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Protein

Tyrosine-protein phosphatase non-receptor type 2

Gene

PTPN2

Organism
Homo sapiens (Human)
Status
Reviewed-Annotation score: -Experimental evidence at protein leveli

Functioni

Non-receptor type tyrosine-specific phosphatase that dephosphorylates receptor protein tyrosine kinases including INSR, EGFR, CSF1R, PDGFR. Also dephosphorylates non-receptor protein tyrosine kinases like JAK1, JAK2, JAK3, Src family kinases, STAT1, STAT3 and STAT6 either in the nucleus or the cytoplasm. Negatively regulates numerous signaling pathways and biological processes like hematopoiesis, inflammatory response, cell proliferation and differentiation, and glucose homeostasis. Plays a multifaceted and important role in the development of the immune system. Functions in T-cell receptor signaling through dephosphorylation of FYN and LCK to control T-cells differentiation and activation. Dephosphorylates CSF1R, negatively regulating its downstream signaling and macrophage differentiation. Negatively regulates cytokine (IL2/interleukin-2 and interferon)-mediated signaling through dephosphorylation of the cytoplasmic kinases JAK1, JAK3 and their substrate STAT1, that propagate signaling downstream of the cytokine receptors. Also regulates the IL6/interleukin-6 and IL4/interleukin-4 cytokine signaling through dephosphorylation of STAT3 and STAT6 respectively. In addition to the immune system, it is involved in anchorage-dependent, negative regulation of EGF-stimulated cell growth. Activated by the integrin ITGA1/ITGB1, it dephosphorylates EGFR and negatively regulates EGF signaling. Dephosphorylates PDGFRB and negatively regulates platelet-derived growth factor receptor-beta signaling pathway and therefore cell proliferation. Negatively regulates tumor necrosis factor-mediated signaling downstream via MAPK through SRC dephosphorylation. May also regulate the hepatocyte growth factor receptor signaling pathway through dephosphorylation of the hepatocyte growth factor receptor MET. Plays also an important role in glucose homeostasis. For instance, negatively regulates the insulin receptor signaling pathway through the dephosphorylation of INSR and control gluconeogenesis and liver glucose production through negative regulation of the IL6 signaling pathways. May also bind DNA.9 Publications

Catalytic activityi

Protein tyrosine phosphate + H2O = protein tyrosine + phosphate.PROSITE-ProRule annotation

Kineticsi

  1. KM=0.48 mM for p-nitrophenyl phosphate (at pH 6.5 and 25 degrees Celsius)1 Publication

    Sites

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Binding sitei182SubstrateBy similarity1
    Active sitei216Phosphocysteine intermediatePROSITE-ProRule annotation1
    Binding sitei260SubstrateBy similarity1

    GO - Molecular functioni

    GO - Biological processi

    Keywordsi

    Molecular functionHydrolase, Protein phosphatase

    Enzyme and pathway databases

    BRENDAi3.1.3.48 2681
    ReactomeiR-HSA-6807004 Negative regulation of MET activity
    R-HSA-877312 Regulation of IFNG signaling
    R-HSA-9008059 Interleukin-37 signaling
    SignaLinkiP17706
    SIGNORiP17706

    Names & Taxonomyi

    Protein namesi
    Recommended name:
    Tyrosine-protein phosphatase non-receptor type 2 (EC:3.1.3.48)
    Alternative name(s):
    T-cell protein-tyrosine phosphatase
    Short name:
    TCPTP
    Gene namesi
    Name:PTPN2
    Synonyms:PTPT
    OrganismiHomo sapiens (Human)
    Taxonomic identifieri9606 [NCBI]
    Taxonomic lineageiEukaryotaMetazoaChordataCraniataVertebrataEuteleostomiMammaliaEutheriaEuarchontogliresPrimatesHaplorrhiniCatarrhiniHominidaeHomo
    Proteomesi
    • UP000005640 Componenti: Chromosome 18

