PTPRN2 (IA-2beta, phogrin) is a single-pass type I transmembrane protein of the dense-core secretory granules of neuroendocrine cells and neurons, and is also found on synaptic vesicles. It has a luminal IA-2 domain and a cytoplasmic receptor-type protein-tyrosine-phosphatase-like domain. That domain has no detectable activity on phosphoprotein substrates, but in the rat ortholog it hydrolyses phosphoinositides, including PI(4,5)P2 and PI(3)P, by a catalytic-cysteine-dependent mechanism. Through this activity and its granule-membrane role, PTPRN2 maintains dense-core granule number and regulates stimulus-coupled secretion of insulin and of neurotransmitters. This horse product (A0A9L0T4W6, 976 aa) is one of eight Ensembl/UniProt models of the horse PTPRN2 gene. It uses an alternative terminal exon that replaces the last 37 residues of the phosphatase-like domain, and the cytoplasmic C-terminus, with 56 non-conserved residues, so the catalytic competence of this exact product is untested.
Summary: Electronic transfer of protein-tyrosine phosphatase activity from the PTP-domain signature. The PTPRN2 subfamily (PANTHER PTHR46106:SF5) has lost this activity; the rat and human orthologs show no activity on phosphoprotein or pNPP substrates.
Reason: The domain-signature mapping (InterPro IPR000242, EC 3.1.3.48) assumes canonical PTP catalysis. The rat ortholog phogrin, in the same PANTHER subfamily (PTHR46106:SF5), shows no detectable activity against phosphoproteins or pNPP. Human PTPRN2 work states the same, attributing it to substitutions in the PTP domain. Its demonstrated substrates are phosphoinositides, covered by the MODIFY of the hydrolase row below. The benchmark horse model also lacks the conserved C-terminal end of the domain. Protein-tyrosine dephosphorylation is not supported for this gene product.
PTPRN2 belongs to the protein tyrosine phosphatase family, but does not exhibit activity against phosphoprotein substrates due to several critical amino acid variations in the PTP domain (Magistrelli et al, 1996).
In the absence of detectable ability to dephosphorylate phosphoproteins or p -nitrophenyl phosphate (pNPP), it has been suggested that phogrin and the closely related DCV protein IA-2 may function as a dominant negatives
In A0A9L0T4W6 only the first 15 of those residues (TYVLIDMVLNKMAKG) are retained; the remaining 47 conserved residues are replaced by 56 unrelated residues
GO:0008138 protein tyrosine/serine/threonine phosphatase activity
IEA GO_REF:0000104
REMOVE
Summary: UniRule transfer of dual-specificity protein phosphatase activity. No PTPRN2 ortholog has shown activity on any phosphoprotein substrate, so this is a stronger version of the unsupported protein-tyrosine phosphatase claim.
Reason: Same basis as the protein-tyrosine phosphatase row. The PTPRN2 subfamily is defined by the loss of phosphoprotein phosphatase activity. The rat ortholog, assayed directly, dephosphorylates phosphoinositides but not phosphoproteins or pNPP. Nothing supports activity on phosphoserine or phosphothreonine. The UniRule rule over-propagates a generic PTP-fold activity to a subfamily that has diverged from it.
In the absence of detectable ability to dephosphorylate phosphoproteins or p -nitrophenyl phosphate (pNPP), it has been suggested that phogrin and the closely related DCV protein IA-2 may function as a dominant negatives
PTPRN2 belongs to the protein tyrosine phosphatase family, but does not exhibit activity against phosphoprotein substrates due to several critical amino acid variations in the PTP domain (Magistrelli et al, 1996).
Summary: True for the gene but uninformative. The PTPRN2 ortholog hydrolyses phosphoinositide monoesters, so the specific activity is phosphatidylinositol phosphate phosphatase activity.
