PTPRN_HUMAN
ID PTPRN_HUMAN Reviewed; 979 AA.
AC Q16849; B4DK12; F5GZS3; Q08319; Q53QD6; Q6NSL1;
DT 01-NOV-1997, integrated into UniProtKB/Swiss-Prot.
DT 01-NOV-1997, sequence version 1.
DT 03-AUG-2022, entry version 193.
DE RecName: Full=Receptor-type tyrosine-protein phosphatase-like N;
DE Short=R-PTP-N;
DE AltName: Full=Islet cell antigen 512 {ECO:0000303|PubMed:8144912};
DE Short=ICA 512 {ECO:0000303|PubMed:8641276};
DE AltName: Full=Islet cell autoantigen 3;
DE AltName: Full=PTP IA-2;
DE Contains:
DE RecName: Full=ICA512-N-terminal fragment;
DE Short=ICA512-NTF;
DE Contains:
DE RecName: Full=ICA512-transmembrane fragment;
DE Short=ICA512-TMF;
DE Contains:
DE RecName: Full=ICA512-cleaved cytosolic fragment;
DE Short=ICA512-CCF;
DE Flags: Precursor;
GN Name=PTPRN; Synonyms=ICA3, ICA512;
OS Homo sapiens (Human).
OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia;
OC Eutheria; Euarchontoglires; Primates; Haplorrhini; Catarrhini; Hominidae;
OC Homo.
OX NCBI_TaxID=9606;
RN [1]
RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 1), AND TISSUE SPECIFICITY.
RC TISSUE=Insulinoma;
RX PubMed=8024693; DOI=10.1089/dna.1994.13.505;
RA Lan M.S., Lu J., Goto Y., Notkins A.L.;
RT "Molecular cloning and identification of a receptor-type protein tyrosine
RT phosphatase, IA-2, from human insulinoma.";
RL DNA Cell Biol. 13:505-514(1994).
RN [2]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 3).
RC TISSUE=Thalamus;
RX PubMed=14702039; DOI=10.1038/ng1285;
RA Ota T., Suzuki Y., Nishikawa T., Otsuki T., Sugiyama T., Irie R.,
RA Wakamatsu A., Hayashi K., Sato H., Nagai K., Kimura K., Makita H.,
RA Sekine M., Obayashi M., Nishi T., Shibahara T., Tanaka T., Ishii S.,
RA Yamamoto J., Saito K., Kawai Y., Isono Y., Nakamura Y., Nagahari K.,
RA Murakami K., Yasuda T., Iwayanagi T., Wagatsuma M., Shiratori A., Sudo H.,
RA Hosoiri T., Kaku Y., Kodaira H., Kondo H., Sugawara M., Takahashi M.,
RA Kanda K., Yokoi T., Furuya T., Kikkawa E., Omura Y., Abe K., Kamihara K.,
RA Katsuta N., Sato K., Tanikawa M., Yamazaki M., Ninomiya K., Ishibashi T.,
RA Yamashita H., Murakawa K., Fujimori K., Tanai H., Kimata M., Watanabe M.,
RA Hiraoka S., Chiba Y., Ishida S., Ono Y., Takiguchi S., Watanabe S.,
RA Yosida M., Hotuta T., Kusano J., Kanehori K., Takahashi-Fujii A., Hara H.,
RA Tanase T.-O., Nomura Y., Togiya S., Komai F., Hara R., Takeuchi K.,
RA Arita M., Imose N., Musashino K., Yuuki H., Oshima A., Sasaki N.,
RA Aotsuka S., Yoshikawa Y., Matsunawa H., Ichihara T., Shiohata N., Sano S.,
RA Moriya S., Momiyama H., Satoh N., Takami S., Terashima Y., Suzuki O.,
RA Nakagawa S., Senoh A., Mizoguchi H., Goto Y., Shimizu F., Wakebe H.,
RA Hishigaki H., Watanabe T., Sugiyama A., Takemoto M., Kawakami B.,
RA Yamazaki M., Watanabe K., Kumagai A., Itakura S., Fukuzumi Y., Fujimori Y.,
RA Komiyama M., Tashiro H., Tanigami A., Fujiwara T., Ono T., Yamada K.,
RA Fujii Y., Ozaki K., Hirao M., Ohmori Y., Kawabata A., Hikiji T.,
RA Kobatake N., Inagaki H., Ikema Y., Okamoto S., Okitani R., Kawakami T.,
RA Noguchi S., Itoh T., Shigeta K., Senba T., Matsumura K., Nakajima Y.,
RA Mizuno T., Morinaga M., Sasaki M., Togashi T., Oyama M., Hata H.,
RA Watanabe M., Komatsu T., Mizushima-Sugano J., Satoh T., Shirai Y.,
RA Takahashi Y., Nakagawa K., Okumura K., Nagase T., Nomura N., Kikuchi H.,
RA Masuho Y., Yamashita R., Nakai K., Yada T., Nakamura Y., Ohara O.,
RA Isogai T., Sugano S.;
RT "Complete sequencing and characterization of 21,243 full-length human
RT cDNAs.";
RL Nat. Genet. 36:40-45(2004).