    Organism-specific databases

    EuPathDBiHostDB:ENSG00000175354.18
    HGNCiHGNC:9650 PTPN2
    MIMi176887 gene
    neXtProtiNX_P17706

    Subcellular locationi

    Extracellular region or secreted Cytosol Plasma membrane Cytoskeleton Lysosome Endosome Peroxisome ER Golgi apparatus Nucleus Mitochondrion Manual annotation Automatic computational assertionGraphics by Christian Stolte; Source: COMPARTMENTS

    Keywords - Cellular componenti

    Cell membrane, Cytoplasm, Endoplasmic reticulum, Membrane, Nucleus

    Pathology & Biotechi

    Mutagenesis

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Mutagenesisi182D → A: Substrate-trapping mutant; catalytically inactive it forms a stable complex with physiological substrates including INSR and EGFR. Accumulates in the cytoplasm upon stimulation by insulin or EGF; isoform 2. 2 Publications1
    Mutagenesisi222R → M: Impairs phosphatase activity. 1
    Mutagenesisi304S → A: Alters phosphorylation by cyclin-dependent kinases of isoform 2 but has no effect on its phosphatase activity. 1 Publication1
    Mutagenesisi350 – 352RKR → QQQ: Alters location to the endoplasmic reticulum; isoform 1. 1 Publication3
    Mutagenesisi380K → Q: Prevents location to the nucleus; isoform 2. 1 Publication1

    Organism-specific databases

    DisGeNETi5771
    MalaCardsiPTPN2
    OpenTargetsiENSG00000175354
    Orphaneti206 Crohn disease
    85408 Juvenile rheumatoid factor-negative polyarthritis
    85410 Oligoarticular juvenile arthritis
    771 Ulcerative colitis
    PharmGKBiPA33993

    Chemistry databases

    ChEMBLiCHEMBL3807

    Polymorphism and mutation databases

    BioMutaiPTPN2
    DMDMi229462762

    PTM / Processingi

    Molecule processing

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    ChainiPRO_00000947521 – 415Tyrosine-protein phosphatase non-receptor type 2Add BLAST415

    Amino acid modifications

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Modified residuei22PhosphotyrosineBy similarity1
    Modified residuei52PhosphoserineBy similarity1
    Modified residuei68PhosphotyrosineBy similarity1
    Modified residuei216S-nitrosocysteineBy similarity1
    Modified residuei293PhosphoserineCombined sources1
    Modified residuei298PhosphoserineCombined sources1
    Modified residuei304PhosphoserineCombined sources1
    Isoform 2 (identifier: P17706-2)
    Modified residuei304Phosphoserine1 Publication1 Publication1

    Post-translational modificationi

    Isoform 2: Specifically phosphorylated in a cell cycle-dependent manner by cyclin-dependent kinases CDK1 and CDK2. Probably activated through phosphorylation by PKR.2 Publications

    Keywords - PTMi

    Phosphoprotein, S-nitrosylation

    Proteomic databases

    EPDiP17706
    MaxQBiP17706
    PaxDbiP17706
    PeptideAtlasiP17706
    PRIDEiP17706
    ProteomicsDBi53507
    53508 [P17706-2]
    53509 [P17706-3]

    PTM databases

    DEPODiP17706
    iPTMnetiP17706
    PhosphoSitePlusiP17706

    Expressioni

    Tissue specificityi

    Ubiquitously expressed. Isoform 2 is probably the major isoform. Isoform 1 is expressed in T-cells and in placenta.2 Publications

    Inductioni

    Up-regulated by IL4/interleukin-4 (at protein level).1 Publication

    Gene expression databases

    BgeeiENSG00000175354 Expressed in 231 organ(s), highest expression level in tendon of biceps brachii
    CleanExiHS_PTPN2
    ExpressionAtlasiP17706 baseline and differential
    GenevisibleiP17706 HS

