Phosphatase Subfamily PTPRN

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

PTPRN is a receptor lipid phosphatase family involved in secretion in neuronal and endocrine tissues, including insulin release.

Evolution

PTPRN subfamily is found across metazoans, with no obvious losses. Human has two members, PTPRN (IA-2/ICA521) and PTPRN2 (phogrin/IA-2b).

Domain Structure

PTPRN has a extracellular region, a transmembrane domain and a cytoplasmic region. The extracellular region contains an N-terminal RESP18 domain and a membrane-proximal a ferredoxin-like fold domain also known as Receptor_IA-2 [1, 2, 3]. One of two C. elegans homologs lacks the signal peptide and extracellular domain homology, which may phenocopy the proteolytic cleavage of the cytoplasmic region seen in mammalian PTPRNs.

The cytoplasmic region of PTPRN has a putative PEST motif, followed by a phosphatase domain flanked by two short regions required to bind the β2‐syntrophin PDZ domain [4].

Functions

Human PTPRN and PTPRN2 are expressed in pancreatic beta cells and were first characterized as autoantigens leading to type I diabetes. They are also abundantly expressed in brain. They cycle between secretory vesicles and the plasma membrane and are believed to be involved in both endocrine and neuronal exocytosis [5].

Both proteins have alterations to key residues in the phosphatase domain and lack phosphatase activity against PNPP or protein substrates. Back mutation of D936A within the Cx5R motif of rat PTPRN2 restored some catalytic function against PNPP [6], and additional mutations to restore the Y of the KNRY motif, and the P and D of the WPD motif further increased PNPP activity in mouse PTPRN (H740Y/A877D/D911A) or PTPRN2 (S762Y/Y898P/D933A) [7]. Rat PTPRN2 has been reported to act as a phosphatidylinositol phosphatase [8], so these alterations to conserved motifs may play a role in substrate specificity rather than catalytic activity.

PTPRN (IA-2/ICA512)

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 [9]. It is an autoantigen of type I diabetes and an intrinsic membrane protein of neurosecretory granules [10, 11]. 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 [12]. (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 [13].

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 [4, 14].

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 [15].

PTPRN2 (IA-2beta/phogrin/ICAAR)

PTPRN2 (Phogrin) is an additional major autoantigen for type I diabetes [16]. In patients with type 1 diabetes, autoantibodies to IA-2beta appear years before the development of clinical disease []. PTPRN2 was found in human brain, pituitary and pancreas, but not or at very low level in a variety of other normal or tumor tissues [17] (also see GTEx). But, its immature isoform proPTPRN2 is overexpressed in various cancers, including breast cancer. High proPTPRN2 expression was associated strongly with lymph node-positive breast cancer and poor clinical outcome [18].

Drosophila IA-2

IA-2 modulates insulin-like peptide expression expression and is expressed in the central nervous system and midgut [19]. The neuronal expression pattern was very similar to that mammalian PTPRN.

C. elegans ida-1

ida-1 is involved in dense-core vesicle cargo release with parallels to insulin signaling in mammals [20, 21].

References

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