity [2].
  • OBJECTIVE: To characterize the phenotype of a large population of Italian patients with adult onset (> or =40 years) diabetes who were attending outpatient clinics and who were screened for glutamic acid decarboxylase 65 autoantibodies (GADA), protein tyrosine phosphatase IA-2 (IA-2A) and IA-2beta/phogrin (IA-2betaA) [9].

Anatomical context of PTPRN2

  • Thus IAR is likely to be an islet cell antigen useful in the preclinical screening of individuals for risk of IDDM [10].
  • An abundant ICAAR mRNA is detectable in the brain and pancreas but not in the other normal human tissues surveyed [7].
  • The identification, quantification, and characterization of T-cells reactive with the islet autoantigens GAD65, proinsulin (PI), and tyrosine phosphatase-like molecules IA-2 and phogrin are major research goals in type 1 diabetes [11].
  • To investigate whether the catalytically inactive cytoplasmic domains of IA-2 and IA-2beta are involved in oligomerization, we exploited interaction trap assay in yeast and glutathione S-transferase pull-down and co-immunoprecipitation strategies on lysates of transfected COS-1 cells [12].
  • Although this subject did not exhibit insulitis, lymphocytes derived from pancreatic lymph nodes reacted to the islet antigen phogrin [13].

Associations of PTPRN2 with chemical compounds

  • Phogrin is 74% identical to the ICA512/IA-2 autoantigen of type 1 diabetes in the cytoplasmic domain, but only 29% in the luminal domain [8].
  • Both cleavage sites are immediately after an arginine residue at position 653 for IA-2 and position 679 for IA-2 beta [14].
  • Sequence analysis revealed five conserved cysteine residues in IA-2 and IA-2 beta that are not present in other PTPs [14].
  • GADA, IA-2A and IA-2betaA were measured with radiobinding assays with in vitro translated S-methionine-labelled glutamic acid decarboxylase 65 (GAD65) or IA-2 or IA-2beta [9].
  • Phogrin is an integral glycoprotein primarily expressed in neuroendocrine cells [15].

Regulatory relationships of PTPRN2


Other interactions of PTPRN2

  • In the 17 relatives who developed type 1 diabetes, progression to disease was associated with reactivity to multiple IA-2/IA-2 beta epitopes [17].
  • Tyrosine phosphatases (IA-2, IAR) represent a major target autoantigen in type 1 diabetes [18].
  • Immunohistochemical staining with a specific antibody against bone morphogenetic protein type IA receptor showed that TNP-470 reduced the number of receptor-positive cells surrounding the BMP pellets [19].
  • We report here expression of the extracellular domain of the human type IA receptor for BMP-2 (BMPR-IA) in Escherichia coli [20].
  • We have analyzed the immunochemical and functional properties of the IA receptor from erythrocytes from species that have been used for in vivo IC clearance studies and have compared these properties to the human IA receptor (which is called complement receptor type 1, CR1) [21].

