Disease relevance of PTPRN

• Islet cell Ag 512 (ICA512) is a recombinant human Ag that was isolated from an islet cDNA expression library by screening with human insulin-dependent diabetes mellitus sera [1].
• Following phage display characterization of ICA512 autoantigenic epitopes, we developed fluid phase autoantibody radioimmunoassays for a series of ICA512 fragments (F1 [amino acids (aa): 761-964], F2A [aa 256-760], F2B [aa 761-928], and F2C [aa 929-979]) [2].
• A novel 3.6-kb cDNA, IA-2, with a 2,937-bp open reading frame was isolated from a human insulinoma subtraction library (ISL-153) [3].
• The biotinylated cytoplasmic domain of IA-2 expressed in Escherichia coli was used as an antigen [4].
• Through this process, we have been able to identify preparations of GAD65 and IA-2, generated in insect cells using the baculovirus expression system, that stimulate relevant clones and display low inhibitory effects on third-party antigens [5].

High impact information on PTPRN

• Type 1, or insulin-dependent diabetes mellitus (IDDM) is an autoimmune disease associated with loss of tolerance to several pancreatic islet cell molecules, including insulin, glutamic acid decarboxylase (GAD), ICA69 and the tyrosine phosphatase IA-2 (refs 1-3) [6].
• We show that during fetal development and childhood, mRNAs for insulin and other islet cell autoantigens (GAD, ICA69, IA-2) are expressed at low levels in the human thymus [6].
• MAIN OUTCOME MEASURES: BCA was defined as elevated levels of insulin autoantibody, glutamic acid decarboxylase autoantibody, or insulinoma-associated islet tyrosine phosphatases autoantibody (IA-2) above the 99th percentile of 198 normal subjects [7].
• Immunoprecipitating IgG autoantibodies to glutamic acid decarboxylase, GAD65, and/or a tyrosine phosphatase, IA2, are present in the majority of individuals experiencing pancreatic beta cell destruction and development of type 1 diabetes [8].
• The 38-kD autoantigen, named glima 38, is an amphiphilic membrane glycoprotein, specifically expressed in islet and neuronal cell lines, and thus shares the neuroendocrine expression patterns of GAD65 and IA2 [8].

Chemical compound and disease context of PTPRN

• AIMS/HYPOTHESIS: The receptor tyrosine phosphatase like-protein ICA512/IA-2 occurs as a proteolytically-processed 65,000 Mr type 1 transmembrane glycoprotein in beta cells and is a major autoantigen of Type I (insulin-dependent) diabetes mellitus [9].
• AIMS/HYPOTHESIS: The majority of patients with Type I (insulin-dependent) diabetes mellitus has autoantibodies to insulin, glutamic acid decarboxylase and the tyrosine phosphatase-like protein IA-2 [10].
• METHODS: A sample of 2076 people aged 40 years or more participating in the population-based Cremona Study and classified in 1990 as having diabetes mellitus, impaired and normal glucose tolerance according to WHO criteria after an oral glucose tolerance test, were tested for antibodies to glutamic acid decarboxylase and IA-2 [11].
• Furthermore, we show that IA-2 is co-localised with serotonin in carcinoid tumours as well as in the pancreatic tumour cell line, BON1, which is interesting as serotonin secretion rate is presumably higher in tumour cells than in resting EC cells [12].
• Utility of ribotyping, restriction endonuclease analysis and pulsed-field gel electrophoresis to discriminate between isolates of Neisseria gonorrhoeae of serovar IA-2 which require arginine, hypoxanthine or uracil for growth [13].

Biological context of PTPRN

• 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 [14].
• Using a mouse protein tyrosine phosphatase cDNA fragment as a probe, cosmid clones containing segments of the human IA-2 PTPase gene (PTPRN) were isolated [14].
• IA-2 (islet cell antigen 512) is the primary target of humoral autoimmunity against type 1 diabetes-associated tyrosine phosphatase autoantigens [15].
• MATERIALS AND METHODS: To determine the proteins with which IA-2 interacts, a yeast two-hybrid system was used to screen a human foetal library, and deletion mutants were used to determine the binding sites [16].
• The physiological role(s) of these proteins remain poorly defined, although recent studies indicate that IA-2 may be involved in granule trafficking and exocytosis [17].

Anatomical context of PTPRN

• IA-2 is located in dense-core secretory vesicles and is involved in the regulation of insulin secretion [16].
• We show that ICA 512 is an intrinsic membrane protein of secretory granules expressed in insulin-producing pancreatic beta-cells as well as in virtually all other peptide-secreting endocrine cells and neurons containing neurosecretory granules [18].
• Here, we show that exocytosis of SGs and insertion of ICA512 in the plasma membrane promotes the Ca(2+)-dependent cleavage of ICA512 cytoplasmic domain by mu-calpain [19].
• ICA 512 is cleaved at its luminal domain and, following exposure at the cell surface, recycles to the Golgi complex region and is sorted into newly formed secretory granules [18].
• Northern blot analysis of poly(A)+ RNAs from several human tissues indicates that ICA512 mRNA is expressed in brain and pancreas [1].

Associations of PTPRN with chemical compounds

• These results indicate that the expression of ICA512/phogrin-A and cytoplasmic ICA is less in patients identified by urinary glucose testing but indicate that with combined autoantibody testing 90% of patients can be identified independent of the mode of diagnosis [20].
• 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 [21].
• Similarly to calpeptin, okadaic acid inhibits ICA512 proteolysis and insulin secretion [22].
• These findings indicate that glutamine at position 862, and residues 876-880 of the WPD loop of IA-2 are important for several of the IA-2 specific PTP domain epitopes [23].
• Both cleavage sites are immediately after an arginine residue at position 653 for IA-2 and position 679 for IA-2 beta [24].

Physical interactions of PTPRN

• The receptor tyrosine phosphatase-like protein ICA512 binds the PDZ domains of beta2-syntrophin and nNOS in pancreatic beta-cells [25].

Other interactions of PTPRN

• In the 17 relatives who developed type 1 diabetes, progression to disease was associated with reactivity to multiple IA-2/IA-2 beta epitopes [15].
• These data suggest that IA-2 is the primary phosphatase-like autoantigen associated with type 1 diabetes and that studying autoantibody epitope diversity may assist in disease prediction [15].
• Dephosphorylation of beta2-syntrophin and Ca2+/mu-calpain-mediated cleavage of ICA512 upon stimulation of insulin secretion [22].
• We report the identification of betaIV spectrin, a novel spectrin isolated as an interactor of the receptor tyrosine phosphatase-like protein ICA512 [26].
• This cleavage occurs at the plasma membrane and generates an ICA512 cytosolic fragment that is targeted to the nucleus, where it binds the E3-SUMO ligase protein inhibitor of activated signal transducer and activator of transcription-y (PIASy) and up-regulates insulin expression [19].

Analytical, diagnostic and therapeutic context of PTPRN

• By immunoprecipitation, anti-ICA 512 autoantibodies were detected in 15/17 (88%) newly diagnosed IDDM patients, but not in 10/10 healthy subjects [18].
• To permit quantitative and rapid serum testing, ICA512 was purified and adapted to an ELISA format [1].
• METHODS: Genomic and cDNA sequence analysis showed the presence of a ICA512 variant in islets and lymphoid tissues with an in-frame deletion of exon 13 which produces a secreted form lacking aa 557-629 including the transmembrane domain (aa 577 to 600) [9].
• BCG vaccination and GAD65 and IA-2 autoantibodies in autoimmune diabetes in southern India [27].
• Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma [3].

References