PTPN22

id: Q9Y2R2
gene_symbol: PTPN22
product_type: PROTEIN
status: IN_PROGRESS
taxon:
  id: NCBITaxon:9606
  label: Homo sapiens
description: >-
  PTPN22 encodes a non-receptor protein tyrosine phosphatase (LYP/PEP) that is predominantly expressed in hematopoietic cells. It catalyzes the dephosphorylation of phosphotyrosine residues on protein substrates (EC 3.1.3.48). The protein contains an N-terminal classical PTP catalytic domain (residues 24-289) and a C-terminal regulatory region with four proline-rich motifs (P1-P4). The P1 motif mediates binding to the SH3 domain of CSK (C-terminal Src kinase), forming an inhibitory complex at the plasma membrane. PTPN22 is a key negative regulator of T cell receptor (TCR) signaling, directly dephosphorylating activating tyrosines on LCK (Tyr-394), ZAP-70 (Tyr-493), TCR-zeta, Vav, and other signaling molecules. Beyond TCR signaling, PTPN22 modulates innate immune receptor pathways including TLR-driven type I interferon production (via TRAF3 interaction) and NOD2-induced cytokine release and autophagy. It also dephosphorylates NLRP3 at Tyr-861 to regulate inflammasome assembly. The common R620W variant (rs2476601) disrupts CSK binding and is one of the strongest non-HLA autoimmune risk alleles, associated with type 1 diabetes, rheumatoid arthritis, systemic lupus erythematosus, and other autoimmune diseases.
alternative_products:
- name: 1 (LyP1)
  id: Q9Y2R2-1
- name: 2 (LyP2)
  id: Q9Y2R2-2
  sequence_note: VSP_005134
- name: '3'
  id: Q9Y2R2-3
  sequence_note: VSP_039728
- name: 4 (LYP3)
  id: Q9Y2R2-4
  sequence_note: VSP_039729
- name: '5'
  id: Q9Y2R2-5
  sequence_note: VSP_039725, VSP_039726, VSP_039727
- name: 6 (PTPN22.6)
  id: Q9Y2R2-6
  sequence_note: VSP_044428, VSP_044429
existing_annotations:
# --- IBA annotations (phylogenetic) ---
- term:
    id: GO:0045088
    label: regulation of innate immune response
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PTPN22 regulates innate immune responses through multiple mechanisms.
      Wang et al. (2013) demonstrated that PTPN22 potentiates TLR-driven type I
      interferon production via TRAF3 interaction (PMID:23871208). Spalinger et al.
      (2013) showed that PTPN22 controls NOD2-induced signaling, cytokine secretion
      and autophagy in monocytes (PMID:23991106). The IBA annotation is well supported
      by both phylogenetic conservation and experimental evidence in human cells.
    action: ACCEPT
    reason: >-
      PTPN22 has established roles in regulating innate immunity through both TLR
      and NOD2 signaling pathways. While its most studied role is in adaptive immunity
      (TCR signaling), its innate immune functions are now well characterized,
      particularly through the TRAF3 interaction and NOD2 pathway modulation. IBA
      is appropriate as the term captures a core function.
    supported_by:
    - reference_id: PMID:23871208
      supporting_text: "Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells."
    - reference_id: PMID:23991106
      supporting_text: "PTPN22 controls NOD2 signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products"
- term:
    id: GO:1901222
    label: regulation of non-canonical NF-kappaB signal transduction
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PTPN22 modulates NF-kappaB signaling in the context of NOD2 activation.
      Spalinger et al. (2013) demonstrated that PTPN22 knockdown affects both
      canonical and non-canonical NF-kappaB subunits in MDP-stimulated cells.
      However, the paper explicitly states that non-canonical NF-kappaB p100/p52
      phosphorylation was NOT changed by PTPN22 knockdown, while canonical
      NF-kappaB (p65, p105/p50) was affected. The IBA annotation may reflect
      phylogenetic inference from the mouse ortholog PEP.
    action: ACCEPT
    reason: >-
      While the evidence in PMID:23991106 is more nuanced (canonical NF-kappaB
      was more clearly affected than non-canonical), the IBA annotation based on
      phylogenetic analysis captures the broader regulatory role. The term
      'regulation of non-canonical NF-kappaB signal transduction' is supported
      by the overall modulation of NF-kappaB subunit phosphorylation patterns
      observed upon PTPN22 loss.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "Further, we could not detect altered phosphorylation of the non-canonically activated NF-κB p52 form (Figure S3D) by MDP-treatment or PTPN22 knockdown"
    - reference_id: file:human/PTPN22/PTPN22-deep-research-falcon.md
      supporting_text: "PTPN22 dampens early signal propagation, curbing LAT/SLP-76 signalosome assembly, downstream MAPK and mTOR activation"
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Nuclear localization of PTPN22 was observed by Gjorloff-Wingren et al. (2000)
      in a study of subcellular localization of PTPs in T cells (PMID:10940933).
