Phosphatase Subfamily PTPRN

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

Domain Structure

....

ectodomain has a ferredoxin-like fold [1, 2].

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

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