ID   PTPR2_MACNE             Reviewed;        1013 AA.
AC   O02695;
DT   01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT   01-JUL-1997, sequence version 1.
DT   27-MAR-2024, entry version 129.
DE   RecName: Full=Receptor-type tyrosine-protein phosphatase N2;
DE            Short=R-PTP-N2;
DE            EC=3.1.3.-;
DE            EC=3.1.3.48;
DE   AltName: Full=M1851;
DE   Contains:
DE     RecName: Full=IA-2beta60;
DE   Flags: Precursor;
GN   Name=PTPRN2;
OS   Macaca nemestrina (Pig-tailed macaque).
OC   Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC   Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini;
OC   Cercopithecidae; Cercopithecinae; Macaca.
OX   NCBI_TaxID=9545;
RN   [1]
RP   NUCLEOTIDE SEQUENCE [MRNA], AND TISSUE SPECIFICITY.
RC   TISSUE=Pancreatic islet;
RX   PubMed=9100223; DOI=10.1007/bf03401670;
RA   Lagasse J., Jelinek L., Sexson S., Lofton-Day C.E., Breininger J.,
RA   Sheppard P., Kindsvogel W., Hagopian W.A.;
RT   "An islet-cell protein tyrosine phosphatase is a likely precursor to the
RT   37-kDa autoantigen in type 1 diabetes: human and macaque sequences, tissue
RT   distribution, unique and shared epitopes, and predictive autoantibodies.";
RL   Mol. Med. 3:163-173(1997).
CC   -!- FUNCTION: Plays a role in vesicle-mediated secretory processes.
CC       Required for normal accumulation of secretory vesicles in hippocampus,
CC       pituitary and pancreatic islets. Required for the accumulation of
CC       normal levels of insulin-containing vesicles and preventing their
CC       degradation. Plays a role in insulin secretion in response to glucose
CC       stimuli. Required for normal accumulation of the neurotransmitters
CC       norepinephrine, dopamine and serotonin in the brain. In females, but
CC       not in males, required for normal accumulation and secretion of
CC       pituitary hormones, such as luteinizing hormone (LH) and follicle-
CC       stimulating hormone (FSH). Required to maintain normal levels of renin
CC       expression and renin release. May regulate catalytic active protein-
CC       tyrosine phosphatases such as PTPRA through dimerization. Has
CC       phosphatidylinositol phosphatase activity; the PIPase activity is
CC       involved in its ability to regulate insulin secretion. Can
CC       dephosphorylate phosphatidylinositol 4,5-biphosphate,
CC       phosphatidylinositol 5-phosphate and phosphatidylinositol 3-phosphate.
CC       Regulates PI(4,5)P2 level in the plasma membrane and localization of
CC       cofilin at the plasma membrane and thus is indirectly involved in
CC       regulation of actin dynamics related to cell migration and metastasis;
CC       upon hydrolyzation of PI(4,5)P2 cofilin is released from the plasma
CC       membrane and acts in the cytoplasm in severing F-actin filaments.
CC       {ECO:0000250|UniProtKB:P80560, ECO:0000250|UniProtKB:Q63475,
CC       ECO:0000250|UniProtKB:Q92932}.
CC   -!- CATALYTIC ACTIVITY:
CC       Reaction=H2O + O-phospho-L-tyrosyl-[protein] = L-tyrosyl-[protein] +
CC         phosphate; Xref=Rhea:RHEA:10684, Rhea:RHEA-COMP:10136, Rhea:RHEA-
CC         COMP:10137, ChEBI:CHEBI:15377, ChEBI:CHEBI:43474, ChEBI:CHEBI:46858,
CC         ChEBI:CHEBI:82620; EC=3.1.3.48; Evidence={ECO:0000255|PROSITE-
CC         ProRule:PRU10044};
CC   -!- SUBUNIT: Self-associates. Interacts (via cytoplasmic domain) with PTPRN
CC       (via cytoplasmic domain). Interacts (precursor form) with CPE.
