ID PTN2_RAT Reviewed; 416 AA. AC P35233; DT 01-FEB-1994, integrated into UniProtKB/Swiss-Prot. DT 16-NOV-2011, sequence version 2. DT 24-JAN-2024, entry version 168. DE RecName: Full=Tyrosine-protein phosphatase non-receptor type 2; DE EC=3.1.3.48; DE AltName: Full=Protein-tyrosine phosphatase PTP-S; GN Name=Ptpn2; OS Rattus norvegicus (Rat). OC Eukaryota; Metazoa; Chordata; Craniata; Vertebrata; Euteleostomi; Mammalia; OC Eutheria; Euarchontoglires; Glires; Rodentia; Myomorpha; Muroidea; Muridae; OC Murinae; Rattus. OX NCBI_TaxID=10116; RN [1] RP NUCLEOTIDE SEQUENCE [MRNA] (ISOFORM 4). RC TISSUE=Spleen; RX PubMed=1849097; DOI=10.1016/0014-5793(91)80205-h; RA Swarup G., Kamatkar S., Radha V., Rema V.; RT "Molecular cloning and expression of a protein-tyrosine phosphatase showing RT homology with transcription factors Fos and Jun."; RL FEBS Lett. 280:65-69(1991). RN [2] RP NUCLEOTIDE SEQUENCE [LARGE SCALE MRNA] (ISOFORM 4). RC TISSUE=Testis; 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 [3] RP DNA-BINDING. RX PubMed=8443161; DOI=10.1021/bi00060a010; RA Radha V., Kamatkar S., Swarup G.; RT "Binding of a protein-tyrosine phosphatase to DNA through its carboxy- RT terminal noncatalytic domain."; RL Biochemistry 32:2194-2201(1993). RN [4] RP ALTERNATIVE SPLICING. RX PubMed=8534367; DOI=10.1089/dna.1995.14.1007; RA Reddy R.S., Swarup G.; RT "Alternative splicing generates four different forms of a non-transmembrane RT protein tyrosine phosphatase mRNA."; RL DNA Cell Biol. 14:1007-1015(1995). RN [5] RP SUBCELLULAR LOCATION (ISOFORMS 1 AND 2). RX PubMed=8900155; DOI=10.1074/jbc.271.43.26755; RA Kamatkar S., Radha V., Nambirajan S., Reddy R.S., Swarup G.; RT "Two splice variants of a tyrosine phosphatase differ in substrate RT specificity, DNA binding, and subcellular location."; RL J. Biol. Chem. 271:26755-26761(1996). CC -!- FUNCTION: Non-receptor type tyrosine-specific phosphatase that CC dephosphorylates receptor protein tyrosine kinases including INSR, CC EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine CC kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3 and CC STAT6 either in the nucleus or the cytoplasm. Negatively regulates CC numerous signaling pathways and biological processes like CC hematopoiesis, inflammatory response, cell proliferation and CC differentiation, and glucose homeostasis. Plays a multifaceted and CC important role in the development of the immune system. Functions in T- CC cell receptor signaling through dephosphorylation of FYN and LCK to CC control T-cells differentiation and activation. Dephosphorylates CSF1R, CC negatively regulating its downstream signaling and macrophage CC differentiation. Negatively regulates cytokine (IL2/interleukin-2 and CC interferon)-mediated signaling through dephosphorylation of the CC cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that CC propagate signaling downstream of the cytokine receptors. Also CC regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine CC signaling through dephosphorylation of STAT3 and STAT6 respectively. In CC addition to the immune system, it is involved in anchorage-dependent, CC negative regulation of EGF-stimulated cell growth. Activated by the CC integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates CC EGF signaling. Dephosphorylates PDGFRB and negatively regulates CC platelet-derived growth factor receptor-beta signaling pathway and CC therefore cell proliferation. Negatively regulates tumor necrosis CC factor-mediated signaling downstream via MAPK through SRC CC dephosphorylation. May also regulate the hepatocyte growth factor CC receptor signaling pathway through dephosphorylation of the hepatocyte CC growth factor receptor MET. Also plays an important role in glucose CC homeostasis. For instance, negatively regulates the insulin receptor CC signaling pathway through the dephosphorylation of INSR and control CC gluconeogenesis and liver glucose production through negative CC regulation of the IL6 signaling pathways. May also bind DNA (By CC similarity). {ECO:0000250|UniProtKB:P17706}. 