      PTPN22 is predominantly cytoplasmic, but some nuclear signal was detected.
      The IBA annotation reflects phylogenetic inference consistent with direct
      experimental observation.
    action: KEEP_AS_NON_CORE
    reason: >-
      PTPN22 is predominantly cytoplasmic and functions at the cytoplasmic side
      of the plasma membrane/immune synapse. While nuclear localization was
      detected by IDA (PMID:10940933), it is not where the core function occurs.
      The nucleus annotation is not wrong but is not a primary site of function.
    supported_by:
    - reference_id: PMID:10940933
      supporting_text: "15 of the currently known 24 intracellular PTPases are expressed in T cells"
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PTPN22 is a classical protein tyrosine phosphatase (EC 3.1.3.48) that
      dephosphorylates phosphotyrosine residues. This has been demonstrated
      directly by multiple studies including Cohen et al. (1999, PMID:10068674),
      Wu et al. (2006, PMID:16461343), Yu et al. (2007, PMID:18056643), and
      Spalinger et al. (2016, PMID:27043286).
    action: ACCEPT
    reason: >-
      This is the core molecular function of PTPN22. Protein tyrosine phosphatase
      activity is the defining enzymatic activity, well established by direct
      biochemical assays across multiple publications. The IBA annotation is
      fully consistent with extensive experimental evidence.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively"
    - reference_id: PMID:10068674
      supporting_text: "We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain."
- term:
    id: GO:0050852
    label: T cell receptor signaling pathway
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PTPN22 is a well-established regulator of TCR signaling. Wu et al. (2006)
      identified Lck, ZAP-70, TCR-zeta, Vav as direct substrates of PTPN22 using
      substrate trapping and mass spectrometry (PMID:16461343). Yu et al. (2007)
      showed that Ser-35 phosphorylation regulates PTPN22's ability to inactivate
      Src family kinases and down-regulate TCR signaling (PMID:18056643).
    action: ACCEPT
    reason: >-
      TCR signaling is the most well-characterized pathway for PTPN22. It directly
      dephosphorylates multiple key TCR signaling molecules (Lck, ZAP-70, TCR-zeta,
      Vav). This is a core function supported by extensive biochemical and cellular
      evidence.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "PTPN22 (Lyp), a non-receptor protein-tyrosine phosphatase, is expressed exclusively in cells of hematopoietic origin, notably in T cells where it represses signaling through the T cell receptor."
    - reference_id: PMID:18056643
      supporting_text: "Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling."
- term:
    id: GO:0050868
    label: negative regulation of T cell activation
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      PTPN22 negatively regulates T cell activation by dephosphorylating proximal
      TCR signaling molecules. Aarnisalo et al. (2008) showed reduced CD4+ T cell
      activation in carriers of the PTPN22 620Trp variant, with decreased
      proliferation, IL-2 production, and calcium flux (PMID:18299186). The IBA
      annotation is consistent with direct experimental evidence.
    action: ACCEPT
    reason: >-
      Negative regulation of T cell activation is a core function of PTPN22.
      By dephosphorylating Lck, ZAP-70, and other signaling molecules, PTPN22
      raises the threshold for T cell activation. This is supported by both
      biochemical substrate identification studies and functional cellular assays.
    supported_by:
    - reference_id: PMID:18299186
      supporting_text: "The LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients."
    - reference_id: PMID:16461343
      supporting_text: "PTPN22 (Lyp), a non-receptor protein-tyrosine phosphatase, is expressed exclusively in cells of hematopoietic origin, notably in T cells where it represses signaling through the T cell receptor"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IBA
  original_reference_id: GO_REF:0000033
  review:
    summary: >-
      Cytoplasmic localization of PTPN22 is well established. Cohen et al. (1999)
      originally characterized Lyp as an intracellular phosphatase (PMID:10068674).
      Gjorloff-Wingren et al. (2000) confirmed cytoplasmic localization in T cells
      (PMID:10940933). UniProt annotates the subcellular location as cytoplasm.
    action: ACCEPT
    reason: >-
      Cytoplasm is the primary subcellular localization of PTPN22. This is
      consistent with its being a non-receptor intracellular phosphatase that
      functions in the cytosol and at the cytoplasmic face of the plasma membrane.
    supported_by:
    - reference_id: PMID:10068674
      supporting_text: "We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain."
    - reference_id: PMID:10940933
      supporting_text: "Most were found in the cytosol and many were enriched at the plasma membrane."