Analytical, diagnostic and therapeutic context of PTPRN2


  1. Autoantigens in insulin-dependent diabetes mellitus: molecular cloning and characterization of human IA-2 beta. Li, Q., Borovitskaya, A.E., DeSilva, M.G., Wasserfall, C., Maclaren, N.K., Notkins, A.L., Lan, M.S. Proc. Assoc. Am. Physicians (1997) [Pubmed]
  2. Definition of multiple ICA512/phogrin autoantibody epitopes and detection of intramolecular epitope spreading in relatives of patients with type 1 diabetes. Kawasaki, E., Yu, L., Rewers, M.J., Hutton, J.C., Eisenbarth, G.S. Diabetes (1998) [Pubmed]
  3. Enterovirus infection may induce humoral immune response reacting with islet cell autoantigens in humans. Härkönen, T., Paananen, A., Lankinen, H., Hovi, T., Vaarala, O., Roivainen, M. J. Med. Virol. (2003) [Pubmed]
  4. Myosin Va transports dense core secretory vesicles in pancreatic MIN6 beta-cells. Varadi, A., Tsuboi, T., Rutter, G.A. Mol. Biol. Cell (2005) [Pubmed]
  5. Targeted disruption of the IA-2beta gene causes glucose intolerance and impairs insulin secretion but does not prevent the development of diabetes in NOD mice. Kubosaki, A., Gross, S., Miura, J., Saeki, K., Zhu, M., Nakamura, S., Hendriks, W., Notkins, A.L. Diabetes (2004) [Pubmed]
  6. Characterization and chromosomal localization of PTP-NP-2, a new isoform of protein tyrosine phosphatase-like receptor, expressed on synaptic boutons. Jiang, S., Tulloch, A.G., Kim, T.A., Fu, Y., Rogers, R., Gaskell, A., White, R.A., Avraham, H., Avraham, S. Gene (1998) [Pubmed]
  7. ICAAR, a novel member of a new family of transmembrane, tyrosine phosphatase-like proteins. Smith, P.D., Barker, K.T., Wang, J., Lu, Y.J., Shipley, J., Crompton, M.R. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  8. Molecular cloning and characterization of the human transmembrane protein tyrosine phosphatase homologue, phogrin, an autoantigen of type 1 diabetes. Kawasaki, E., Hutton, J.C., Eisenbarth, G.S. Biochem. Biophys. Res. Commun. (1996) [Pubmed]
  9. Clinical phenotype and beta-cell autoimmunity in Italian patients with adult-onset diabetes. Genovese, S., Bazzigaluppi, E., Gonçalves, D., Ciucci, A., Cavallo, M.G., Purrello, F., Anello, M., Rotella, C.M., Bardini, G., Vaccaro, O., Riccardi, G., Travaglini, P., Morenghi, E., Bosi, E., Pozzilli, P. Eur. J. Endocrinol. (2006) [Pubmed]
  10. Cloning and characterization of islet cell antigen-related protein-tyrosine phosphatase (PTP), a novel receptor-like PTP and autoantigen in insulin-dependent diabetes. Cui, L., Yu, W.P., DeAizpurua, H.J., Schmidli, R.S., Pallen, C.J. J. Biol. Chem. (1996) [Pubmed]
  11. Characterization of preparations of GAD65, proinsulin, and the islet tyrosine phosphatase IA-2 for use in detection of autoreactive T-cells in type 1 diabetes: report of phase II of the Second International Immunology of Diabetes Society Workshop for Standardization of T-cell assays in type 1 diabetes. Peakman, M., Tree, T.I., Endl, J., van Endert, P., Atkinson, M.A., Roep, B.O. Diabetes (2001) [Pubmed]
  12. Multimerization of the protein-tyrosine phosphatase (PTP)-like insulin-dependent diabetes mellitus autoantigens IA-2 and IA-2beta with receptor PTPs (RPTPs). Inhibition of RPTPalpha enzymatic activity. Gross, S., Blanchetot, C., Schepens, J., Albet, S., Lammers, R., den Hertog, J., Hendriks, W. J. Biol. Chem. (2002) [Pubmed]
  13. Initial results of screening of nondiabetic organ donors for expression of islet autoantibodies. Gianani, R., Putnam, A., Still, T., Yu, L., Miao, D., Gill, R.G., Beilke, J., Supon, P., Valentine, A., Iveson, A., Dunn, S., Eisenbarth, G.S., Hutton, J., Gottlieb, P., Wiseman, A. J. Clin. Endocrinol. Metab. (2006) [Pubmed]
  14. Autoantibodies to IA-2 and IA-2 beta in insulin-dependent diabetes mellitus recognize conformational epitopes: location of the 37- and 40-kDa fragments determined. Xie, H., Zhang, B., Matsumoto, Y., Li, Q., Notkins, A.L., Lan, M.S. J. Immunol. (1997) [Pubmed]
  15. Cytoplasmic transport signal is involved in phogrin targeting and localization to secretory granules. Torii, S., Saito, N., Kawano, A., Zhao, S., Izumi, T., Takeuchi, T. Traffic (2005) [Pubmed]
  16. Type I bone morphogenetic protein receptors are expressed on cerebellar granular neurons and a constitutively active form of the type IA receptor induces cerebellar abnormalities. Ming, J.E., Elkan, M., Tang, K., Golden, J.A. Neuroscience (2002) [Pubmed]
  17. IA-2 (islet cell antigen 512) is the primary target of humoral autoimmunity against type 1 diabetes-associated tyrosine phosphatase autoantigens. Bonifacio, E., Lampasona, V., Bingley, P.J. J. Immunol. (1998) [Pubmed]
  18. Enterovirus infection can induce immune responses that cross-react with beta-cell autoantigen tyrosine phosphatase IA-2/IAR. Härkönen, T., Lankinen, H., Davydova, B., Hovi, T., Roivainen, M. J. Med. Virol. (2002) [Pubmed]
  19. Antiangiogenic agent (TNP-470) inhibition of ectopic bone formation induced by bone morphogenetic protein-2. Mori, S., Yoshikawa, H., Hashimoto, J., Ueda, T., Funai, H., Kato, M., Takaoka, K. Bone (1998) [Pubmed]
  20. Isolation of recombinant BMP receptor IA ectodomain and its 2:1 complex with BMP-2. Kirsch, T., Nickel, J., Sebald, W. FEBS Lett. (2000) [Pubmed]
  21. Functional characterization of non-human primate erythrocyte immune adherence receptors: implications for the uptake of immune complexes by the cells of the mononuclear phagocytic system. Edberg, J.C., Kimberly, R.P., Taylor, R.P. Eur. J. Immunol. (1992) [Pubmed]
  22. IA-2 and IA-2 beta are major autoantigens in IDDM and the precursors of the 40 kDa and 37 kDa tryptic fragments. Notkins, A.L., Lu, J., Li, Q., VanderVegt, F.P., Wasserfall, C., Maclaren, N.K., Lan, M.S. J. Autoimmun. (1996) [Pubmed]
  23. Assignment of Ptprn2, the gene encoding receptor-type protein tyrosine phosphatase IA-2beta, a major autoantigen in insulin-dependent diabetes mellitus, to mouse chromosome region 12F. van den Maagdenberg, A.M., Schepens, J.T., Schepens, M.T., Pepers, B., Wieringa, B., van Kessel, A.G., Hendriks, W.J. Cytogenet. Cell Genet. (1998) [Pubmed]
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