Difference between revisions of "Phosphatase Subfamily PTPRN"

Revision as of 05:51, 10 March 2015

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

PTPRN is a subfamily emerged in eumetazoan and duplicated in deuterostome. Human has two members, PTPRN (IA-2/ICA521) and PTPRN2 (phogrin), both of which are autoantigens of type I diabetes.

Evolution

PTPRN subfamily emerged in eumetazoan and duplicated in deuterostome.

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, a sheet of four antiparallel beta-strands packed against two alpha-helices [1, 2, 3]. Cytoplasmic region has a putative PEST motif, a PDZ domain, a phosphatase domain and another PDZ domain at the C terminus [4].

Functions

PTPRN subfamily is conserved in function as evidenced by studies in human, fruit fly and C. elegans. Both human PTPRN and PTPRN2 are autoantigens of type I diabetes. They are abundantly expressed in brain. They are expressed at limited level or even not expressed in other normal tissues. Human PTPRN and PTPRN2 have been proposed to be enzymatically inactive due to mutations at catalytic Cx5R motif and WPD motif [5]. However, PTPRN2 has been reported to be phosphatidylinositol phosphatase [6].

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 [7]. It is an autoantigen of type I diabetes and an intrinsic membrane protein of neurosecretory granules [8, 9]. 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 [10]. (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 [11].

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, 12].

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 [13].

PTPRN2 (IA-2beta/phogrin/ICAAR)

Phogrin is an additional major autoantigen for type I diabetes [14]. 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 [15] (also see GTEx).

IA-2 of fruit fly

Fruit fly IA-2 modules insulin expression. It was expressed in the central nervous system and midgut region. The neuronal expression pattern was very similar to that of IA-2 in mammals.

ida-1 of C. elegans

C. elegans ida-1 is involved in dense-core vesicle cargo release with parallels to insulin signaling in mammals [16, 17].

References

1. Error fetching PMID 18048354: [Primo08]
2. Error fetching PMID 21935384: [Primo11]
3. Error fetching PMID 25421040: [Noguera15]
4. Error fetching PMID 11483505: [Ort01]
5. Error fetching PMID 24064037: [Kharitidi13]
6. Error fetching PMID 20097759: [Caromile10]
7. Error fetching PMID 8144912: [Rabin94]
8. Error fetching PMID 8641276: [Solimena96]
9. Error fetching PMID 8798755: [Cui96]
10. Error fetching PMID 8024693: [Lan94]
11. Error fetching PMID 15596545: [Trajkovski04]
12. Error fetching PMID 11043403: [Ort00]
13. Error fetching PMID 11289059: [Diez01]
14. Error fetching PMID 8878534: [Kawasaki96]
15. Error fetching PMID 8954911: [Smith96]
16. Error fetching PMID 11086294: [Zahn01]
17. Error fetching PMID 15044551: [Cai04]
18. Error fetching PMID 15220191: [Kubosaki04]