RN [3]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RX PubMed=15815621; DOI=10.1038/nature03466;
RA Hillier L.W., Graves T.A., Fulton R.S., Fulton L.A., Pepin K.H., Minx P.,
RA Wagner-McPherson C., Layman D., Wylie K., Sekhon M., Becker M.C.,
RA Fewell G.A., Delehaunty K.D., Miner T.L., Nash W.E., Kremitzki C., Oddy L.,
RA Du H., Sun H., Bradshaw-Cordum H., Ali J., Carter J., Cordes M., Harris A.,
RA Isak A., van Brunt A., Nguyen C., Du F., Courtney L., Kalicki J.,
RA Ozersky P., Abbott S., Armstrong J., Belter E.A., Caruso L., Cedroni M.,
RA Cotton M., Davidson T., Desai A., Elliott G., Erb T., Fronick C., Gaige T.,
RA Haakenson W., Haglund K., Holmes A., Harkins R., Kim K., Kruchowski S.S.,
RA Strong C.M., Grewal N., Goyea E., Hou S., Levy A., Martinka S., Mead K.,
RA McLellan M.D., Meyer R., Randall-Maher J., Tomlinson C.,
RA Dauphin-Kohlberg S., Kozlowicz-Reilly A., Shah N., Swearengen-Shahid S.,
RA Snider J., Strong J.T., Thompson J., Yoakum M., Leonard S., Pearman C.,
RA Trani L., Radionenko M., Waligorski J.E., Wang C., Rock S.M.,
RA Tin-Wollam A.-M., Maupin R., Latreille P., Wendl M.C., Yang S.-P., Pohl C.,
RA Wallis J.W., Spieth J., Bieri T.A., Berkowicz N., Nelson J.O., Osborne J.,
RA Ding L., Meyer R., Sabo A., Shotland Y., Sinha P., Wohldmann P.E.,
RA Cook L.L., Hickenbotham M.T., Eldred J., Williams D., Jones T.A., She X.,
RA Ciccarelli F.D., Izaurralde E., Taylor J., Schmutz J., Myers R.M.,
RA Cox D.R., Huang X., McPherson J.D., Mardis E.R., Clifton S.W., Warren W.C.,
RA Chinwalla A.T., Eddy S.R., Marra M.A., Ovcharenko I., Furey T.S.,
RA Miller W., Eichler E.E., Bork P., Suyama M., Torrents D., Waterston R.H.,
RA Wilson R.K.;
RT "Generation and annotation of the DNA sequences of human chromosomes 2 and
RT 4.";
RL Nature 434:724-731(2005).
RN [4]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE GENOMIC DNA].
RA Mural R.J., Istrail S., Sutton G.G., Florea L., Halpern A.L., Mobarry C.M.,
RA Lippert R., Walenz B., Shatkay H., Dew I., Miller J.R., Flanigan M.J.,
RA Edwards N.J., Bolanos R., Fasulo D., Halldorsson B.V., Hannenhalli S.,
RA Turner R., Yooseph S., Lu F., Nusskern D.R., Shue B.C., Zheng X.H.,
RA Zhong F., Delcher A.L., Huson D.H., Kravitz S.A., Mouchard L., Reinert K.,
RA Remington K.A., Clark A.G., Waterman M.S., Eichler E.E., Adams M.D.,
RA Hunkapiller M.W., Myers E.W., Venter J.C.;
RL Submitted (JUL-2005) to the EMBL/GenBank/DDBJ databases.
RN [5]
RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 2).
RC TISSUE=Brain;
RX PubMed=15489334; DOI=10.1101/gr.2596504;
RG The MGC Project Team;
RT "The status, quality, and expansion of the NIH full-length cDNA project:
RT the Mammalian Gene Collection (MGC).";
RL Genome Res. 14:2121-2127(2004).
RN [6]
RP PRELIMINARY NUCLEOTIDE SEQUENCE OF 389-789, AND ROLE IN DIABETES MELLITUS.
RC TISSUE=Pancreatic islet;
RX PubMed=8144912;
RA Rabin D.U., Pleasic S.M., Shapiro J.A., Yoo-Warren H., Oles J., Hicks J.M.,
RA Goldstein D.E., Rae P.M.;
RT "Islet cell antigen 512 is a diabetes-specific islet autoantigen related to
RT protein tyrosine phosphatases.";
RL J. Immunol. 152:3183-3188(1994).
RN [7]
RP SEQUENCE REVISION, AND ROLE IN DIABETES MELLITUS.
RX PubMed=8641276; DOI=10.1002/j.1460-2075.1996.tb00564.x;
RA Solimena M., Dirkx R. Jr., Hermel J.-M., Pleasic-Williams S., Shapiro J.A.,
RA Caron L., Rabin D.U.;
RT "ICA 512, an autoantigen of type I diabetes, is an intrinsic membrane
RT protein of neurosecretory granules.";
RL EMBO J. 15:2102-2114(1996).
RN [8]
RP SUBCELLULAR LOCATION.
RX PubMed=10457160; DOI=10.1046/j.1460-9568.1999.00677.x;
RA Hermel J.-M., Dirkx R., Solimena M.;
RT "Post-translational modifications of ICA512, a receptor tyrosine
RT phosphatase-like protein of secretory granules.";
RL Eur. J. Neurosci. 11:2609-2620(1999).
RN [9]
RP INTERACTION WITH SNTB2, PROTEOLYTIC PROCESSING, AND PARTIAL PROTEIN
RP SEQUENCE.
RX PubMed=11483505; DOI=10.1093/emboj/20.15.4013;
RA Ort T., Voronov S., Guo J., Zawalich K., Froehner S.C., Zawalich W.,
RA Solimena M.;
RT "Dephosphorylation of beta2-syntrophin and Ca2+/mu-calpain-mediated
RT cleavage of ICA512 upon stimulation of insulin secretion.";
RL EMBO J. 20:4013-4023(2001).
RN [10]
RP FUNCTION, INTERACTION WITH PIAS4, SUBCELLULAR LOCATION, AND PROTEOLYTIC
RP CLEAVAGE.