    Organism-specific databases

    HPAiHPA015004
    HPA046176

    Interactioni

    Subunit structurei

    Interacts with RMDN3. Isoform 1 interacts with TMED9. Isoform 1 interacts with STX17; dephosphorylates STX17. Interacts with ITGA1 (via cytoplasmic domain); activates the phosphatase activity towards EGFR. Interacts with TRAF2; probably involved in tumor necrosis factor-mediated signaling. Interacts with MET.7 Publications

    Binary interactionsi

    GO - Molecular functioni

    Protein-protein interaction databases

    BioGridi111737, 90 interactors
    CORUMiP17706
    IntActiP17706, 26 interactors
    MINTiP17706
    STRINGi9606.ENSP00000311857

    Chemistry databases

    BindingDBiP17706

    Structurei

    Secondary structure

    1415
    Legend: HelixTurnBeta strandPDB Structure known for this area
    Show more details

    3D structure databases

    ProteinModelPortaliP17706
    SMRiP17706
    ModBaseiSearch...
    MobiDBiSearch...

    Miscellaneous databases

    EvolutionaryTraceiP17706

    Family & Domainsi

    Domains and Repeats

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Domaini5 – 275Tyrosine-protein phosphatasePROSITE-ProRule annotationAdd BLAST271

    Region

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Regioni216 – 222Substrate bindingBy similarity7
    Regioni346 – 415Endoplasmic reticulum locationAdd BLAST70
    Regioni376 – 415Mediates interaction with STX171 PublicationAdd BLAST40

    Sequence similaritiesi

    Phylogenomic databases

    eggNOGiKOG0789 Eukaryota
    COG5599 LUCA
    GeneTreeiENSGT00900000140785
    HOGENOMiHOG000273908
    HOVERGENiHBG008321
    InParanoidiP17706
    KOiK18026
    OMAiWQQLYLE
    OrthoDBiEOG091G082B
    PhylomeDBiP17706
    TreeFamiTF315897

    Family and domain databases

    Gene3Di3.90.190.10, 1 hit
    InterProiView protein in InterPro
    IPR029021 Prot-tyrosine_phosphatase-like
    IPR000242 PTPase_domain
    IPR012265 Ptpn1/Ptpn2
    IPR016130 Tyr_Pase_AS
    IPR003595 Tyr_Pase_cat
    IPR000387 TYR_PHOSPHATASE_dom
    PfamiView protein in Pfam
    PF00102 Y_phosphatase, 1 hit
    PIRSFiPIRSF000926 Tyr-Ptase_nr1, 1 hit
    PRINTSiPR00700 PRTYPHPHTASE
    SMARTiView protein in SMART
    SM00194 PTPc, 1 hit
    SM00404 PTPc_motif, 1 hit
    SUPFAMiSSF52799 SSF52799, 1 hit
    PROSITEiView protein in PROSITE
    PS00383 TYR_PHOSPHATASE_1, 1 hit
    PS50056 TYR_PHOSPHATASE_2, 1 hit
    PS50055 TYR_PHOSPHATASE_PTP, 1 hit

    Sequences (4+)i

    Sequence statusi: Complete.

    This entry describes 4 isoformsi produced by alternative splicing. AlignAdd to basket

    This entry has 4 described isoforms and 9 potential isoforms that are computationally mapped.iShow all

    Isoform 1 (identifier: P17706-1) [UniParc]FASTAAdd to basket
    Also known as: PTPB, p48TC, TC48, TC-PTPb

    This isoform has been chosen as the 'canonical' sequence. All positional information in this entry refers to it. This is also the sequence that appears in the downloadable versions of the entry.