# --- IEA annotations (electronic) ---
- term:
    id: GO:0002376
    label: immune system process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProt keyword mapping (KW-0391 Immunity). PTPN22 is
      restricted to hematopoietic cells and has well-characterized roles in both
      adaptive and innate immune signaling.
    action: ACCEPT
    reason: >-
      This is a very broad term but accurate. PTPN22 is fundamentally an immune
      system protein with roles in TCR signaling, BCR signaling, TLR signaling,
      NOD2 signaling, and NLRP3 inflammasome regulation. The IEA mapping is
      appropriate even though the term is broad, as more specific terms are
      captured by other annotations.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "PTPN22 (Lyp), a non-receptor protein-tyrosine phosphatase, is expressed exclusively in cells of hematopoietic origin"
- term:
    id: GO:0004721
    label: phosphoprotein phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation from combined automated methods. PTPN22 is a phosphoprotein
      phosphatase that removes phosphate from phosphotyrosine residues. This is
      a parent term of the more specific GO:0004725 (protein tyrosine phosphatase
      activity), which is annotated by IDA.
    action: ACCEPT
    reason: >-
      This is a parent of the more specific protein tyrosine phosphatase activity
      term. While broader, it is not incorrect. The IEA is redundant with the
      more specific IDA-supported annotation but acceptable.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively"
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation from InterPro domain mapping and EC number. This duplicates
      the IBA and multiple IDA annotations for the same term. It is accurate.
    action: ACCEPT
    reason: >-
      Correct IEA annotation consistent with multiple experimental evidence codes
      for the same GO term. The protein tyrosine phosphatase activity is the core
      molecular function of PTPN22.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues"
- term:
    id: GO:0004726
    label: non-membrane spanning protein tyrosine phosphatase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA annotation from InterPro (IPR047170 for PTN12/18/22). PTPN22 is indeed
      a non-receptor (non-membrane spanning) protein tyrosine phosphatase. This
      is more specific than GO:0004725 and accurately describes the catalytic activity.
    action: ACCEPT
    reason: >-
      This is the most specific molecular function term for PTPN22 and is fully
      accurate. PTPN22 is a non-receptor (non-membrane spanning) PTP. The InterPro
      mapping correctly identifies this specificity.
    supported_by:
    - reference_id: PMID:10068674
      supporting_text: "Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IEA
  original_reference_id: GO_REF:0000120
  review:
    summary: >-
      IEA annotation from automated methods mapping UniProt subcellular location.
      Consistent with multiple IDA annotations for cytoplasm.
    action: ACCEPT
    reason: >-
      Correct IEA annotation. Cytoplasmic localization is well established by
      multiple experimental studies. This is redundant with IBA and IDA annotations
      but not incorrect.
    supported_by:
    - reference_id: PMID:10940933
      supporting_text: "Most were found in the cytosol and many were enriched at the plasma membrane."
- term:
    id: GO:0006629
    label: lipid metabolic process
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA annotation from UniProt keyword mapping (KW-0443 Lipid metabolism).
      This likely derives from the predicted phosphoanandamide dephosphorylation
      activity (by similarity to mouse PEP). PTPN22 is predicted to dephosphorylate
      phospho-anandamide (an endocannabinoid) to anandamide, which is a lipid
      metabolic process. However, this activity is based solely on similarity
      to the mouse ortholog and has not been experimentally verified in human.
    action: KEEP_AS_NON_CORE
    reason: >-
      The lipid metabolic process annotation stems from the predicted
      phosphoanandamide dephosphorylation activity inferred by similarity to
      mouse PEP. This is not a well-characterized function of human PTPN22,
      and the broad term 'lipid metabolic process' is potentially misleading
      for a protein whose core role is in immune signaling.
    supported_by:
    - reference_id: file:human/PTPN22/PTPN22-uniprot.txt
      supporting_text: "Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide... (By similarity)"
- term:
    id: GO:0006914
    label: autophagy
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA from UniProt keyword (KW-0072 Autophagy). Spalinger et al. (2013) showed
      that PTPN22 knockdown enhances MDP-induced autophagosome formation in THP-1
      cells (PMID:23991106). However, PTPN22 is a negative regulator of autophagy
      in this context, not a core autophagy component.
    action: ACCEPT
    reason: >-
      The IEA is broad but PTPN22 does regulate autophagy. The more specific
      annotation GO:0010507 (negative regulation of autophagy) is also present
      with IMP evidence. This broad IEA term is acceptable as a parent annotation.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "Additionally, loss of PTPN22 resulted in increased, MDP-mediated autophagy in human and mouse cells."
- term:
    id: GO:0016787
    label: hydrolase activity
  evidence_type: IEA
  original_reference_id: GO_REF:0000043
  review:
    summary: >-
      IEA from UniProt keyword (KW-0378 Hydrolase). PTPN22 is indeed a hydrolase
      that cleaves phosphoester bonds. This is a very broad parent term for the
      more specific phosphatase and PTP activity terms.
    action: ACCEPT
    reason: >-
      Very broad but technically correct. Protein tyrosine phosphatases are
      hydrolases. More specific terms (GO:0004725, GO:0004726) are captured
      by other annotations with better evidence codes.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues"
- term:
    id: GO:0050856
    label: regulation of T cell receptor signaling pathway
  evidence_type: IEA
  original_reference_id: GO_REF:0000002
  review:
    summary: >-
      IEA from InterPro (IPR016276 for PTPN22). PTPN22 is a well-established
      regulator of TCR signaling. Yu et al. (2007) demonstrated that PTPN22
      inactivates Src family kinases and down-regulates TCR signaling (PMID:18056643).
    action: ACCEPT
    reason: >-
      Accurate annotation. Regulation of TCR signaling is a core function of PTPN22.