RX PubMed=15596545; DOI=10.1083/jcb.200408172;
RA Trajkovski M., Mziaut H., Altkrueger A., Ouwendijk J., Knoch K.P.,
RA Mueller S., Solimena M.;
RT "Nuclear translocation of an ICA512 cytosolic fragment couples granule
RT exocytosis and insulin expression in {beta}-cells.";
RL J. Cell Biol. 167:1063-1074(2004).
RN [11]
RP INTERACTION WITH SNX19.
RX PubMed=16273344; DOI=10.1007/s00125-005-0037-y;
RA Hu Y.F., Zhang H.L., Cai T., Harashima S., Notkins A.L.;
RT "The IA-2 interactome.";
RL Diabetologia 48:2576-2581(2005).
RN [12]
RP FUNCTION, INTERACTION WITH STAT5B AND PIAS4, AND SUMOYLATION AT LYS-754.
RX PubMed=16622421; DOI=10.1038/ncb1395;
RA Mziaut H., Trajkovski M., Kersting S., Ehninger A., Altkrueger A.,
RA Lemaitre R.P., Schmidt D., Saeger H.D., Lee M.S., Drechsel D.N.,
RA Mueller S., Solimena M.;
RT "Synergy of glucose and growth hormone signalling in islet cells through
RT ICA512 and STAT5.";
RL Nat. Cell Biol. 8:435-445(2006).
RN [13]
RP FUNCTION, AND SUBUNIT.
RX PubMed=18824546; DOI=10.1074/jbc.m804928200;
RA Trajkovski M., Mziaut H., Schubert S., Kalaidzidis Y., Altkrueger A.,
RA Solimena M.;
RT "Regulation of insulin granule turnover in pancreatic beta-cells by cleaved
RT ICA512.";
RL J. Biol. Chem. 283:33719-33729(2008).
RN [14]
RP FUNCTION.
RX PubMed=18178618; DOI=10.1073/pnas.0710931105;
RA Mziaut H., Kersting S., Knoch K.P., Fan W.H., Trajkovski M., Erdmann K.,
RA Bergert H., Ehehalt F., Saeger H.D., Solimena M.;
RT "ICA512 signaling enhances pancreatic beta-cell proliferation by regulating
RT cyclins D through STATs.";
RL Proc. Natl. Acad. Sci. U.S.A. 105:674-679(2008).
RN [15]
RP FUNCTION.
RX PubMed=20886068; DOI=10.1371/journal.pone.0012929;
RA Schubert S., Knoch K.P., Ouwendijk J., Mohammed S., Bodrov Y., Jaeger M.,
RA Altkrueger A., Wegbrod C., Adams M.E., Kim Y., Froehner S.C., Jensen O.N.,
RA Kalaidzidis Y., Solimena M.;
RT "beta2-Syntrophin is a Cdk5 substrate that restrains the motility of
RT insulin secretory granules.";
RL PLoS ONE 5:E12929-E12929(2010).
RN [16]
RP GLYCOSYLATION AT THR-441, STRUCTURE OF CARBOHYDRATES, AND IDENTIFICATION BY
RP MASS SPECTROMETRY.
RX PubMed=22171320; DOI=10.1074/mcp.m111.013649;
RA Halim A., Nilsson J., Ruetschi U., Hesse C., Larson G.;
RT "Human urinary glycoproteomics; attachment site specific analysis of N- and
RT O-linked glycosylations by CID and ECD.";
RL Mol. Cell. Proteomics 11:1-17(2012).
RN [17]
RP FUNCTION.
RX PubMed=24843546; DOI=10.1111/j.2040-1124.2011.00138.x;
RA Harashima S., Horiuchi T., Wang Y., Notkins A.L., Seino Y., Inagaki N.;
RT "Sorting nexin 19 regulates the number of dense core vesicles in pancreatic
RT beta-cells.";
RL J. Diabetes Investig. 3:52-61(2012).
RN [18]
RP GLYCOSYLATION AT THR-441, AND IDENTIFICATION BY MASS SPECTROMETRY.
RX PubMed=23234360; DOI=10.1021/pr300963h;
RA Halim A., Ruetschi U., Larson G., Nilsson J.;
RT "LC-MS/MS characterization of O-glycosylation sites and glycan structures
RT of human cerebrospinal fluid glycoproteins.";
RL J. Proteome Res. 12:573-584(2013).
RN [19]
RP SUBUNIT, SUBCELLULAR LOCATION, MUTAGENESIS OF ASN-506; ASN-524 AND GLY-553,
RP AND GLYCOSYLATION AT ASN-506 AND ASN-524.
RX PubMed=25561468; DOI=10.1128/mcb.00994-14;
RA Torkko J.M., Primo M.E., Dirkx R., Friedrich A., Viehrig A., Vergari E.,
RA Borgonovo B., Soenmez A., Wegbrod C., Lachnit M., Muenster C., Sica M.P.,
RA Ermacora M.R., Solimena M.;
RT "Stability of proICA512/IA-2 and its targeting to insulin secretory
RT granules require beta4-sheet-mediated dimerization of its ectodomain in the
RT endoplasmic reticulum.";
RL Mol. Cell. Biol. 35:914-927(2015).
RN [20]
RP SUBUNIT, INTERACTION WITH INSULIN, AND DISULFIDE BONDS.
RX PubMed=26836020; DOI=10.1016/j.bbapap.2016.01.013;
RA Sosa L., Torkko J.M., Primo M.E., Llovera R.E., Toledo P.L., Rios A.S.,
RA Flecha F.L., Trabucchi A., Valdez S.N., Poskus E., Solimena M.,
RA Ermacora M.R.;
RT "Biochemical, biophysical, and functional properties of ICA512/IA-2 RESP18
RT homology domain.";
RL Biochim. Biophys. Acta 1864:511-522(2016).