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: Interacts with RMDN3. Interacts with TMED9. Interacts with CC STX17; dephosphorylates STX17. Interacts with ITGA1 (via cytoplasmic CC domain); activates the phosphatase activity towards EGFR. Interacts CC with TRAF2; probably involved in tumor necrosis factor-mediated CC signaling. Interacts with MET (By similarity). {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: Cytoplasm. Endoplasmic reticulum-Golgi CC intermediate compartment {ECO:0000250}. Note=Targeted to the CC endoplasmic reticulum by its C-terminal hydrophobic region. CC {ECO:0000250}. CC -!- SUBCELLULAR LOCATION: [Isoform 1]: Endoplasmic reticulum CC {ECO:0000269|PubMed:8900155}. Nucleus membrane CC {ECO:0000269|PubMed:8900155}. CC -!- SUBCELLULAR LOCATION: [Isoform 2]: Nucleus {ECO:0000250}. Cytoplasm CC {ECO:0000250}. Cell membrane {ECO:0000250}. Note=Predominantly CC localizes to chromatin. Able to shuttle between the nucleus and the CC cytoplasm and to dephosphorylate plasma membrane receptors. Recruited CC by activated ITGA1 at the plasma membrane (By similarity). CC {ECO:0000250}. CC -!- ALTERNATIVE PRODUCTS: CC Event=Alternative splicing; Named isoforms=4; CC Name=1; Synonyms=PTP-S4; CC IsoId=P35233-1; Sequence=Displayed; CC Name=2; Synonyms=PTP-S2; CC IsoId=P35233-2; Sequence=VSP_042002; CC Name=3; Synonyms=PTP-S3; CC IsoId=P35233-3; Sequence=VSP_042001; CC Name=4; Synonyms=PTP-S1; CC IsoId=P35233-4; Sequence=VSP_042001, VSP_042002; CC -!- TISSUE SPECIFICITY: Does not show tissue- or cell-type specificity CC although levels of transcription show variability. Macrophages showed CC higher levels of expression than lymphocytes. CC -!- PTM: [Isoform 2]: Specifically phosphorylated in a cell cycle-dependent CC manner by cyclin-dependent kinases CDK1 and CDK2. Probably activated CC through phosphorylation by PKR. {ECO:0000250|UniProtKB:P17706}. CC -!- MISCELLANEOUS: [Isoform 3]: Minor. {ECO:0000305}. CC -!- MISCELLANEOUS: [Isoform 4]: Minor. {ECO:0000305}. CC -!- SIMILARITY: Belongs to the protein-tyrosine phosphatase family. Non- CC receptor class 1 subfamily. {ECO:0000305}. CC --------------------------------------------------------------------------- CC Copyrighted by the UniProt Consortium, see https://www.uniprot.org/terms CC Distributed under the Creative Commons Attribution (CC BY 4.0) License CC --------------------------------------------------------------------------- DR EMBL; X58828; CAA41633.1; -; mRNA. DR EMBL; BC078758; AAH78758.1; -; mRNA. DR PIR; S14294; S14294. DR RefSeq; NP_446442.1; NM_053990.1. [P35233-4] DR AlphaFoldDB; P35233; -. DR SMR; P35233; -. DR IntAct; P35233; 1. DR STRING; 10116.ENSRNOP00000023763; -. DR BindingDB; P35233; -. DR PhosphoSitePlus; P35233; -. DR jPOST; P35233; -. DR PaxDb; 10116-ENSRNOP00000063665; -. DR GeneID; 117063; -. DR KEGG; rno:117063; -. DR UCSC; RGD:620710; rat. [P35233-1] DR AGR; RGD:620710; -. DR CTD; 5771; -. DR RGD; 620710; Ptpn2. DR VEuPathDB; HostDB:ENSRNOG00000017453; -. DR eggNOG; KOG0789; Eukaryota. DR InParanoid; P35233; -. DR OrthoDB; 2911650at2759; -. DR Reactome; R-RNO-6807004; Negative regulation of MET activity. DR Reactome; R-RNO-877312; Regulation