PTPRN

Receptor-type tyrosine-protein phosphatase-like N, also called "IA-2", is an enzyme that in humans is encoded by the PTPRN gene.[5][6]

PTPRN
Available structures
PDBOrtholog search: PDBe RCSB
Identifiers
AliasesPTPRN, IA-2, IA-2/PTP, IA2, ICA512, R-PTP-N, protein tyrosine phosphatase, receptor type N, protein tyrosine phosphatase receptor type N
External IDsOMIM: 601773 MGI: 102765 HomoloGene: 48142 GeneCards: PTPRN
Orthologs
SpeciesHumanMouse
Entrez

5798

19275

Ensembl

ENSG00000054356

ENSMUSG00000026204

UniProt

Q16849

Q60673

RefSeq (mRNA)

NM_001199763
NM_001199764
NM_002846

NM_008985
NM_001359281

RefSeq (protein)

NP_001186692
NP_001186693
NP_002837

n/a

Location (UCSC)Chr 2: 219.29 – 219.31 MbChr 1: 75.22 – 75.24 Mb
PubMed search[3][4]
Wikidata
View/Edit HumanView/Edit Mouse

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.[6]

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.[7][8]

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),[9] which is required for enzymatic activity. These proteins thus fail to show enzymatic activity and their function remains unclear.[7] They could play role in insulin secretory pathways, sorting out proteins or regulates other PTPs.[10]

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.[11] 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.[7]

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.[12]

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).[13]

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.[14]

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.[15]

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.[14]

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.[13]

Interactions

PTPRN has been shown to interact with SPTBN4.[16]

References

  1. GRCh38: Ensembl release 89: ENSG00000054356 - Ensembl, May 2017
  2. GRCm38: Ensembl release 89: ENSMUSG00000026204 - Ensembl, May 2017
  3. "Human PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  4. "Mouse PubMed Reference:". National Center for Biotechnology Information, U.S. National Library of Medicine.
  5. Lan MS, Lu J, Goto Y, Notkins AL (May 1994). "Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma". DNA and Cell Biology. 13 (5): 505–514. doi:10.1089/dna.1994.13.505. PMID 8024693.
  6. "Entrez Gene: PTPRN protein tyrosine phosphatase, receptor type, N".
  7. Notkins AL, Lan MS, Leslie RD (March 1998). "IA-2 and IA-2beta: the immune response in IDDM". Diabetes/Metabolism Reviews. 14 (1): 85–93. doi:10.1002/(SICI)1099-0895(199803)14:1<85::AID-DMR205>3.0.CO;2-I. PMID 9605631.
  8. Lan MS, Lu J, Goto Y, Notkins AL (May 1994). "Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma". DNA and Cell Biology. 13 (5): 505–514. doi:10.1089/dna.1994.13.505. PMID 8024693.
  9. Notkins AL (November 2002). "Immunologic and genetic factors in type 1 diabetes". The Journal of Biological Chemistry. 277 (46): 43545–43548. doi:10.1074/jbc.R200012200. PMID 12270944.
  10. Torii S (2009). "Expression and function of IA-2 family proteins, unique neuroendocrine-specific protein-tyrosine phosphatases". Endocrine Journal. 56 (5): 639–648. doi:10.1507/endocrj.K09E-157. PMID 19550073. S2CID 12710545.
  11. Belhiba O, Aadam Z, Jeddane L, Saile R, Salih Alj H, Bousfiha AA, Jennane F (September 2020). "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. doi:10.4314/ahs.v20i3.40. PMC 7751543. PMID 33402983.
  12. Naserke HE, Ziegler AG, Lampasona V, Bonifacio E (December 1998). "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. doi:10.4049/jimmunol.161.12.6963. PMID 9862731. S2CID 46571282.
  13. In't Veld P, Lievens D, De Grijse J, Ling Z, Van der Auwera B, Pipeleers-Marichal M, et al. (September 2007). "Screening for insulitis in adult autoantibody-positive organ donors". Diabetes. 56 (9): 2400–2404. doi:10.2337/db07-0416. PMID 17563060. S2CID 2572529.
  14. Ilonen J, Hammais A, Laine AP, Lempainen J, Vaarala O, Veijola R, et al. (October 2013). "Patterns of β-cell autoantibody appearance and genetic associations during the first years of life". Diabetes. 62 (10): 3636–3640. doi:10.2337/db13-0300. PMC 3781470. PMID 23835325.
  15. Katsarou A, Gudbjörnsdottir S, Rawshani A, Dabelea D, Bonifacio E, Anderson BJ, et al. (March 2017). "Type 1 diabetes mellitus". Nature Reviews. Disease Primers. 3 (1): 17016. doi:10.1038/nrdp.2017.16. PMID 28358037. S2CID 23127616.
  16. Berghs S, Aggujaro D, Dirkx R, Maksimova E, Stabach P, Hermel JM, et al. (November 2000). "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. doi:10.1083/jcb.151.5.985. PMC 2174349. PMID 11086001.

Further reading

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