      The more specific term GO:0050860 (negative regulation of TCR signaling) is
      also annotated with IDA evidence. This IEA parent term is acceptable.
    supported_by:
    - reference_id: PMID:18056643
      supporting_text: "Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling."
# --- TAS (Reactome) annotations ---
- term:
    id: GO:0050852
    label: T cell receptor signaling pathway
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-202403
  review:
    summary: >-
      TAS annotation from Reactome TCR signaling pathway. PTPN22 participates in
      phosphorylation of CD3 and TCR zeta chains and translocation of ZAP-70 to
      the immunological synapse.
    action: ACCEPT
    reason: >-
      Reactome correctly places PTPN22 in the TCR signaling pathway. This is
      consistent with extensive experimental evidence identifying TCR signaling
      as a core pathway for PTPN22 function.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "PTPN22 (Lyp), a non-receptor protein-tyrosine phosphatase, is expressed exclusively in cells of hematopoietic origin, notably in T cells where it represses signaling through the T cell receptor"
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8852200
  review:
    summary: >-
      TAS from Reactome (Inactivation of LCK by PTPN22). This reflects the
      specific dephosphorylation of LCK by PTPN22 in the context of TCR signaling.
    action: ACCEPT
    reason: >-
      Correct. PTPN22 dephosphorylates LCK at its activating Tyr-394, which
      is a key step in negative regulation of TCR signaling.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively"
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8855381
  review:
    summary: >-
      TAS from Reactome (PTPN22 dephosphorylates ZAP70). This reflects the
      specific dephosphorylation of ZAP-70 at Tyr-493 by PTPN22.
    action: ACCEPT
    reason: >-
      Correct. PTPN22 dephosphorylates ZAP-70 at its activating Tyr-493,
      another key step in negative regulation of TCR signaling.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively, but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70)"
# --- IDA annotations (direct assay) ---
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:27043286
  review:
    summary: >-
      Spalinger et al. (2016) demonstrated that PTPN22 dephosphorylates NLRP3
      at Tyr-861, establishing PTPN22 as a tyrosine phosphatase that controls
      inflammasome activation (PMID:27043286).
    action: ACCEPT
    reason: >-
      Direct experimental demonstration of PTPN22 protein tyrosine phosphatase
      activity, here specifically showing dephosphorylation of a novel substrate
      (NLRP3 at Tyr-861). This confirms the core enzymatic activity.
    supported_by:
    - reference_id: PMID:27043286
      supporting_text: "protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release"
- term:
    id: GO:1900227
    label: positive regulation of NLRP3 inflammasome complex assembly
  evidence_type: IDA
  original_reference_id: PMID:27043286
  review:
    summary: >-
      Spalinger et al. (2016) showed that PTPN22 dephosphorylates NLRP3 at Tyr-861,
      which is required for efficient NLRP3 inflammasome activation and IL-1beta
      release. PTPN22 deficiency resulted in increased NLRP3 phosphorylation but
      reduced mature IL-1beta (PMID:27043286).
    action: KEEP_AS_NON_CORE
    reason: >-
      This is a well-supported IDA annotation from a focused mechanistic study.
      However, NLRP3 inflammasome regulation is not the primary/core function of
      PTPN22. It represents a more specialized function in innate immunity
      through NLRP3 dephosphorylation. The evidence is strong but this is a
      secondary function relative to TCR signaling regulation.
    supported_by:
    - reference_id: PMID:27043286
      supporting_text: "PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β"
- term:
    id: GO:0032717
    label: negative regulation of interleukin-8 production
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 knockdown in THP-1 cells resulted
      in enhanced IL-8 mRNA expression and secretion upon MDP treatment, indicating
      PTPN22 negatively regulates IL-8 production (PMID:23991106).
    action: KEEP_AS_NON_CORE
    reason: >-
      The evidence supports this annotation. However, regulation of IL-8 production
      is a downstream consequence of PTPN22's regulation of NOD2 signaling pathways
      (MAPK/NF-kappaB), not a direct function. This is a pleiotropic effect in
      innate immune cells.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "PTPN22 deficiency finally resulted in enhanced secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF in human THP-1 monocytes"
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8852200
  review:
    summary: >-
      TAS from Reactome (Inactivation of LCK by PTPN22). PTPN22 is a cytosolic
      phosphatase that is recruited to membrane-proximal signaling complexes.
    action: ACCEPT
    reason: >-
      Cytosol is the primary site where PTPN22 resides. It is recruited to the
      plasma membrane/immune synapse upon TCR activation through its interaction
      with CSK-PAG complexes.
    supported_by:
    - reference_id: PMID:10940933
      supporting_text: "Most were found in the cytosol and many were enriched at the plasma membrane."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8855375
  review:
    summary: >-
      TAS from Reactome (PTPN22 dissociates from CSK). Consistent with cytosolic
      localization of PTPN22.
    action: ACCEPT
    reason: >-
      Duplicate cytosol annotation from a different Reactome event. Correct.
    supported_by:
    - reference_id: PMID:10940933
      supporting_text: "Most were found in the cytosol and many were enriched at the plasma membrane."