RN [21]
RP X-RAY CRYSTALLOGRAPHY (2.23 ANGSTROMS) OF 681-979.
RX PubMed=18058037; DOI=10.1007/s10969-007-9036-1;
RA Almo S.C., Bonanno J.B., Sauder J.M., Emtage S., Dilorenzo T.P.,
RA Malashkevich V., Wasserman S.R., Swaminathan S., Eswaramoorthy S.,
RA Agarwal R., Kumaran D., Madegowda M., Ragumani S., Patskovsky Y.,
RA Alvarado J., Ramagopal U.A., Faber-Barata J., Chance M.R., Sali A.,
RA Fiser A., Zhang Z.Y., Lawrence D.S., Burley S.K.;
RT "Structural genomics of protein phosphatases.";
RL J. Struct. Funct. Genomics 8:121-140(2007).
RN [22]
RP X-RAY CRYSTALLOGRAPHY (1.3 ANGSTROMS) OF 468-558.
RX PubMed=18048354; DOI=10.1074/jbc.m708144200;
RA Primo M.E., Klinke S., Sica M.P., Goldbaum F.A., Jakoncic J., Poskus E.,
RA Ermacora M.R.;
RT "Structure of the mature ectodomain of the human receptor-type protein-
RT tyrosine phosphatase IA-2.";
RL J. Biol. Chem. 283:4674-4681(2008).
CC -!- FUNCTION: Plays a role in vesicle-mediated secretory processes
CC (PubMed:24843546). Required for normal accumulation of secretory
CC vesicles in hippocampus, pituitary and pancreatic islets (By
CC similarity). Required for the accumulation of normal levels of insulin-
CC containing vesicles and preventing their degradation (PubMed:24843546).
CC Plays a role in insulin secretion in response to glucose stimuli
CC (PubMed:24843546). Required for normal accumulation of the
CC neurotransmitters norepinephrine, dopamine and serotonin in the brain
CC (By similarity). In females, but not in males, required for normal
CC accumulation and secretion of pituitary hormones, such as luteinizing
CC hormone (LH) and follicle-stimulating hormone (FSH) (By similarity).
CC Required to maintain normal levels of renin expression and renin
CC release (By similarity). Seems to lack intrinsic enzyme activity (By
CC similarity). May regulate catalytic active protein-tyrosine
CC phosphatases such as PTPRA through dimerization (By similarity).
CC {ECO:0000250|UniProtKB:Q60673, ECO:0000269|PubMed:24843546}.
CC -!- FUNCTION: [ICA512-transmembrane fragment]: ICA512-TMF regulates
CC dynamics and exocytosis of insulin secretory granules (SGs); binding of
CC ICA512-TMF to SNTB2/beta-2-syntrophin is proposed to restrain SGs
CC mobility and exocytosis by tethering them to the actin cytoskeleton
CC depending on UTRN; the function is inhibited by cytoplasmic ICA512-CFF
CC dimerizing with ICA512-TMF and displacing SNTB2.
CC {ECO:0000269|PubMed:18824546, ECO:0000269|PubMed:20886068}.
CC -!- FUNCTION: [ICA512-cleaved cytosolic fragment]: ICA512-CCF translocated
CC to the nucleus promotes expression of insulin and other granule-related
CC genes; the function implicates binding to and regulating activity of
CC STAT5B probably by preventing its dephosphorylation and potentially by
CC inducing its sumoylation by recruiting PIAS4 (PubMed:15596545,
CC PubMed:16622421, PubMed:18178618). Enhances pancreatic beta-cell
CC proliferation by converging with signaling by STAT5B and STAT3
CC (PubMed:15596545, PubMed:16622421, PubMed:18178618). ICA512-CCF located
CC in the cytoplasm regulates dynamics and exocytosis of insulin secretory
CC granules (SGs) by dimerizing with ICA512-TMF and displacing SNTB2 thus
CC enhancing SGs mobility and exocytosis (PubMed:18824546,
CC PubMed:20886068). {ECO:0000269|PubMed:15596545,
CC ECO:0000269|PubMed:16622421, ECO:0000269|PubMed:18178618,
CC ECO:0000269|PubMed:18824546, ECO:0000269|PubMed:20886068}.
CC -!- SUBUNIT: Homodimer; shown for the unprocessed protein (proICA512) in
CC the endoplasmic reticulum and resolved during protein maturation as
CC ICA512-TMF seems to be predominantly monomeric in secretory granules;
CC however, ICA512-CCF interacts with ICA512-TMF disrupting the ICA512-
CC TMF:SNTB2 complex. The isolated lumenal RESP18 homology domain has been
CC shown to form disulfide-linked homooligomers (PubMed:25561468,
CC PubMed:18824546, PubMed:26836020). Interacts (via cytoplasmic domain)
CC with phosphorylated SNTB2; this protects PTPRN against cleavage by
CC CAPN1 to produce ICA512-CCF. Dephosphorylation of SNTB2 upon insulin
CC stimulation disrupts the interaction and results in PTPRN cleavage
CC (PubMed:11483505). Interacts with SNX19 (PubMed:16273344). ICA512-CCF
CC interacts with PIAS4; in the nucleus (PubMed:15596545). Interacts with
CC STAT5B (phosphorylated); down-regulated by ICA512-CCF sumoylation;
CC ICA512-CCF prevents STAT5B dephosphorylation; ICA512-CCF mediates
CC interaction of STAT5B with PIAS4 (PubMed:15596545, PubMed:16622421).