CC       Interacts with HAP1. Interacts with AP2A1 or AP2A2 and AP1G1;
CC       indicative for an association with adaptor protein complex 2 (AP-2) and
CC       adaptor protein complex 1 (AP-1). Interacts with AP2M1; indicative for
CC       an association with adaptor protein complex 2 (AP-2). Interacts with
CC       MYO5A. {ECO:0000250|UniProtKB:P80560, ECO:0000250|UniProtKB:Q63475}.
CC   -!- SUBCELLULAR LOCATION: Cytoplasmic vesicle, secretory vesicle membrane
CC       {ECO:0000250|UniProtKB:P80560}; Single-pass type I membrane protein
CC       {ECO:0000250|UniProtKB:P80560}. Cytoplasmic vesicle, secretory vesicle,
CC       synaptic vesicle membrane {ECO:0000250|UniProtKB:P80560}; Single-pass
CC       type I membrane protein {ECO:0000250|UniProtKB:P80560}.
CC       Note=Predominantly found on dense-core secretory granules. Sorting to
CC       secretory granules in part is dependent of the N-terminal propeptide
CC       domain of the precursor and its interaction with CPE. Transiently found
CC       at the cell membrane, when secretory vesicles fuse with the cell
CC       membrane to release their cargo. Is then endocytosed and recycled to
CC       secretory vesicles involving clathrin-dependent AP2-mediated
CC       endocytosis. Recycled via STX6- but not TTTGN1/TGN38-containing
CC       compartments. {ECO:0000250|UniProtKB:P80560,
CC       ECO:0000250|UniProtKB:Q63475}.
CC   -!- TISSUE SPECIFICITY: Detected in pancreatic islets and adrenal medulla.
CC       {ECO:0000269|PubMed:9100223}.
CC   -!- DOMAIN: The tyrosine-based internalization signal is proposed to
CC       function in clathrin-mediated endocytosis and recycling.
CC       {ECO:0000250|UniProtKB:Q63475}.
CC   -!- DOMAIN: The leucine-based sorting signal is proposed to function in
CC       trafficking at the plasma membrane. {ECO:0000250|UniProtKB:P80560}.
CC   -!- PTM: Subject to proteolytic cleavage at multiple sites.
CC       {ECO:0000250|UniProtKB:P80560}.
CC   -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC       Receptor class 8 subfamily. {ECO:0000305}.
CC   -!- CAUTION: Has no tyrosine-protein phosphatase activity at mild acidic
CC       conditions (pH 5.5). The in vivo relevance of the low PPase activity
CC       for the human protein at acidic conditions (pH 4.5) is questioned. This
CC       catalytic activity seems to be affected by the replacement of a highly
CC       conserved residue in the tyrosine-protein phosphatase domain.
CC       {ECO:0000305}.
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DR   EMBL; U91574; AAC51186.1; -; mRNA.
DR   RefSeq; NP_001292849.1; NM_001305920.1.
DR   AlphaFoldDB; O02695; -.
DR   SMR; O02695; -.
DR   STRING; 9545.ENSMNEP00000016459; -.
DR   GlyCosmos; O02695; 1 site, No reported glycans.
DR   GeneID; 105474981; -.
DR   KEGG; mni:105474981; -.
DR   CTD; 5799; -.
DR   OrthoDB; 2911650at2759; -.
DR   Proteomes; UP000233120; Whole Genome Shotgun Assembly.
DR   Proteomes; UP000694946; Unplaced.
DR   GO; GO:0030667; C:secretory granule membrane; ISS:UniProtKB.
DR   GO; GO:0030672; C:synaptic vesicle membrane; ISS:UniProtKB.
DR   GO; GO:0004725; F:protein tyrosine phosphatase activity; IEA:UniProtKB-EC.
DR   GO; GO:0016311; P:dephosphorylation; IEA:InterPro.
DR   GO; GO:0035773; P:insulin secretion involved in cellular response to glucose stimulus; ISS:UniProtKB.