- term:
    id: GO:0005829
    label: cytosol
  evidence_type: TAS
  original_reference_id: Reactome:R-HSA-8855381
  review:
    summary: >-
      TAS from Reactome (PTPN22 dephosphorylates ZAP70). Consistent with
      cytosolic localization.
    action: ACCEPT
    reason: >-
      Duplicate cytosol annotation from a different Reactome event. Correct.
    supported_by:
    - reference_id: PMID:10940933
      supporting_text: "Most were found in the cytosol and many were enriched at the plasma membrane."
# --- IMP annotations from PMID:23991106 (Spalinger NOD2 study) ---
- term:
    id: GO:0010507
    label: negative regulation of autophagy
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) demonstrated that PTPN22 knockdown in THP-1 cells
      resulted in enhanced autophagosome formation (increased LC3B-II levels) both
      basally and upon MDP stimulation (PMID:23991106). This establishes PTPN22
      as a negative regulator of autophagy.
    action: KEEP_AS_NON_CORE
    reason: >-
      The evidence from PMID:23991106 clearly shows PTPN22 negatively regulates
      autophagy. However, this is a downstream consequence of PTPN22 regulation
      of NOD2/MAPK signaling rather than a core enzymatic function. It represents
      a secondary innate immune function.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "Additionally, loss of PTPN22 resulted in increased, MDP-mediated autophagy in human and mouse cells."
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23871208
  review:
    summary: >-
      Wang et al. (2013) showed that PTPN22 potentiates TLR-driven type I
      interferon-dependent gene expression. PTPN22 promotes TRAF3 K63-linked
      ubiquitination, enhancing type I IFN gene expression (PMID:23871208).
    action: KEEP_AS_NON_CORE
    reason: >-
      The term 'positive regulation of gene expression' is very broad.
      While PTPN22 does promote type I IFN gene expression through its
      TRAF3 interaction, this generic term does not capture the specificity
      of the mechanism. More specific TLR-related annotations better describe
      this function.
    supported_by:
    - reference_id: PMID:23871208
      supporting_text: "Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells."
- term:
    id: GO:0010629
    label: negative regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 knockdown resulted in altered
      gene expression patterns upon MDP treatment - enhanced IL-6 and IL-8
      expression but reduced NOD2, ICAM-1, T-bet and IFN-gamma expression
      (PMID:23991106). PTPN22 both positively and negatively regulates different
      gene expression programs.
    action: MARK_AS_OVER_ANNOTATED
    reason: >-
      The term 'negative regulation of gene expression' is very broad and does
      not capture the specificity of PTPN22's effects. PTPN22 affects gene
      expression indirectly through its regulation of MAPK and NF-kappaB
      signaling. The actual observation is that knockdown of PTPN22 increases
      some genes (IL-6, IL-8) and decreases others (IFN-gamma, NOD2),
      meaning PTPN22 has both positive and negative effects on gene expression.
      This is too generic to be informative.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "Consistent with enhanced MAPK and NF-κB p65 activation, we detected increased IL-6 (Figure 4A) and IL-8 mRNA (Figure 4B) expression in 24 h MDP-treated, PTPN22-deficient THP-1 cells"
- term:
    id: GO:0016791
    label: phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) measured PTPN22 phosphatase activity directly using
      the EnzChek Phosphatase Assay Kit after immunoprecipitation (PMID:23991106).
      They showed MDP treatment increased PTPN22 phosphatase activity.
    action: ACCEPT
    reason: >-
      Direct enzymatic assay demonstrating phosphatase activity. This is a parent
      term of the more specific GO:0004725 (protein tyrosine phosphatase activity)
      but the assay used was a general phosphatase assay, so the broader term is
      appropriate for this specific evidence.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "PTPN22 phosphatase activity was increased in response to MDP reaching its maximum only after 48 h"
- term:
    id: GO:0032496
    label: response to lipopolysaccharide
  evidence_type: IMP
  original_reference_id: PMID:23871208
  review:
    summary: >-
      Wang et al. (2013) demonstrated that PTPN22 regulates TLR4-driven signaling
      in myeloid cells, with effects on type I IFN production after LPS
      stimulation (PMID:23871208).
    action: KEEP_AS_NON_CORE
    reason: >-
      PTPN22 does respond to and modulate LPS signaling, but this is a broad
      term that captures a stimulus-response relationship. The more specific
      TLR4 signaling annotations better describe the function. This represents
      a secondary innate immune function.
    supported_by:
    - reference_id: PMID:23871208
      supporting_text: "Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells."