Reason: The specific hydrolase activity of the PTPRN2 subfamily is known. Rat phogrin (Ptprn2, Q63475, same PANTHER subfamily PTHR46106:SF5 as this horse protein) dephosphorylates PI(3)P, PI(5)P and PI(4,5)P2 but not PI(3,4,5)P3. The activity depends on the catalytic cysteine and is about 75-fold higher in the purified full-length transmembrane protein than in the isolated catalytic domain. GO:0052866 phosphatidylinositol phosphate phosphatase activity is an is_a descendant of hydrolase activity; it is broad enough not to assert one phosphate-position specificity. The transfer is a gene-level, subfamily-level transfer. The benchmark horse model retains the catalytic cysteine loop (HCSDGAGRSG), but its non-conserved C-terminal exon removes the end of the domain, so this exact product is not established to be active.
We report here that phogrin is able to dephosphorylate specific inositol phospholipids, including phosphatidylinositol (PI) 3-phosphate and PI 4,5-diphosphate but not PI 3,4,5-trisphosphate.
Summary: Correct but general. PTPRN2 is an integral membrane protein of dense-core secretory granules, so the precise location is dense core granule membrane.
Reason: The IA-2/IA-2beta family signature (IPR033522) correctly places the protein on secretory granules. Ortholog data are more specific. Rat phogrin is on the membrane of insulin-containing dense-core vesicles, and mouse IA-2beta is described as a dense-core vesicle transmembrane protein. The horse protein keeps the signal peptide and the single transmembrane helix (Phobius 568-592). GO:0032127 dense core granule membrane is a part_of descendant of secretory granule, via secretory granule membrane.
Phogrin is a transmembrane protein expressed in cells with stimulus-coupled peptide hormone secretion, including pancreatic beta cells, in which it is localized to the membrane of insulin-containing dense-core vesicles.
Summary: General term from the UniProt subcellular-location mapping. Of the PTPRN2 compartments, only the synaptic vesicle membrane falls under transport vesicle membrane in GO, and mouse IA-2beta co-fractionates with synaptic vesicles.
Reason: In GO, the dense-core (secretory) granule membrane is not a descendant of transport vesicle membrane, but synaptic vesicle membrane (GO:0030672) is. Mouse IA-2beta (Ptprn2) co-purifies with synaptic-vesicle-rich fractions and is described as present in both dense-core and synaptic vesicles. The human ortholog already carries GO:0030672 by ISS/IEA from mouse. The specific transport-vesicle location supported for the gene is therefore the synaptic vesicle membrane. The main location, the dense core granule membrane, is captured by the MODIFY of the secretory granule row.
Summary: Correct but general. The synaptic location supported for PTPRN2 is the synaptic vesicle membrane.
Reason: The synaptic localisation of PTPRN2 rests on mouse IA-2beta co-fractionating with synaptic vesicles. In the same experiments, deleting IA-2 and IA-2beta reduced synaptosomal neurotransmitter release and synaptic vesicle number. GO:0030672 synaptic vesicle membrane is a descendant of synapse and states the compartment precisely. It is the same replacement as for the transport vesicle membrane row.
Phosphatidylinositol phosphate phosphatase of the dense-core granule membrane. The cytoplasmic PTP-like domain dephosphorylates phosphoinositides such as PI(4,5)P2 and PI(3)P, using the catalytic cysteine of its CX5R loop, rather than phosphoproteins. Inferred for horse PTPRN2 from the rat ortholog (same PANTHER subfamily, PTHR46106:SF5). The benchmark model keeps the catalytic loop but has a non-conserved C-terminal exon.
We report here that phogrin is able to dephosphorylate specific inositol phospholipids, including phosphatidylinositol (PI) 3-phosphate and PI 4,5-diphosphate but not PI 3,4,5-trisphosphate.
The PIPase activity of phogrin depended on the catalytic site cysteine and correlated with effects on glucose-stimulated insulin secretion.
Regulates stimulus-coupled secretion from dense-core granules and synaptic vesicles. Granule PTPRN2 is needed to maintain the number and half-life of insulin-containing dense-core granules. Its loss in mouse lowers insulin content and glucose-stimulated insulin secretion, and the catalytic cysteine is required for its effect on insulin secretion.
Q: Is the horse PTPRN2-208 transcript (ENSECAT00000094767), with its alternative terminal exon, expressed in any horse tissue, or is it a gene-build artifact?
Q: Does the C-terminal end of the PTPRN2 phosphatase-like domain, which this model replaces, affect folding or phosphoinositide phosphatase activity?