DR   GO; GO:0006629; P:lipid metabolic process; IEA:UniProtKB-KW.
DR   GO; GO:0007269; P:neurotransmitter secretion; ISS:UniProtKB.
DR   CDD; cd14610; R-PTP-N2; 1.
DR   Gene3D; 3.90.190.10; Protein tyrosine phosphatase superfamily; 1.
DR   Gene3D; 3.30.70.2470; Protein-tyrosine phosphatase receptor IA-2 ectodomain; 1.
DR   InterPro; IPR033522; IA-2/IA-2_beta.
DR   InterPro; IPR029021; Prot-tyrosine_phosphatase-like.
DR   InterPro; IPR000242; PTP_cat.
DR   InterPro; IPR021613; Receptor_IA-2_dom.
DR   InterPro; IPR038112; Receptor_IA-2_ectodomain_sf.
DR   InterPro; IPR029403; RESP18_dom.
DR   InterPro; IPR016130; Tyr_Pase_AS.
DR   InterPro; IPR003595; Tyr_Pase_cat.
DR   InterPro; IPR000387; Tyr_Pase_dom.
DR   PANTHER; PTHR46106; IA-2 PROTEIN TYROSINE PHOSPHATASE, ISOFORM C; 1.
DR   PANTHER; PTHR46106:SF5; RECEPTOR-TYPE TYROSINE-PROTEIN PHOSPHATASE N2; 1.
DR   Pfam; PF11548; Receptor_IA-2; 1.
DR   Pfam; PF14948; RESP18; 1.
DR   Pfam; PF00102; Y_phosphatase; 1.
DR   PRINTS; PR00700; PRTYPHPHTASE.
DR   SMART; SM00194; PTPc; 1.
DR   SMART; SM00404; PTPc_motif; 1.
DR   SMART; SM01305; RESP18; 1.
DR   SUPFAM; SSF52799; (Phosphotyrosine protein) phosphatases II; 1.
DR   PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR   PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
DR   PROSITE; PS50055; TYR_PHOSPHATASE_PTP; 1.
PE   2: Evidence at transcript level;
KW   Acetylation; Cytoplasmic vesicle; Glycoprotein; Hydrolase;
KW   Lipid metabolism; Membrane; Phospholipid metabolism; Phosphoprotein;
KW   Protein phosphatase; Receptor; Reference proteome; Signal; Synapse;
KW   Transmembrane; Transmembrane helix.
FT   SIGNAL          1..19
FT                   /evidence="ECO:0000255"
FT   CHAIN           20..1013
FT                   /note="Receptor-type tyrosine-protein phosphatase N2"
FT                   /id="PRO_0000025455"
FT   CHAIN           500..1013
FT                   /note="IA-2beta60"
FT                   /evidence="ECO:0000250|UniProtKB:P80560"
FT                   /id="PRO_0000438069"
FT   TOPO_DOM        20..613
FT                   /note="Extracellular"
FT                   /evidence="ECO:0000255"
FT   TRANSMEM        614..634
FT                   /note="Helical"
FT                   /evidence="ECO:0000255"
FT   TOPO_DOM        635..1013
FT                   /note="Cytoplasmic"
FT                   /evidence="ECO:0000255"
FT   DOMAIN          743..1003
FT                   /note="Tyrosine-protein phosphatase"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00160"
FT   REGION          1..419
FT                   /note="Involved in localization to secretory granules;
FT                   interaction with CPE"
FT                   /evidence="ECO:0000250|UniProtKB:P80560"
FT   REGION          116..137
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          273..302
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          342..382
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          401..487
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   REGION          673..717
FT                   /note="Disordered"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   MOTIF           664..673