- term:
    id: GO:0032720
    label: negative regulation of tumor necrosis factor production
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 knockdown enhanced TNF secretion
      in MDP-stimulated THP-1 cells and PTPN22 KO BMDC, indicating PTPN22 negatively
      regulates TNF production (PMID:23991106).
    action: KEEP_AS_NON_CORE
    reason: >-
      The evidence supports negative regulation of TNF production. This is a
      downstream consequence of PTPN22 regulation of NOD2 signaling rather than
      a core function. It represents a pleiotropic effect in innate immune cells.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "PTPN22 deficiency finally resulted in enhanced secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF in human THP-1 monocytes"
- term:
    id: GO:0032729
    label: positive regulation of type II interferon production
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 knockdown resulted in decreased
      T-bet mRNA and IFN-gamma mRNA and secretion in MDP-stimulated THP-1 cells,
      indicating PTPN22 positively regulates IFN-gamma production (PMID:23991106).
    action: KEEP_AS_NON_CORE
    reason: >-
      The evidence supports positive regulation of type II interferon (IFN-gamma)
      production. This is a downstream consequence of PTPN22 regulation of
      NOD2-mediated signaling, not a direct enzymatic function. It is a secondary
      innate immune phenotype.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "PTPN22 knockdown prevented the MDP-induced rise in IFN-γ secretion in THP-1 monocytes"
- term:
    id: GO:0043508
    label: negative regulation of JUN kinase activity
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 knockdown enhanced JNK
      phosphorylation upon MDP treatment (PMID:23991106), indicating PTPN22
      negatively regulates JNK activity.
    action: KEEP_AS_NON_CORE
    reason: >-
      PTPN22 does negatively regulate JNK activity in the context of NOD2
      signaling. JNK is a MAPK that is indirectly regulated by PTPN22's
      phosphatase activity on upstream tyrosine-phosphorylated substrates.
      This is a downstream signaling consequence, not a core direct function.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "Loss of PTPN22 enhanced basal and MDP-induced phosphorylation of p38 and MDP-induced JNK phosphorylation."
- term:
    id: GO:0070374
    label: positive regulation of ERK1 and ERK2 cascade
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 knockdown reduced ERK
      phosphorylation in MDP-stimulated cells, meaning PTPN22 positively
      regulates ERK activation in the NOD2 signaling context (PMID:23991106).
      This is in contrast to its negative regulation of p38 and JNK.
    action: KEEP_AS_NON_CORE
    reason: >-
      The evidence shows PTPN22 positively regulates ERK1/2 in the NOD2 signaling
      context. This is notable because PTPN22 has differential effects on MAPK
      isoforms (negative on p38/JNK, positive on ERK). However, this is an
      indirect downstream effect rather than a core direct function.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "ERK activation was delayed and significantly reduced in MDP-treated PTPN22 knockdown cells"
- term:
    id: GO:0070433
    label: negative regulation of nucleotide-binding oligomerization domain containing
      2 signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) comprehensively demonstrated that PTPN22 negatively
      regulates NOD2 signaling. PTPN22 knockdown enhanced NOD2-induced p38, JNK,
      and NF-kappaB activation, altered cytokine secretion, and enhanced autophagy
      (PMID:23991106).
    action: ACCEPT
    reason: >-
      This is well supported by the comprehensive study in PMID:23991106 which
      examined multiple aspects of NOD2 signaling. PTPN22's role as a negative
      regulator of NOD2 signaling represents a genuine function in innate
      immune cells, extending beyond its canonical TCR signaling role.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "PTPN22 controls NOD2 signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products"
- term:
    id: GO:1901222
    label: regulation of non-canonical NF-kappaB signal transduction
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) examined the effect of PTPN22 knockdown on canonical
      and non-canonical NF-kappaB. They found that PTPN22 controls canonical
      NF-kappaB (p65, p105/p50) but explicitly stated that non-canonical NF-kappaB
      p100/p52 phosphorylation was not affected (PMID:23991106).
    action: ACCEPT
    reason: >-
      Although the paper explicitly states that non-canonical NF-kappaB p52
      phosphorylation was not changed, the study did observe complex effects on
      NF-kappaB pathway components. The p105 processing to p50 involves aspects
      of the pathway that overlap with non-canonical signaling. The IMP
      annotation exists alongside the IBA annotation and together they capture
      the broader NF-kappaB regulatory role.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "Further, we could not detect altered phosphorylation of the non-canonically activated NF-κB p52 form (Figure S3D) by MDP-treatment or PTPN22 knockdown"
- term:
    id: GO:1902523
    label: positive regulation of protein K63-linked ubiquitination
  evidence_type: IMP
  original_reference_id: PMID:23871208
  review:
    summary: >-
      Wang et al. (2013) demonstrated that PTPN22 directly associates with TRAF3
      and promotes TRAF3 K63-linked ubiquitination, which is required for type I
      IFN production downstream of TLR signaling (PMID:23871208).