    « Hide
            10         20         30         40         50
    MPTTIEREFE ELDTQRRWQP LYLEIRNESH DYPHRVAKFP ENRNRNRYRD
    60 70 80 90 100
    VSPYDHSRVK LQNAENDYIN ASLVDIEEAQ RSYILTQGPL PNTCCHFWLM
    110 120 130 140 150
    VWQQKTKAVV MLNRIVEKES VKCAQYWPTD DQEMLFKETG FSVKLLSEDV
    160 170 180 190 200
    KSYYTVHLLQ LENINSGETR TISHFHYTTW PDFGVPESPA SFLNFLFKVR
    210 220 230 240 250
    ESGSLNPDHG PAVIHCSAGI GRSGTFSLVD TCLVLMEKGD DINIKQVLLN
    260 270 280 290 300
    MRKYRMGLIQ TPDQLRFSYM AIIEGAKCIK GDSSIQKRWK ELSKEDLSPA
    310 320 330 340 350
    FDHSPNKIMT EKYNGNRIGL EEEKLTGDRC TGLSSKMQDT MEENSESALR
    360 370 380 390 400
    KRIREDRKAT TAQKVQQMKQ RLNENERKRK RWLYWQPILT KMGFMSVILV
    410
    GAFVGWTLFF QQNAL
    Note: Minor isoform.
    Length:415
    Mass (Da):48,473
    Last modified:May 5, 2009 - v2
    Checksum:i0207694A4F058E68
    GO
    Isoform 2 (identifier: P17706-2) [UniParc]FASTAAdd to basket
    Also known as: PTPA, p45TC, TC45, TC-PTPa

    The sequence of this isoform differs from the canonical sequence as follows:
         382-415: WLYWQPILTKMGFMSVILVGAFVGWTLFFQQNAL → PRLTDT

    Note: Major isoform.1 Publication1 Publication Contains a nuclear location signal at positions 377-381 (PubMed:7593185) and an autoinhibitory region acting through intramolecular interactions is found at positions 353-387.1 Publication1 Publication
    Show »
    Length:387
    Mass (Da):45,168
    Checksum:i0F3E622EBA5A92CB
    GO
    Isoform 3 (identifier: P17706-3) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         347-380: Missing.
         382-415: WLYWQPILTKMGFMSVILVGAFVGWTLFFQQNAL → PRLTDT

    Note: No experimental confirmation available.
    Show »
    Length:353
    Mass (Da):40,990
    Checksum:i5AE668EB7D76CB93
    GO
    Isoform 4 (identifier: P17706-4) [UniParc]FASTAAdd to basket

    The sequence of this isoform differs from the canonical sequence as follows:
         165-165: N → NYIENLWITLYLKLLMLDVKRSLK
         382-415: WLYWQPILTKMGFMSVILVGAFVGWTLFFQQNAL → PRLTDT

    Note: No experimental confirmation available. Gene prediction based on cDNA data.
    Show »
    Length:410
    Mass (Da):48,017
    Checksum:iD6463B9A0F952068
    GO

    Computationally mapped potential isoform sequencesi

    There are 9 potential isoforms mapped to this entry.BLASTAlignShow allAdd to basket
    EntryEntry nameProtein names
    Gene namesLengthAnnotation
    K7EQG9K7EQG9_HUMAN
    Tyrosine-protein phosphatase non-re...
    PTPN2
    386Annotation score:
    K7ENP9K7ENP9_HUMAN
    Tyrosine-protein phosphatase
    PTPN2
    146Annotation score:
    K7EIE9K7EIE9_HUMAN
    Tyrosine-protein phosphatase
    PTPN2
    151Annotation score:
    K7EIY0K7EIY0_HUMAN
    Tyrosine-protein phosphatase
    PTPN2
    112Annotation score:
    D3DUJ3D3DUJ3_HUMAN
    Tyrosine-protein phosphatase
    PTPN2 hCG_1999834
    316Annotation score:
    K7ERU1K7ERU1_HUMAN
    Tyrosine-protein phosphatase
    PTPN2
    42Annotation score:
    K7ER87K7ER87_HUMAN
    Tyrosine-protein phosphatase
    PTPN2
    165Annotation score:
    K7ELS9K7ELS9_HUMAN
    Tyrosine-protein phosphatase
    PTPN2
    68Annotation score:
    A0A2R8YD79A0A2R8YD79_HUMAN
    Tyrosine-protein phosphatase
    PTPN2
    166Annotation score:

    Experimental Info

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Sequence conflicti407T → R in AAA65997 (PubMed:2546150).Curated1
    Sequence conflicti407T → R in M81478 (PubMed:1731319).Curated1

    Alternative sequence

    Feature keyPosition(s)DescriptionActionsGraphical viewLength
    Alternative sequenceiVSP_054821165N → NYIENLWITLYLKLLMLDVK RSLK in isoform 4. Curated1
    Alternative sequenceiVSP_043383347 – 380Missing in isoform 3. 1 PublicationAdd BLAST34
    Alternative sequenceiVSP_005125382 – 415WLYWQ…QQNAL → PRLTDT in isoform 2, isoform 3 and isoform 4. 2 PublicationsAdd BLAST34

    Sequence databases

    Select the link destinations:
    EMBLi
    GenBanki
    DDBJi
    Links Updated
    M25393 mRNA Translation: AAA65997.1
    AK292570 mRNA Translation: BAF85259.1
    EF445017 Genomic DNA Translation: ACA06062.1
    EF445017 Genomic DNA Translation: ACA06064.1
    AP001077 Genomic DNA No translation available.
    AP002449 Genomic DNA No translation available.
    AP005482 Genomic DNA No translation available.
    CH471113 Genomic DNA Translation: EAX01532.1
    CH471113 Genomic DNA Translation: EAX01539.1
    BC008244 mRNA Translation: AAH08244.1
    BC016727 mRNA Translation: AAH16727.1
    M81478 mRNA No translation available.
    CCDSiCCDS11863.1 [P17706-2]
    CCDS11864.1 [P17706-3]
    CCDS11865.1 [P17706-1]
    CCDS59306.1 [P17706-4]
    PIRiA33899
    RefSeqiNP_001193942.1, NM_001207013.1 [P17706-4]
    NP_002819.2, NM_002828.3 [P17706-1]
    NP_536347.1, NM_080422.2 [P17706-2]
    NP_536348.1, NM_080423.2 [P17706-3]
    UniGeneiHs.654527
    Hs.663373

    Genome annotation databases

    EnsembliENST00000309660; ENSP00000311857; ENSG00000175354 [P17706-1]
    ENST00000327283; ENSP00000320298; ENSG00000175354 [P17706-2]
    ENST00000353319; ENSP00000320546; ENSG00000175354 [P17706-3]
    ENST00000591115; ENSP00000466936; ENSG00000175354 [P17706-4]
    GeneIDi5771
    KEGGihsa:5771
    UCSCiuc002krl.4 human [P17706-1]

    Keywords - Coding sequence diversityi

    Alternative splicing

    Similar proteinsi

    Entry informationi

    Entry nameiPTN2_HUMAN
    AccessioniPrimary (citable) accession number: P17706
    Secondary accession number(s): A8K955
    , A8MXU3, K7ENG3, Q96AU5, Q96HR2
    Entry historyiIntegrated into UniProtKB/Swiss-Prot: August 1, 1990
    Last sequence update: May 5, 2009
    Last modified: September 12, 2018
    This is version 195 of the entry and version 2 of the sequence. See complete history.
    Entry statusiReviewed (UniProtKB/Swiss-Prot)
    Annotation programChordata Protein Annotation Program
    DisclaimerAny medical or genetic information present in this entry is provided for research, educational and informational purposes only. It is not in any way intended to be used as a substitute for professional medical advice, diagnosis, treatment or care.

    Miscellaneousi

    Keywords - Technical termi

    3D-structure, Complete proteome, Reference proteome
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    Main funding by: National Institutes of Health

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