PTPRN explained

Receptor-type tyrosine-protein phosphatase-like N, also called "IA-2", is an enzyme that in humans is encoded by the PTPRN gene.^{[1] [2]}

Overview

The IA-2 protein encoded by PTPRN gene is a member of the protein tyrosine phosphatase (PTP) family and PTPRN subfamily. PTPs are known to be signaling molecules that regulate a variety of cellular processes including cell growth, differentiation, mitotic cycle, and oncogenic transformation. This PTP possesses an extracellular region, a single transmembrane region, and a single catalytic domain, and thus represents a receptor-type PTP. This PTP was found to be an autoantigen that is reactive with insulin-dependent diabetes mellitus (IDDM) patient sera, and thus may be a potential target of autoimmunity in diabetes mellitus.

Structure

IA-2 and IA-2b belong to family of protein tyrosine phosphatase-like (PTP) molecules. IA-2 is a transmembrane protein with 979 amino acids encoded by a gene on human chromosome 2q35. Similarly, IA-2b has 986 amino acids, and it is located on human chromosome 7q36. The IA-2 is synthesised as a pro-protein of 110 kDa which is then converted by post-translational modifications into a 130 kDa protein.

The IA-2 and IA-2b shares 74% identity within the intracellular domains, but only 27% in the extracellular domains.

The IA-2 protein is expressed mainly in cells of neuroendocrine origin, such as pancreatic islets and brain. The IA-2 protein is localised in the membrane of secretory granules of pancreatic β-cells.^{[3] [4]}

Function

Even though the IA-2/b has a similar structure to other PTPs, there is a critical amino acid replacement at position 911 (Asp for Ala),^[5] which is required for enzymatic activity. These proteins thus fail to show enzymatic activity and their function remains unclear.^[3] They could play role in insulin secretory pathways, sorting out proteins or regulates other PTPs.^[6]

Autoantigen in Type 1 Diabetes

The IA-2 is a second major autoantigen in Type 1 Diabetes. IA-2 autoantibodies are found in 78% type 1 diabetics at the time of diagnosis.^[7] It has been shown that the autoantibodies exclusively react with the intracellular domain, also called juxtamembrane, but not with the extracellular domain of IA-2/b.^[3]

It is suggested that IA-2 and not the IA-2b is the primary PTP-like autoantigen in Type 1 Diabetes. The juxtamembrane region in IA-2 is probably the early antibody target.  Followed by multiple epitope spreading which is believed to take place in the early development of the disease.^[8]

Autoantibodies in Type 1 Diabetes

Autoantibodies targeting pancreatic islet cell can occur years before a hyperglycaemia is established, therefore these autoantibodies are used in prediction of Type 1 Diabetes.

Islet cell autoantibodies are detected in serum, including ICA (islet cell cytoplasma autoantibodies), IAA (autoantibodies to insulin), GAD (glutamic acid decarboxylase), IA-2 (insulinoma-associated protein 2), and ZnT8 (zinc transporter of islet beta cells).^[9]

However, it is not clear if a primary autoantigen exists and immune reaction against other molecules results from secondary antigen spreading, or multiple molecules represent a primary target.^[10]

The first autoimmune targets are usually aimed against insulin or GAD, and it is unique to observe IA-2 or ZnT8 as the first autoantibodies. What set off the appearance of a first β-cell targeting autoantibody is unclear.^[11]

The IAA antibody usually appears early in life, median age is 1.49. Presence of GAD as the first autoantibody is more widespread with median age 4.04. It is relatively rare to see IA-2 as the primary autoantibody, median age 3.03. Interestingly, secondary autoantibodies follow different patterns to mask the primary autoantibodies, if both are combined. If the primary autoantibody is IAA then GAD briskly appears with peak of 2 years age. Secondary IAA usually occurs after GAD, where the age distribution is over wide range.^[10]

It is unknown whether the appearance of autoantibodies corresponds with insulitis process in the pancreas and if so, what is the combination of the autoantibodies.^[9]

Interactions

PTPRN has been shown to interact with SPTBN4.^[12]