CC Interacts (via RESP18 homology domain) with insulin and proinsulin
CC (PubMed:26836020). Interacts with PTPRN2, PTPRA and PTPRE (By
CC similarity). {ECO:0000250|UniProtKB:Q60673,
CC ECO:0000269|PubMed:11483505, ECO:0000269|PubMed:15596545,
CC ECO:0000269|PubMed:16273344, ECO:0000269|PubMed:16622421,
CC ECO:0000269|PubMed:18824546, ECO:0000269|PubMed:25561468,
CC ECO:0000269|PubMed:26836020}.
CC -!- INTERACTION:
CC Q16849; Q8WXG6: MADD; NbExp=4; IntAct=EBI-728153, EBI-310528;
CC Q16849; P62937: PPIA; NbExp=3; IntAct=EBI-728153, EBI-437708;
CC Q16849; Q13332: PTPRS; NbExp=5; IntAct=EBI-728153, EBI-711536;
CC Q16849; O14522: PTPRT; NbExp=3; IntAct=EBI-728153, EBI-728180;
CC Q16849; Q92543: SNX19; NbExp=4; IntAct=EBI-728153, EBI-728232;
CC Q16849; Q9H254: SPTBN4; NbExp=2; IntAct=EBI-728153, EBI-308543;
CC Q16849-3; Q9H6E4: CCDC134; NbExp=3; IntAct=EBI-10200782, EBI-953766;
CC Q16849-3; P48165: GJA8; NbExp=3; IntAct=EBI-10200782, EBI-17458373;
CC Q16849-3; Q8TDT2: GPR152; NbExp=3; IntAct=EBI-10200782, EBI-13345167;
CC Q16849-3; P21145: MAL; NbExp=3; IntAct=EBI-10200782, EBI-3932027;
CC Q16849-3; P60201: PLP1; NbExp=3; IntAct=EBI-10200782, EBI-8653150;
CC Q16849-3; P60201-2: PLP1; NbExp=9; IntAct=EBI-10200782, EBI-12188331;
CC Q16849-3; Q9NPL8: TIMMDC1; NbExp=3; IntAct=EBI-10200782, EBI-6268651;
CC Q16849-3; Q96HE8: TMEM80; NbExp=3; IntAct=EBI-10200782, EBI-11742770;
CC Q16849-3; Q13061-2: TRDN; NbExp=3; IntAct=EBI-10200782, EBI-17257686;
CC -!- SUBCELLULAR LOCATION: Membrane {ECO:0000250|UniProtKB:Q63259}; Single-
CC pass type I membrane protein {ECO:0000250|UniProtKB:Q63259}.
CC Cytoplasmic vesicle, secretory vesicle membrane
CC {ECO:0000305|PubMed:25561468}; Single-pass type I membrane protein
CC {ECO:0000305}. Perikaryon {ECO:0000250|UniProtKB:Q63259}. Cell
CC projection, axon {ECO:0000250|UniProtKB:Q63259}. Synapse
CC {ECO:0000250|UniProtKB:Q63259}. Cell membrane
CC {ECO:0000269|PubMed:10457160}; Single-pass type I membrane protein
CC {ECO:0000250|UniProtKB:Q63259}. Endosome
CC {ECO:0000250|UniProtKB:Q63259}. Note=Detected on neuronal secretory
CC vesicles, but not on synaptic vesicles. Colocalizes with insulin-
CC containing secretory granules (PubMed:25561468). Primarily detected on
CC secretory vesicle membranes. Transiently found at the cell membrane,
CC when secretory vesicles fuse with the cell membrane to release their
CC cargo. Is then endocytosed and recycled to secretory vesicles via the
CC Golgi apparatus membranes. {ECO:0000250|UniProtKB:Q63259,
CC ECO:0000269|PubMed:25561468}.
CC -!- SUBCELLULAR LOCATION: [ICA512-transmembrane fragment]: Cytoplasmic
CC vesicle, secretory vesicle membrane {ECO:0000250|UniProtKB:Q63259}.
CC -!- SUBCELLULAR LOCATION: [ICA512-cleaved cytosolic fragment]: Nucleus
CC {ECO:0000269|PubMed:15596545}.
CC -!- ALTERNATIVE PRODUCTS:
CC Event=Alternative splicing; Named isoforms=3;
CC Name=1;
CC IsoId=Q16849-1; Sequence=Displayed;
CC Name=2;
CC IsoId=Q16849-2; Sequence=VSP_043654;
CC Name=3;
CC IsoId=Q16849-3; Sequence=VSP_045867;
CC -!- TISSUE SPECIFICITY: Expression is restricted to neuroendocrine cells.
CC Found in pancreas, brain and pituitary. {ECO:0000269|PubMed:8024693}.
CC -!- DOMAIN: The RESP18 homology domain is sufficient for targeting
CC proICA512 to secretory granules. {ECO:0000269|PubMed:25561468}.
CC -!- PTM: N-glycosylated. {ECO:0000269|PubMed:25561468}.
CC -!- PTM: O-glycosylated with core 1 or possibly core 8 glycans.
CC {ECO:0000269|PubMed:22171320, ECO:0000269|PubMed:23234360,
CC ECO:0000269|PubMed:25561468}.
CC -!- PTM: Subject to proteolytic cleavage at multiple sites
CC (PubMed:11483505). Subject to cleavage on a pair of basic residues (By
CC similarity). On exocytosis of secretory granules in pancreatic beta-
CC cells ICA512-TMF is transiently inserted in the plasma-membrane and
CC cleaved by mu-type calpain CPN1 to yield ICA512-CCF (By similarity).
CC {ECO:0000250|UniProtKB:P56722, ECO:0000250|UniProtKB:Q63259,
CC ECO:0000269|PubMed:11483505, ECO:0000305|PubMed:15596545}.