of IFNG signaling. DR Reactome; R-RNO-9833482; PKR-mediated signaling. DR PRO; PR:P35233; -. DR Proteomes; UP000002494; Chromosome 18. DR Bgee; ENSRNOG00000017453; Expressed in thymus and 20 other cell types or tissues. DR GO; GO:0005737; C:cytoplasm; IBA:GO_Central. DR GO; GO:0005783; C:endoplasmic reticulum; ISS:UniProtKB. DR GO; GO:0005793; C:endoplasmic reticulum-Golgi intermediate compartment; ISS:UniProtKB. DR GO; GO:0031904; C:endosome lumen; ISO:RGD. DR GO; GO:0031965; C:nuclear membrane; IEA:UniProtKB-SubCell. DR GO; GO:0005634; C:nucleus; ISS:UniProtKB. DR GO; GO:0005886; C:plasma membrane; IEA:UniProtKB-SubCell. DR GO; GO:0003677; F:DNA binding; TAS:RGD. DR GO; GO:0005178; F:integrin binding; ISO:RGD. DR GO; GO:0004726; F:non-membrane spanning protein tyrosine phosphatase activity; IDA:RGD. DR GO; GO:0019901; F:protein kinase binding; ISO:RGD. DR GO; GO:0004725; F:protein tyrosine phosphatase activity; ISS:UniProtKB. DR GO; GO:0030971; F:receptor tyrosine kinase binding; ISO:RGD. DR GO; GO:0097677; F:STAT family protein binding; ISO:RGD. DR GO; GO:0019905; F:syntaxin binding; ISO:RGD. DR GO; GO:0030183; P:B cell differentiation; ISS:UniProtKB. DR GO; GO:0030218; P:erythrocyte differentiation; ISS:UniProtKB. DR GO; GO:0042593; P:glucose homeostasis; ISS:UniProtKB. DR GO; GO:0038020; P:insulin receptor recycling; ISO:RGD. DR GO; GO:0008286; P:insulin receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0008285; P:negative regulation of cell population proliferation; ISS:UniProtKB. DR GO; GO:0050922; P:negative regulation of chemotaxis; ISS:UniProtKB. DR GO; GO:0042059; P:negative regulation of epidermal growth factor receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0070373; P:negative regulation of ERK1 and ERK2 cascade; ISS:UniProtKB. DR GO; GO:0050728; P:negative regulation of inflammatory response; ISS:UniProtKB. DR GO; GO:0046627; P:negative regulation of insulin receptor signaling pathway; ISS:UniProtKB. DR GO; GO:1902206; P:negative regulation of interleukin-2-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:1902215; P:negative regulation of interleukin-4-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0070104; P:negative regulation of interleukin-6-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0010888; P:negative regulation of lipid storage; ISS:UniProtKB. DR GO; GO:1902227; P:negative regulation of macrophage colony-stimulating factor signaling pathway; ISS:UniProtKB. DR GO; GO:0045650; P:negative regulation of macrophage differentiation; ISS:UniProtKB. DR GO; GO:2000587; P:negative regulation of platelet-derived growth factor receptor-beta signaling pathway; ISS:UniProtKB. DR GO; GO:1902233; P:negative regulation of positive thymic T cell selection; ISS:UniProtKB. DR GO; GO:0046426; P:negative regulation of receptor signaling pathway via JAK-STAT; IBA:GO_Central. DR GO; GO:0050860; P:negative regulation of T cell receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0000122; P:negative regulation of transcription by RNA polymerase II; ISO:RGD. DR GO; GO:0010804; P:negative regulation of tumor necrosis factor-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0060339; P:negative regulation of type I interferon-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0060336; P:negative regulation of type II interferon-mediated signaling pathway; ISS:UniProtKB. DR GO; GO:0042532; P:negative regulation of tyrosine phosphorylation of STAT protein; ISS:UniProtKB. DR GO; GO:0035335; P:peptidyl-tyrosine dephosphorylation; ISS:UniProtKB. DR GO; GO:1902237; P:positive regulation of endoplasmic reticulum stress-induced