Further reading

• Rabin DU, Pleasic SM, Shapiro JA, Yoo-Warren H, Oles J, Hicks JM, Goldstein DE, Rae PM . 6 . Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases . Journal of Immunology . 152 . 6 . 3183–3188 . March 1994 . 10.4049/jimmunol.152.6.3183 . 8144912 . 25401081 . free .
• Solimena M, Dirkx R, Hermel JM, Pleasic-Williams S, Shapiro JA, Caron L, Rabin DU . ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules . The EMBO Journal . 15 . 9 . 2102–2114 . May 1996 . 8641276 . 450132 . 10.1002/j.1460-2075.1996.tb00564.x .
• van den Maagdenberg AM, Olde Weghuis D, Rijss J, van de Wetering RA, Wieringa B, Geurts van Kessel A, Hendriks WJ . Assignment of the human gene for receptor-type protein tyrosine phosphatase IA-2 (PTPRN) to chromosome region 2q35 → q36.1 and identification of an intragenic genetic marker . Cytogenetics and Cell Genetics . 73 . 1–2 . 145–148 . 1996 . 8646884 . 10.1159/000134327 . 2066/23317 . free .
• Cui L, Yu WP, DeAizpurua HJ, Schmidli RS, Pallen CJ . Cloning and characterization of islet cell antigen-related protein-tyrosine phosphatase (PTP), a novel receptor-like PTP and autoantigen in insulin-dependent diabetes . The Journal of Biological Chemistry . 271 . 40 . 24817–24823 . October 1996 . 8798755 . 10.1074/jbc.271.40.24817 . free .
• Xie J, Zhang B, Lan MS, Notkins AL . Genomic structure and promoter sequence of the insulin-dependent diabetes mellitus autoantigen, IA-2 (PTPRN) . Genomics . 54 . 2 . 338–343 . December 1998 . 9828138 . 10.1006/geno.1998.5583 .
• Ort T, Maksimova E, Dirkx R, Kachinsky AM, Berghs S, Froehner SC, Solimena M . The receptor tyrosine phosphatase-like protein ICA512 binds the PDZ domains of beta2-syntrophin and nNOS in pancreatic beta-cells . European Journal of Cell Biology . 79 . 9 . 621–630 . September 2000 . 11043403 . 10.1078/0171-9335-00095 .
• Park YS, Kawasaki E, Kelemen K, Yu L, Schiller MR, Rewers M, Mizuta M, Eisenbarth GS, Hutton JC . 6 . Humoral autoreactivity to an alternatively spliced variant of ICA512/IA-2 in Type I diabetes . Diabetologia . 43 . 10 . 1293–1301 . October 2000 . 11079748 . 10.1007/s001250051525 . free .
• Berghs S, Aggujaro D, Dirkx R, Maksimova E, Stabach P, Hermel JM, Zhang JP, Philbrick W, Slepnev V, Ort T, Solimena M . 6 . betaIV spectrin, a new spectrin localized at axon initial segments and nodes of ranvier in the central and peripheral nervous system . The Journal of Cell Biology . 151 . 5 . 985–1002 . November 2000 . 11086001 . 2174349 . 10.1083/jcb.151.5.985 .
• Diez J, Park Y, Zeller M, Brown D, Garza D, Ricordi C, Hutton J, Eisenbarth GS, Pugliese A . 6 . Differential splicing of the IA-2 mRNA in pancreas and lymphoid organs as a permissive genetic mechanism for autoimmunity against the IA-2 type 1 diabetes autoantigen . Diabetes . 50 . 4 . 895–900 . April 2001 . 11289059 . 10.2337/diabetes.50.4.895 . free .
• Ort T, Voronov S, Guo J, Zawalich K, Froehner SC, Zawalich W, Solimena M . Dephosphorylation of beta2-syntrophin and Ca2+/mu-calpain-mediated cleavage of ICA512 upon stimulation of insulin secretion . The EMBO Journal . 20 . 15 . 4013–4023 . August 2001 . 11483505 . 149140 . 10.1093/emboj/20.15.4013 .
• Mikulecký M, Michalková D . Secular and seasonal cycling of IA2-ab autoantibody in Slovak diabetic children . Biomedicine & Pharmacotherapy . 55 . 106s–109s . 2002 . Suppl 1 . 11774856 . 10.1016/s0753-3322(01)90014-9 .
• Miao D, Yu L, Tiberti C, Cuthbertson DD, Rewers M, di Mario U, Eisenbarth GS, Dotta F . 6 . ICA512(IA-2) epitope specific assays distinguish transient from diabetes associated autoantibodies . Journal of Autoimmunity . 18 . 2 . 191–196 . March 2002 . 11908951 . 10.1006/jaut.2001.0577 .
• Kawasaki E, Yamaguchi H, Hattori H, Egashira T, Eguchi K . Autoantibodies to IA-2 in type 1 diabetes: measurements with a new enzyme-linked immunosorbent assay . Annals of the New York Academy of Sciences . 958 . 241–246 . April 2002 . 12021115 . 10.1111/j.1749-6632.2002.tb02978.x . 45659598 .
• Sanjeevi CB, Das AK, Shtauvere-Brameus A . BCG vaccination and GAD65 and IA-2 autoantibodies in autoimmune diabetes in southern India . Annals of the New York Academy of Sciences . 958 . 293–296 . April 2002 . 1 . 12021127 . 10.1111/j.1749-6632.2002.tb02990.x . 2002NYASA.958..293S . 44799912 .
• Bearzatto M, Lampasona V, Belloni C, Bonifacio E . Fine mapping of diabetes-associated IA-2 specific autoantibodies . Journal of Autoimmunity . 21 . 4 . 377–382 . December 2003 . 14624760 . 10.1016/j.jaut.2003.08.002 .
• Trajkovski M, Mziaut H, Altkrüger A, Ouwendijk J, Knoch KP, Müller S, Solimena M . Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in -cells . The Journal of Cell Biology . 167 . 6 . 1063–1074 . December 2004 . 15596545 . 2172607 . 10.1083/jcb.200408172 .
• Ota T, Takamura T, Nagai Y, Bando Y, Usuda R . Significance of IA-2 antibody in Japanese type 1 diabetes: its association with GAD antibody . Diabetes Research and Clinical Practice . 67 . 1 . 63–69 . January 2005 . 15620435 . 10.1016/j.diabres.2004.05.004 .