Suggested Experiments
Experiment: Express full-length horse A0A9L0T4W6 and canonical A0A9L0RAE3, each with a catalytic-cysteine-to-serine mutant, in HEK293 or INS-1 cells. Compare plasma-membrane PI(4,5)P2 levels and purified-protein PIPase activity, as in the rat phogrin assays.
Type: in vitro enzymology and cell-based PI(4,5)P2 imaging
Experiment: Use RT-PCR or long-read sequencing of horse pancreatic islet and brain RNA to test whether the alternative terminal exon used by A0A9L0T4W6 is present in real transcripts.
Type: transcript structure validation
External Prediction Reviews
These computational predictions are reviewed separately from the GOA annotation set used for this review. The assessments below are from this project and do not constitute official GO annotations or endorsement by GO/UniProt. They are not included in the existing annotation review above.
Protein dephosphorylation is over-propagated to horse PTPRN2 from a receptor-type protein-tyrosine-phosphatase-like fold; mammalian PTPRN2 is a pseudophosphatase whose demonstrated catalytic activity is lipid dephosphorylation, not GO:0006470 protein dephosphorylation.
Prediction method: ProtNLM2 Β· Version: UniProt API snapshot 2026-09-08
PSEUDOENZYME OVERANNOTATION
Review rationale: GO:0006470 asserts that PTPRN2 itself takes part in removing phosphate from proteins. PTPRN2 (IA-2beta/phogrin) is an IA-2 family pseudophosphatase (PANTHER PTHR46106:SF5) with no detectable activity on phosphoprotein or pNPP substrates. Its only demonstrated intrinsic catalytic activity, shown for the rat ortholog in the same subfamily, is dephosphorylation of phosphoinositide lipids. That is a different substrate class and supports phosphatidylinositol phosphate phosphatase activity, not protein dephosphorylation. The horse and human gene reviews remove the protein tyrosine phosphatase activity rows and the human GO:0006470 row on these grounds. Reported protein-directed effects are indirect. Phogrin protects PTP1B from oxidation and so allows PTP1B to dephosphorylate the insulin receptor, and a correlative cancer study proposes that PTPRN2 promotes STAT1 dephosphorylation without identifying an enzyme. At most these would support regulation of protein dephosphorylation, in which another phosphatase does the work. The horse model also lacks the conserved C-terminal end of the PTP-like domain. The prediction transfers a PTP-fold process to a pseudophosphatase and is refuted.
Supporting Evidence:
PMID:26620550: "PTPRN2 belongs to the protein tyrosine phosphatase family, but does not exhibit activity against phosphoprotein substrates due to several critical amino acid variations in the PTP domain (Magistrelli etΒ al, 1996)."
PMID:26620550: "Recently, PTPRN2 was found to exhibit phosphatidylinositol phosphatase (PIP) activity against PI(4,5)P2 and, to a lesser extent, PI3P"
PMID:20097759: "In the absence of detectable ability to dephosphorylate phosphoproteins or p -nitrophenyl phosphate (pNPP), it has been suggested that phogrin and the closely related DCV protein IA-2 may function as a dominant negatives"
PMID:29483197: "protected recombinant PTP1B from oxidation to potentiate its activity toward the IR"
PMID:42139752: "PTPRN2 may promote STAT1 Y701 dephosphorylation and inhibit STAT1 activation"
file:HORSE/PTPRN2/PTPRN2-bioinformatics/RESULTS.md: "The selected horse sequence has a divergent C-terminal region, including deletion of human residues 989β1003 within the annotated phosphatase domain. The N-terminal signal sequence and transmembrane segment are retained. Substrate-specific enzymatic activity requires more than the global homology assignment."
file:HORSE/PTPRN2/PTPRN2-hypotheses/horse40-protein-dephosphorylation/openscientist.md: "Horse A0A9L0T4W6 is the ortholog of human **PTPRN2 (IA-2Ξ² / phogrin)** ... Across multiple independent biochemical studies the wild-type IA-2 family PTP-like domain has **no activity against conventional (protein/phosphotyrosine) substrates** ... The **only demonstrated intrinsic catalytic activity** of phogrin/PTPRN2 is toward **phosphoinositide lipids**"