CC -!- PTM: Sumoylated at two sites including Lys-754. Sumoylation decreases
CC interaction with STAT5. {ECO:0000269|PubMed:16622421}.
CC -!- DISEASE: Note=Autoantigen in insulin-dependent diabetes mellitus
CC (IDDM). {ECO:0000269|PubMed:8144912, ECO:0000269|PubMed:8641276}.
CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family.
CC Receptor class 8 subfamily. {ECO:0000305}.
CC -!- CAUTION: Does not possess catalytic activity due to replacement of
CC highly conserved residues in tyrosine-protein phosphatase domain.
CC {ECO:0000305}.
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DR EMBL; L18983; AAA90974.1; -; mRNA.
DR EMBL; AK296335; BAG59024.1; -; mRNA.
DR EMBL; AC114803; AAY24038.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70724.1; -; Genomic_DNA.
DR EMBL; CH471063; EAW70726.1; -; Genomic_DNA.
DR EMBL; BC070053; AAH70053.1; -; mRNA.
DR EMBL; X62899; CAA44688.2; -; mRNA.
DR CCDS; CCDS2440.1; -. [Q16849-1]
DR CCDS; CCDS56167.1; -. [Q16849-3]
DR CCDS; CCDS56168.1; -. [Q16849-2]
DR PIR; I37577; I37577.
DR RefSeq; NP_001186692.1; NM_001199763.1. [Q16849-2]
DR RefSeq; NP_001186693.1; NM_001199764.1. [Q16849-3]
DR RefSeq; NP_002837.1; NM_002846.3. [Q16849-1]
DR PDB; 2I1Y; X-ray; 2.23 A; A/B=681-979.
DR PDB; 2QT7; X-ray; 1.30 A; A/B=468-558.
DR PDB; 3N01; X-ray; 1.30 A; A/B=470-558.
DR PDB; 3N4W; X-ray; 1.45 A; A/B=470-558.
DR PDB; 3NG8; X-ray; 1.35 A; A/B=470-558.
DR PDB; 3NP5; X-ray; 1.80 A; A/B/C/D=470-558.
DR PDBsum; 2I1Y; -.
DR PDBsum; 2QT7; -.
DR PDBsum; 3N01; -.
DR PDBsum; 3N4W; -.
DR PDBsum; 3NG8; -.
DR PDBsum; 3NP5; -.
DR AlphaFoldDB; Q16849; -.
DR SMR; Q16849; -.
DR BioGRID; 111762; 123.
DR IntAct; Q16849; 28.
DR MINT; Q16849; -.
DR STRING; 9606.ENSP00000295718; -.
DR DEPOD; PTPRN; -.
DR GlyConnect; 697; 1 O-Linked glycan (1 site).
DR GlyGen; Q16849; 3 sites, 2 O-linked glycans (1 site).
DR iPTMnet; Q16849; -.
DR PhosphoSitePlus; Q16849; -.
DR BioMuta; PTPRN; -.
DR DMDM; 2499754; -.
DR jPOST; Q16849; -.
DR MassIVE; Q16849; -.
DR PaxDb; Q16849; -.
DR PeptideAtlas; Q16849; -.
DR PRIDE; Q16849; -.
DR ProteomicsDB; 25116; -.
DR ProteomicsDB; 61099; -. [Q16849-1]
DR ProteomicsDB; 61100; -. [Q16849-2]
DR Antibodypedia; 1516; 307 antibodies from 33 providers.
DR DNASU; 5798; -.
DR Ensembl; ENST00000295718.7; ENSP00000295718.2; ENSG00000054356.14. [Q16849-1]
DR Ensembl; ENST00000409251.7; ENSP00000386638.3; ENSG00000054356.14. [Q16849-2]
DR Ensembl; ENST00000423636.6; ENSP00000392598.2; ENSG00000054356.14. [Q16849-3]
DR GeneID; 5798; -.
DR KEGG; hsa:5798; -.
DR MANE-Select; ENST00000295718.7; ENSP00000295718.2; NM_002846.4; NP_002837.1.
DR UCSC; uc002vkz.3; human. [Q16849-1]
DR CTD; 5798; -.
DR DisGeNET; 5798; -.
DR GeneCards; PTPRN; -.
DR HGNC; HGNC:9676; PTPRN.
DR HPA; ENSG00000054356; Group enriched (brain, pituitary gland).
DR MIM; 601773; gene.
DR neXtProt; NX_Q16849; -.
DR OpenTargets; ENSG00000054356; -.
DR PharmGKB; PA34021; -.
DR VEuPathDB; HostDB:ENSG00000054356; -.
DR eggNOG; KOG0793; Eukaryota.
DR GeneTree; ENSGT00940000154095; -.
DR HOGENOM; CLU_007905_2_0_1; -.
DR InParanoid; Q16849; -.
DR OMA; AQTGFQI; -.
DR OrthoDB; 411281at2759; -.
DR PhylomeDB; Q16849; -.
DR TreeFam; TF351976; -.
DR BRENDA; 3.1.3.48; 2681.
DR PathwayCommons; Q16849; -.
DR SignaLink; Q16849; -.
DR BioGRID-ORCS; 5798; 11 hits in 1068 CRISPR screens.
DR ChiTaRS; PTPRN; human.
DR EvolutionaryTrace; Q16849; -.
DR GeneWiki; PTPRN; -.
DR GenomeRNAi; 5798; -.
DR Pharos; Q16849; Tbio.
DR PRO; PR:Q16849; -.
DR Proteomes; UP000005640; Chromosome 2.
DR RNAct; Q16849; protein.
DR Bgee; ENSG00000054356; Expressed in islet of Langerhans and 139 other tissues.
DR ExpressionAtlas; Q16849; baseline and differential.