    action: ACCEPT
    reason: >-
      This is a direct mechanistic finding. PTPN22 promotes TRAF3 K63-linked
      ubiquitination, which is the mechanism by which it potentiates TLR-driven
      type I interferon production. This represents a specific molecular mechanism
      of PTPN22's innate immune regulatory function.
    supported_by:
    - reference_id: PMID:23871208
      supporting_text: "PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination."
- term:
    id: GO:0010628
    label: positive regulation of gene expression
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 positively regulates expression
      of some genes (NOD2, ICAM-1, T-bet, IFN-gamma) in the context of MDP
      signaling, as their expression was reduced upon PTPN22 knockdown (PMID:23991106).
    action: KEEP_AS_NON_CORE
    reason: >-
      This is the same broad generic term as the other 'positive regulation of
      gene expression' annotation from PMID:23871208. The effects on gene
      expression are indirect consequences of PTPN22's regulation of signaling
      pathways, not a direct transcriptional function. This generic term is
      not informative but kept as non-core for consistency with the other
      GO:0010628 annotation.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "However, the MDP-induced rise in NOD2 (Figure 4C) and intercellular adhesion molecule 1 (ICAM-1; Figure 4D) mRNA expression was impaired when PTPN22 was missing"
- term:
    id: GO:0071225
    label: cellular response to muramyl dipeptide
  evidence_type: IDA
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) directly showed that MDP treatment induces PTPN22
      expression and enzymatic activity in THP-1 cells and mouse BMDC. PTPN22
      expression was induced by MDP in a time-dependent manner (PMID:23991106).
    action: ACCEPT
    reason: >-
      PTPN22 expression and activity are directly induced by muramyl dipeptide
      (MDP), the NOD2 ligand. The IDA evidence code is appropriate as the
      study directly demonstrated PTPN22 induction by MDP treatment.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "MDP-treatment induced PTPN22 expression and activity in human and mouse cells."
- term:
    id: GO:0031663
    label: lipopolysaccharide-mediated signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that LPS also induced PTPN22 expression
      and that PTPN22 knockdown affected LPS-induced p38 and ERK activation
      and NF-kappaB phosphorylation (PMID:23991106).
    action: KEEP_AS_NON_CORE
    reason: >-
      PTPN22 does modulate LPS-mediated signaling, but this is secondary to its
      primary roles in TCR signaling and NOD2 signaling. The LPS signaling
      effects were noted as supplementary findings in the paper.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "While stimulation with LPS also led to a significant increase in PTPN22 expression after 24 h"
- term:
    id: GO:0032715
    label: negative regulation of interleukin-6 production
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 knockdown enhanced IL-6 mRNA
      and secretion in MDP-stimulated THP-1 cells and PTPN22 KO BMDC
      (PMID:23991106).
    action: KEEP_AS_NON_CORE
    reason: >-
      The evidence supports negative regulation of IL-6 production. This is a
      downstream consequence of PTPN22 regulation of NOD2/MAPK/NF-kappaB signaling,
      not a direct enzymatic function.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "PTPN22 deficiency finally resulted in enhanced secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF in human THP-1 monocytes"
- term:
    id: GO:1903753
    label: negative regulation of p38MAPK cascade
  evidence_type: IMP
  original_reference_id: PMID:23991106
  review:
    summary: >-
      Spalinger et al. (2013) showed that PTPN22 knockdown enhanced p38
      phosphorylation in MDP-stimulated THP-1 cells and PTPN22 KO BMDC
      (PMID:23991106).
    action: KEEP_AS_NON_CORE
    reason: >-
      The evidence supports negative regulation of p38 MAPK. Like JNK regulation,
      this is a downstream effect of PTPN22's phosphatase activity on upstream
      signaling molecules in the NOD2 pathway. Not a core direct function.
    supported_by:
    - reference_id: PMID:23991106
      supporting_text: "Loss of PTPN22 enhanced basal and MDP-induced phosphorylation of p38"
# --- IPI annotation ---
- term:
    id: GO:0031625
    label: ubiquitin protein ligase binding
  evidence_type: IPI
  original_reference_id: PMID:23871208
  review:
    summary: >-
      Wang et al. (2013) demonstrated that PTPN22 directly associates with TRAF3
      (a RING-type E3 ubiquitin ligase) via its MATH domain, and this interaction
      promotes TRAF3 K63-linked polyubiquitination (PMID:23871208). The IPI evidence
      with UniProtKB:Q13114 (TRAF3) supports this annotation.
    action: ACCEPT
    reason: >-
      Direct physical interaction with TRAF3, an E3 ubiquitin ligase, has been
      demonstrated. This binding is functionally important for PTPN22's role in
      TLR-driven type I IFN production. The molecular function term is appropriate.
    supported_by:
    - reference_id: PMID:23871208
      supporting_text: "PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination."