Notes and References

1. Lan MS, Lu J, Goto Y, Notkins AL . Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma . DNA and Cell Biology . 13 . 5 . 505–514 . May 1994 . 8024693 . 10.1089/dna.1994.13.505 .
2. Web site: Entrez Gene: PTPRN protein tyrosine phosphatase, receptor type, N.
3. Notkins AL, Lan MS, Leslie RD . IA-2 and IA-2beta: the immune response in IDDM . Diabetes/Metabolism Reviews . 14 . 1 . 85–93 . March 1998 . 9605631 . 10.1002/(SICI)1099-0895(199803)14:1<85::AID-DMR205>3.0.CO;2-I .
4. Lan MS, Lu J, Goto Y, Notkins AL . Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma . DNA and Cell Biology . 13 . 5 . 505–514 . May 1994 . 8024693 . 10.1089/dna.1994.13.505 .
5. Notkins AL . Immunologic and genetic factors in type 1 diabetes . The Journal of Biological Chemistry . 277 . 46 . 43545–43548 . November 2002 . 12270944 . 10.1074/jbc.R200012200 . free .
6. Torii S . Expression and function of IA-2 family proteins, unique neuroendocrine-specific protein-tyrosine phosphatases . Endocrine Journal . 56 . 5 . 639–648 . 2009 . 19550073 . 10.1507/endocrj.K09E-157 . 12710545 . free .
7. Belhiba O, Aadam Z, Jeddane L, Saile R, Salih Alj H, Bousfiha AA, Jennane F . Research of anti-GAD and anti-IA2 autoantibodies by ELISA test in a series of Moroccan pediatric patients with diabetes type 1 . African Health Sciences . 20 . 3 . 1337–1343 . September 2020 . 33402983 . 10.4314/ahs.v20i3.40 . 7751543 .
8. Naserke HE, Ziegler AG, Lampasona V, Bonifacio E . Early development and spreading of autoantibodies to epitopes of IA-2 and their association with progression to type 1 diabetes . Journal of Immunology . 161 . 12 . 6963–6969 . December 1998 . 10.4049/jimmunol.161.12.6963 . 9862731 . 46571282 . free .
9. In't Veld P, Lievens D, De Grijse J, Ling Z, Van der Auwera B, Pipeleers-Marichal M, Gorus F, Pipeleers D . 6 . Screening for insulitis in adult autoantibody-positive organ donors . Diabetes . 56 . 9 . 2400–2404 . September 2007 . 17563060 . 10.2337/db07-0416 . 2572529 . free .
10. Ilonen J, Hammais A, Laine AP, Lempainen J, Vaarala O, Veijola R, Simell O, Knip M . 6 . Patterns of β-cell autoantibody appearance and genetic associations during the first years of life . Diabetes . 62 . 10 . 3636–3640 . October 2013 . 23835325 . 3781470 . 10.2337/db13-0300 .
11. Katsarou A, Gudbjörnsdottir S, Rawshani A, Dabelea D, Bonifacio E, Anderson BJ, Jacobsen LM, Schatz DA, Lernmark Å . 6 . Type 1 diabetes mellitus . Nature Reviews. Disease Primers . 3 . 1 . 17016 . March 2017 . 28358037 . 10.1038/nrdp.2017.16 . 23127616 .
12. Berghs S, Aggujaro D, Dirkx R, Maksimova E, Stabach P, Hermel JM, Zhang JP, Philbrick W, Slepnev V, Ort T, Solimena M . 6 . betaIV spectrin, a new spectrin localized at axon initial segments and nodes of ranvier in the central and peripheral nervous system . The Journal of Cell Biology . 151 . 5 . 985–1002 . November 2000 . 11086001 . 2174349 . 10.1083/jcb.151.5.985 .