DR Genevisible; Q16849; HS.
DR GO; GO:0070161; C:anchoring junction; IEA:UniProtKB-KW.
DR GO; GO:0043679; C:axon terminus; ISS:UniProtKB.
DR GO; GO:0005768; C:endosome; IEA:UniProtKB-SubCell.
DR GO; GO:0016021; C:integral component of membrane; IEA:UniProtKB-KW.
DR GO; GO:0043025; C:neuronal cell body; ISS:UniProtKB.
DR GO; GO:0005634; C:nucleus; IDA:UniProtKB.
DR GO; GO:0043204; C:perikaryon; IEA:UniProtKB-SubCell.
DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030141; C:secretory granule; ISS:UniProtKB.
DR GO; GO:0045202; C:synapse; ISS:UniProtKB.
DR GO; GO:0030658; C:transport vesicle membrane; IEA:UniProtKB-SubCell.
DR GO; GO:0030507; F:spectrin binding; IPI:BHF-UCL.
DR GO; GO:0008134; F:transcription factor binding; IDA:UniProtKB.
DR GO; GO:0044389; F:ubiquitin-like protein ligase binding; IDA:UniProtKB.
DR GO; GO:1990502; P:dense core granule maturation; IGI:GO_Central.
DR GO; GO:0030073; P:insulin secretion; IGI:GO_Central.
DR GO; GO:0035773; P:insulin secretion involved in cellular response to glucose stimulus; ISS:UniProtKB.
DR GO; GO:0001553; P:luteinization; ISS:UniProtKB.
DR GO; GO:0045944; P:positive regulation of transcription by RNA polymerase II; IDA:UniProtKB.
DR GO; GO:1904692; P:positive regulation of type B pancreatic cell proliferation; IDA:UniProtKB.
DR GO; GO:0051046; P:regulation of secretion; IBA:GO_Central.
DR GO; GO:0000302; P:response to reactive oxygen species; IDA:UniProtKB.
DR Gene3D; 3.30.70.2470; -; 1.
DR Gene3D; 3.90.190.10; -; 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; PTHR46106; 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 SUPFAM; SSF52799; SSF52799; 1.
DR PROSITE; PS00383; TYR_PHOSPHATASE_1; 1.
DR PROSITE; PS50056; TYR_PHOSPHATASE_2; 1.
DR PROSITE; PS50055; TYR_PHOSPHATASE_PTP; 1.
PE 1: Evidence at protein level;
KW 3D-structure; Alternative splicing; Cell membrane; Cell projection;
KW Cytoplasmic vesicle; Diabetes mellitus; Direct protein sequencing;
KW Disulfide bond; Endosome; Glycoprotein; Isopeptide bond; Membrane; Nucleus;
KW Phosphoprotein; Receptor; Reference proteome; Signal; Synapse;
KW Transcription; Transcription regulation; Transmembrane;
KW Transmembrane helix; Ubl conjugation.
FT SIGNAL 1..34
FT /evidence="ECO:0000250"
FT CHAIN 35..979
FT /note="Receptor-type tyrosine-protein phosphatase-like N"
FT /id="PRO_0000025451"
FT CHAIN 35..448
FT /note="ICA512-N-terminal fragment"
FT /evidence="ECO:0000250|UniProtKB:P56722,
FT ECO:0000305|PubMed:26836020"
FT /id="PRO_0000438079"
FT CHAIN 449..979
FT /note="ICA512-transmembrane fragment"
FT /evidence="ECO:0000250|UniProtKB:P56722,
FT ECO:0000305|PubMed:26836020"
FT /id="PRO_0000438080"
FT CHAIN 659..979
FT /note="ICA512-cleaved cytosolic fragment"
FT /evidence="ECO:0000305|PubMed:15596545,
FT ECO:0000305|PubMed:26836020"
FT /id="PRO_0000438081"
FT TOPO_DOM 35..575
FT /note="Lumenal"
FT /evidence="ECO:0000255"
FT TRANSMEM 576..600
FT /note="Helical"
FT /evidence="ECO:0000255"
FT TOPO_DOM 601..979
FT /note="Cytoplasmic"
FT /evidence="ECO:0000255"
FT DOMAIN 709..969
FT /note="Tyrosine-protein phosphatase"
FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160"
FT REGION 35..131
FT /note="RESP18 homology domain"
FT REGION 112..173
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 289..329
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 393..439
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT REGION 449..575
FT /note="Sufficient for dimerization of proICA512"
FT /evidence="ECO:0000269|PubMed:25561468"
FT REGION 601..732
FT /note="Sufficient for dimerization of proICA512"
FT /evidence="ECO:0000250|UniProtKB:P80560"
FT REGION 643..680
FT /note="Disordered"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 113..129
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 307..321
FT /note="Basic and acidic residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 410..429
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT COMPBIAS 652..680
FT /note="Polar residues"
FT /evidence="ECO:0000256|SAM:MobiDB-lite"
FT SITE 448..449
FT /note="Cleavage"
FT /evidence="ECO:0000250|UniProtKB:P56722"
FT MOD_RES 308
FT /note="Phosphoserine"
FT /evidence="ECO:0000250|UniProtKB:Q60673"
FT CARBOHYD 441
FT /note="O-linked (GalNAc...) threonine"
FT /evidence="ECO:0000269|PubMed:22171320,
FT ECO:0000269|PubMed:23234360"
FT CARBOHYD 506
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25561468"
FT CARBOHYD 524
FT /note="N-linked (GlcNAc...) asparagine"
FT /evidence="ECO:0000255, ECO:0000269|PubMed:25561468"
FT DISULFID 40
FT /note="Interchain (with C-40 or C-47); in multimeric form"
FT /evidence="ECO:0000305|PubMed:26836020"
FT DISULFID 47
FT /note="Interchain (with C-40 or C-47); in multimeric form"
FT /evidence="ECO:0000305|PubMed:26836020"
FT DISULFID 53..62
FT /evidence="ECO:0000305|PubMed:26836020"
FT CROSSLNK 754
FT /note="Glycyl lysine isopeptide (Lys-Gly) (interchain with
FT G-Cter in SUMO)"
FT /evidence="ECO:0000269|PubMed:16622421"
FT VAR_SEQ 1..90
FT /note="Missing (in isoform 3)"
FT /evidence="ECO:0000303|PubMed:14702039"
FT /id="VSP_045867"
FT VAR_SEQ 479..508
FT /note="KPLSLAAGVKLLEILAEHVHMSSGSFINIS -> N (in isoform 2)"
FT /evidence="ECO:0000303|PubMed:15489334"
FT /id="VSP_043654"
FT VARIANT 419
FT /note="S -> R (in dbSNP:rs35314717)"
FT /id="VAR_051762"
FT MUTAGEN 506
FT /note="N->A: Reduces N-glycosylation."