FT                   /note="Tyrosine-based internalization motif"
FT                   /evidence="ECO:0000250|UniProtKB:Q63475"
FT   MOTIF           1002..1008
FT                   /note="Leucine-based sorting signal"
FT                   /evidence="ECO:0000250|UniProtKB:P80560"
FT   COMPBIAS        276..294
FT                   /note="Pro residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        418..434
FT                   /note="Basic and acidic residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        437..456
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   COMPBIAS        685..717
FT                   /note="Polar residues"
FT                   /evidence="ECO:0000256|SAM:MobiDB-lite"
FT   ACT_SITE        943
FT                   /note="Phosphocysteine intermediate"
FT                   /evidence="ECO:0000255|PROSITE-ProRule:PRU00160,
FT                   ECO:0000255|PROSITE-ProRule:PRU10044"
FT   BINDING         911
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         943..949
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   BINDING         988
FT                   /ligand="substrate"
FT                   /evidence="ECO:0000250"
FT   SITE            425..426
FT                   /note="Cleavage"
FT                   /evidence="ECO:0000250"
FT   MOD_RES         434
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P80560"
FT   MOD_RES         435
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:P80560"
FT   MOD_RES         690
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q63475"
FT   MOD_RES         696
FT                   /note="Phosphoserine"
FT                   /evidence="ECO:0000250|UniProtKB:Q63475"
FT   MOD_RES         968
FT                   /note="N6-acetyllysine"
FT                   /evidence="ECO:0000250|UniProtKB:Q92932"
FT   CARBOHYD        562
FT                   /note="N-linked (GlcNAc...) asparagine"
FT                   /evidence="ECO:0000255"
SQ   SEQUENCE   1013 AA;  111191 MW;  4808D43937A2EF59 CRC64;
     MALPLLLLLL LLLPPRVLPA APSSVPHGRQ LPGRLGCLLE EGLCGASEAC VNDGVFGRCQ
     KVPAMDFYRY EVSPVALQRL RVALQKLSGT GFTWQDDYTQ YVMDQELADL PKTYLRHPEA
     SGPARPSKHS IGSERRYSQE GGAALAKAFR RHLPFLEALS QAPASDALAR TRMAQDRPRA
     EGDDRFSKSI LTYVAHTSVL TYPPGPQAQL PEDLLPRTLS QLQPDELSPK VDSSVERHHL
     MAALSAYAAQ RPPAPPGKGS LEPQYLLRAP SRMPRPLLSP AVPQKWPSPL GDPEDPPSTG
     EGARIHTLLK DLQRQPAEAR GLSDLELDSM AELMAGLMQG MDHRGALGGP GKAALGESGE
     QADGPKAALR GESFPDDGVQ DDDDRLYQEV HRLSATLGGL LQDHGSRLSP GALPFAKPLK
     MERKKSERPE ASLSSEEETA GVENVKSQTY SKDLLGQQPH SEPGAGAFGE LQNQMPGPSE
     EEQSLPAGAQ EALGDGLQLE VKPSEEEARG YIVTDRDPLR PEEGRQLVED VARLLQMPSS
     TFADVEVLGP AVTFKVGANV QNVTTADVEK ATVDNKDKLE ETSGLKILQT GVGSKSKLKF
     LPPQAEQEDS TKFIALTLVS LACILGVLLA SGLIYCLRHS SQHRLKEKLS GLGRDPGADA
     TAAYQELCRQ RMATRPPDRP EGPHTSRISS VSSQFSDGPM PSPSARSSAS SWSEEPVQSN
     MDISTGHMIL SYMEDHLKNK NRLEKEWEAL CAYQAEPNSS LVAQKEENVP KNRSLAVLTY
     DHSRVLLKAE NSHSHSDYIN ASPIMDHDPR NPAYIATQGP LPATVADFWQ MVWESGCVVI
     VMLTPLTENG VRQCYHYWPD EGSNLYHIYE VNLVSEHIWC EDFLVRSFYL KNLQTNETRT
     VTQFHFLSWY DRGVPSSSRS LLDFRRKVNK CYRGRSCPII VHCSDGAGRS GTYVLIDMVL
     NKMAKGAKEI DIAATLEHLR DQRPGMVQTK EQFEFALTAV AEEVNAILKA LPQ
//