intrinsic apoptotic signaling pathway; ISO:RGD. DR GO; GO:0045722; P:positive regulation of gluconeogenesis; ISS:UniProtKB. DR GO; GO:1903899; P:positive regulation of PERK-mediated unfolded protein response; ISO:RGD. DR GO; GO:1902202; P:regulation of hepatocyte growth factor receptor signaling pathway; ISS:UniProtKB. DR GO; GO:0030217; P:T cell differentiation; ISS:UniProtKB. DR Gene3D; 3.90.190.10; Protein tyrosine phosphatase superfamily; 1. DR InterPro; IPR029021; Prot-tyrosine_phosphatase-like. DR InterPro; IPR000242; PTP_cat. DR InterPro; IPR012265; Ptpn1/Ptpn2. DR InterPro; IPR016130; Tyr_Pase_AS. DR InterPro; IPR003595; Tyr_Pase_cat. DR InterPro; IPR000387; Tyr_Pase_dom. DR PANTHER; PTHR46047:SF1; TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 2; 1. DR PANTHER; PTHR46047; TYROSINE-PROTEIN PHOSPHATASE NON-RECEPTOR TYPE 61F; 1. DR Pfam; PF00102; Y_phosphatase; 1. DR PIRSF; PIRSF000926; Tyr-Ptase_nr1; 1. DR PRINTS; PR00700; PRTYPHPHTASE. DR SMART; SM00194; PTPc; 1. DR SMART; SM00404; PTPc_motif; 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 1: Evidence at protein level; KW Alternative splicing; Cell membrane; Cytoplasm; Endoplasmic reticulum; KW Hydrolase; Membrane; Nucleus; Phosphoprotein; Protein phosphatase; KW Reference proteome; S-nitrosylation. FT CHAIN 1..416 FT /note="Tyrosine-protein phosphatase non-receptor type 2" FT /id="PRO_0000094754" FT DOMAIN 5..275 FT /note="Tyrosine-protein phosphatase" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160" FT REGION 341..410 FT /note="Endoplasmic reticulum location" FT /evidence="ECO:0000250" FT REGION 371..410 FT /note="May mediate interaction with STX17" FT /evidence="ECO:0000250" FT ACT_SITE 216 FT /note="Phosphocysteine intermediate" FT /evidence="ECO:0000255|PROSITE-ProRule:PRU00160, FT ECO:0000255|PROSITE-ProRule:PRU10044" FT BINDING 182 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 216..222 FT /ligand="substrate" FT /evidence="ECO:0000250" FT BINDING 260 FT /ligand="substrate" FT /evidence="ECO:0000250" FT MOD_RES 22 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT MOD_RES 52 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT MOD_RES 68 FT /note="Phosphotyrosine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT MOD_RES 216 FT /note="S-nitrosocysteine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT MOD_RES 293 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P17706" FT MOD_RES 298 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P17706" FT MOD_RES 304 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P17706" FT MOD_RES 320 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:Q06180" FT MOD_RES 339 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P18031" FT VAR_SEQ 287..305 FT /note="Missing (in isoform 3 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:1849097" FT /id="VSP_042001" FT VAR_SEQ 377..410 FT /note="Missing (in isoform 2 and isoform 4)" FT /evidence="ECO:0000303|PubMed:15489334, FT ECO:0000303|PubMed:1849097" FT /id="VSP_042002" FT MOD_RES P35233-2:304 FT /note="Phosphoserine" FT /evidence="ECO:0000250|UniProtKB:P17706" SQ SEQUENCE 416 AA; 48446 MW; E8FB1E670FFC5308 CRC64; MSATIEREFE ELDAQCRWQP LYLEIRNESH DYPHRVAKFP ENRNRNRYRD VSPYDHSRVK LQSAENDYIN ASLVDIEEAQ RSYILTQGPL PNTCCHFWLM VWQQKTRAVV MLNRTVEKES VKCAQYWPTD DREMVFKETG FSVKLLSEDV KSYYTVHLLQ LENINSGETR TISHFHYTTW PDFGVPESPA SFLNFLFKVR ESGSLNPDHG PAVIHCSAGI GRSGTFSLVD TCLVLMEKGE DVNVKQILLS MRKYRMGLIQ TPDQLRFSYM AIIEGAKYTK GDSNIQKRWK ELSKEDLSPV CRHSQNRTMT EKYNGKRIGS EDEKLTGLSS KVPDTVEESS ESILRKRIRE DRKATTAQKV QQMRQRLNET ERKRKRWLYW QPILTKMGFV SVILVGALVG WTLLFQLNVL PRLTDT //