Phosphatase Subfamily PTPRN

Phosphatase Classification: Fold CC1: Superfamily CC1: Family PTP: Subfamily PTPRN

Domain Structure

PTPRN has a extracellular region, a transmembrane domain and a cytoplasmic region. Part of the extracellular region has crystal structure, which has a ferredoxin-like fold [1, 2]. Cytoplasmic region has a putative PEST motif, a PDZ domain, a phosphatase domain and another PDZ domain at the C terminus [].

Functions

Both human PTPRN and PTPRN2 are abundantly expressed in brain. It is expressed at limited level or even not expressed in other normal tissues [] (see GTEx PTPRN2.

PTPRN (IA-2/ICA512)

PTPRN is an enzymatically inactive due to mutations at catalytic and WPD motifs (???? reference).

PTPRN, aka IA-2 or ICA512 (Islet cell antigen 512), was first isolated from an islet cDNA expression library by screening with human insulin-dependent diabetes mellitus sera [3]. It is an autoantigen of type I diabetes and an intrinsic membrane protein of neurosecretory granules [4, 5]. PTPRN was found in normal human brain, pituitary, pancreas, and brain tumor cell lines, but not in a variety of other normal or tumor tissues [6]. (note: the tissue expression is supported by RNA-seq data from GTEx project).

PTPRN associates with the secretory granules (SGs) of neuroendocrine cells including pancreatic beta-cells. The exocytosis of SGs and insertion of PTPRN in the plasma membrane promotes the calcium-dependent cleavage of PTPRN cytoplasmic domain by mu-calpain, a calcium-dependent, non-lysosomal cysteine proteases (proteolytic enzymes). The cleavage occurs at the plasma membrane and generates an PTPRN 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 [7].

Meanwhile, PTPRN binds beta2-syntrophin, a modular adapter interacts with proteins in actin cytoskeleton (e.g. utrophin). The association is mediated by PTPRN cytoplasmic region (663-700) and beta2-syntrophin PDZ domain. In vitro mu-calpain cleaves PTPRN at the site within the region mediates PTPRN binding to beta2-syntrophin [8, 9].

Alternative splicing determines differential PTPRN expression in islets compared with thymus and spleen. Islets express full-length mRNA and two alternatively spliced transcripts, whereas thymus and spleen exclusively express an alternatively spliced transcript lacking exon 13. This difference in splicing may play a permissive role in the development of autoimmune responses to PTPRN [10].

References

1. Primo ME, Klinke S, Sica MP, Goldbaum FA, Jakoncic J, Poskus E, and Ermácora MR. Structure of the mature ectodomain of the human receptor-type protein-tyrosine phosphatase IA-2. J Biol Chem. 2008 Feb 22;283(8):4674-81. DOI:10.1074/jbc.M708144200 |
2. Primo ME, Jakoncic J, Noguera ME, Risso VA, Sosa L, Sica MP, Solimena M, Poskus E, and Ermácora MR. Protein-protein interactions in crystals of the human receptor-type protein tyrosine phosphatase ICA512 ectodomain. PLoS One. 2011;6(9):e24191. DOI:10.1371/journal.pone.0024191 |
3. Rabin DU, Pleasic SM, Shapiro JA, Yoo-Warren H, Oles J, Hicks JM, Goldstein DE, and Rae PM. Islet cell antigen 512 is a diabetes-specific islet autoantigen related to protein tyrosine phosphatases. J Immunol. 1994 Mar 15;152(6):3183-8.
4. Solimena M, Dirkx R Jr, Hermel JM, Pleasic-Williams S, Shapiro JA, Caron L, and Rabin DU. ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane protein of neurosecretory granules. EMBO J. 1996 May 1;15(9):2102-14.
5. Cui L, Yu WP, DeAizpurua HJ, Schmidli RS, and 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. J Biol Chem. 1996 Oct 4;271(40):24817-23.
6. Lan MS, Lu J, Goto Y, and Notkins AL. Molecular cloning and identification of a receptor-type protein tyrosine phosphatase, IA-2, from human insulinoma. DNA Cell Biol. 1994 May;13(5):505-14. DOI:10.1089/dna.1994.13.505 |
7. Trajkovski M, Mziaut H, Altkrüger A, Ouwendijk J, Knoch KP, Müller S, and Solimena M. Nuclear translocation of an ICA512 cytosolic fragment couples granule exocytosis and insulin expression in {beta}-cells. J Cell Biol. 2004 Dec 20;167(6):1063-74. DOI:10.1083/jcb.200408172 |
8. Ort T, Maksimova E, Dirkx R, Kachinsky AM, Berghs S, Froehner SC, and Solimena M. The receptor tyrosine phosphatase-like protein ICA512 binds the PDZ domains of beta2-syntrophin and nNOS in pancreatic beta-cells. Eur J Cell Biol. 2000 Sep;79(9):621-30. DOI:10.1078/0171-9335-00095 |
9. Ort T, Voronov S, Guo J, Zawalich K, Froehner SC, Zawalich W, and Solimena M. Dephosphorylation of beta2-syntrophin and Ca2+/mu-calpain-mediated cleavage of ICA512 upon stimulation of insulin secretion. EMBO J. 2001 Aug 1;20(15):4013-23. DOI:10.1093/emboj/20.15.4013 |
10. Diez J, Park Y, Zeller M, Brown D, Garza D, Ricordi C, Hutton J, Eisenbarth GS, and Pugliese A. 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. 2001 Apr;50(4):895-900. DOI:10.2337/diabetes.50.4.895 |