FT /evidence="ECO:0000269|PubMed:25561468"
FT MUTAGEN 524
FT /note="N->A: Reduces N-glycosylation."
FT /evidence="ECO:0000269|PubMed:25561468"
FT MUTAGEN 553
FT /note="G->D: Impairs normal processing and leads to
FT retention in the endoplasmic reticulum and degradation."
FT /evidence="ECO:0000269|PubMed:25561468"
FT CONFLICT 673
FT /note="S -> G (in Ref. 2; BAG59024)"
FT /evidence="ECO:0000305"
FT STRAND 471..477
FT /evidence="ECO:0007829|PDB:2QT7"
FT HELIX 483..497
FT /evidence="ECO:0007829|PDB:2QT7"
FT HELIX 501..503
FT /evidence="ECO:0007829|PDB:2QT7"
FT STRAND 504..510
FT /evidence="ECO:0007829|PDB:2QT7"
FT STRAND 513..518
FT /evidence="ECO:0007829|PDB:2QT7"
FT HELIX 527..536
FT /evidence="ECO:0007829|PDB:2QT7"
FT HELIX 538..545
FT /evidence="ECO:0007829|PDB:2QT7"
FT STRAND 549..555
FT /evidence="ECO:0007829|PDB:2QT7"
FT HELIX 692..704
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 706..717
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 727..730
FT /evidence="ECO:0007829|PDB:2I1Y"
FT TURN 732..734
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 735..737
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 755..757
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 766..770
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 780..783
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 788..790
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 791..801
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 805..808
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 812..814
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 826..832
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 835..844
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 846..858
FT /evidence="ECO:0007829|PDB:2I1Y"
FT TURN 859..861
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 864..872
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 877..880
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 885..896
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 905..908
FT /evidence="ECO:0007829|PDB:2I1Y"
FT STRAND 910..913
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 914..930
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 938..946
FT /evidence="ECO:0007829|PDB:2I1Y"
FT HELIX 956..975
FT /evidence="ECO:0007829|PDB:2I1Y"
SQ SEQUENCE 979 AA; 105848 MW; A852B9063D29399D CRC64;
MRRPRRPGGL GGSGGLRLLL CLLLLSSRPG GCSAVSAHGC LFDRRLCSHL EVCIQDGLFG
QCQVGVGQAR PLLQVTSPVL QRLQGVLRQL MSQGLSWHDD LTQYVISQEM ERIPRLRPPE
PRPRDRSGLA PKRPGPAGEL LLQDIPTGSA PAAQHRLPQP PVGKGGAGAS SSLSPLQAEL
LPPLLEHLLL PPQPPHPSLS YEPALLQPYL FHQFGSRDGS RVSEGSPGMV SVGPLPKAEA
PALFSRTASK GIFGDHPGHS YGDLPGPSPA QLFQDSGLLY LAQELPAPSR ARVPRLPEQG
SSSRAEDSPE GYEKEGLGDR GEKPASPAVQ PDAALQRLAA VLAGYGVELR QLTPEQLSTL
LTLLQLLPKG AGRNPGGVVN VGADIKKTME GPVEGRDTAE LPARTSPMPG HPTASPTSSE
VQQVPSPVSS EPPKAARPPV TPVLLEKKSP LGQSQPTVAG QPSARPAAEE YGYIVTDQKP
LSLAAGVKLL EILAEHVHMS SGSFINISVV GPALTFRIRH NEQNLSLADV TQQAGLVKSE
LEAQTGLQIL QTGVGQREEA AAVLPQTAHS TSPMRSVLLT LVALAGVAGL LVALAVALCV
RQHARQQDKE RLAALGPEGA HGDTTFEYQD LCRQHMATKS LFNRAEGPPE PSRVSSVSSQ
FSDAAQASPS SHSSTPSWCE EPAQANMDIS TGHMILAYME DHLRNRDRLA KEWQALCAYQ
AEPNTCATAQ GEGNIKKNRH PDFLPYDHAR IKLKVESSPS RSDYINASPI IEHDPRMPAY
IATQGPLSHT IADFWQMVWE SGCTVIVMLT PLVEDGVKQC DRYWPDEGAS LYHVYEVNLV
SEHIWCEDFL VRSFYLKNVQ TQETRTLTQF HFLSWPAEGT PASTRPLLDF RRKVNKCYRG
RSCPIIVHCS DGAGRTGTYI LIDMVLNRMA KGVKEIDIAA TLEHVRDQRP GLVRSKDQFE
FALTAVAEEV NAILKALPQ