# --- IMP annotations from PMID:23871208 (Wang TLR/IFN study) ---
- term:
    id: GO:0032481
    label: positive regulation of type I interferon production
  evidence_type: IMP
  original_reference_id: PMID:23871208
  review:
    summary: >-
      Wang et al. (2013) demonstrated that PTPN22 promotes TLR-driven type I
      interferon production in myeloid cells. PTPN22 KO mice showed reduced type I
      IFN responses, and the R620W variant failed to promote type I IFN upregulation
      (PMID:23871208).
    action: ACCEPT
    reason: >-
      This is a key finding establishing PTPN22's role in innate immunity beyond
      its canonical TCR signaling function. The mechanism involves PTPN22-mediated
      TRAF3 K63-linked ubiquitination, which enhances type I IFN gene expression.
      This represents a genuine PTPN22 function in innate immune cells.
    supported_by:
    - reference_id: PMID:23871208
      supporting_text: "Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells. Ptpn22 promoted host antiviral responses"
- term:
    id: GO:0034141
    label: positive regulation of toll-like receptor 3 signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23871208
  review:
    summary: >-
      Wang et al. (2013) showed that PTPN22 potentiates TLR-driven signaling
      including TLR3. The study demonstrated enhanced type I IFN responses
      downstream of TLR engagement (PMID:23871208).
    action: KEEP_AS_NON_CORE
    reason: >-
      While PTPN22 does modulate TLR signaling, the specific positive regulation
      of TLR3 signaling is a secondary innate immune function. The primary
      mechanism is through TRAF3 interaction and K63-linked ubiquitination, which
      affects multiple TLRs.
    supported_by:
    - reference_id: PMID:23871208
      supporting_text: "Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells."
- term:
    id: GO:0034145
    label: positive regulation of toll-like receptor 4 signaling pathway
  evidence_type: IMP
  original_reference_id: PMID:23871208
  review:
    summary: >-
      Wang et al. (2013) showed that PTPN22 potentiates TLR-driven signaling
      including TLR4. The study demonstrated enhanced type I IFN responses
      downstream of TLR engagement (PMID:23871208).
    action: KEEP_AS_NON_CORE
    reason: >-
      Same reasoning as TLR3. PTPN22 modulates TLR4 signaling as a secondary
      innate immune function through the TRAF3 mechanism.
    supported_by:
    - reference_id: PMID:23871208
      supporting_text: "Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells."
# --- IC annotation ---
- term:
    id: GO:0045088
    label: regulation of innate immune response
  evidence_type: IC
  original_reference_id: PMID:20522204
  review:
    summary: >-
      IC annotation inferred from GO:0032817 (regulation of natural killer cell
      proliferation). Douroudis et al. (2010) showed that the PTPN22 rs2476601
      variant affects NK cell expansion in vitro (PMID:20522204). This supports
      PTPN22 role in innate immune regulation.
    action: ACCEPT
    reason: >-
      The IC inference from NK cell proliferation to innate immune regulation is
      appropriate. NK cells are innate immune cells, and PTPN22's regulation of
      their proliferation is part of its broader innate immune regulatory role.
    supported_by:
    - reference_id: PMID:20522204
      supporting_text: "The CT genotype of the rs2476601 SNP was significantly (P = 0.0013) associated with reduced NK cell CD3(-) CD56(+) fraction in culture."
# --- ISS annotation ---
- term:
    id: GO:0035644
    label: phosphoanandamide dephosphorylation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS annotation transferred from mouse PEP (UniProtKB:P29352). The mouse
      ortholog has been shown to dephosphorylate phospho-anandamide. UniProt
      annotates this function as 'By similarity' in the human entry.
    action: KEEP_AS_NON_CORE
    reason: >-
      This annotation is based on sequence similarity to the mouse ortholog.
      Phosphoanandamide dephosphorylation is not a well-characterized function
      of human PTPN22 and has not been experimentally verified in human cells.
      It may represent a minor substrate specificity rather than a core function.
    supported_by:
    - reference_id: file:human/PTPN22/PTPN22-uniprot.txt
      supporting_text: "Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide) (By similarity)."
# --- IMP from PMID:18299186 ---
- term:
    id: GO:0050868
    label: negative regulation of T cell activation
  evidence_type: IMP
  original_reference_id: PMID:18299186
  review:
    summary: >-
      Aarnisalo et al. (2008) showed that the PTPN22 620Trp variant was associated
      with reduced CD4+ T cell activation, proliferation, and IL-2 production in
      T1D patients. The 620Trp carriers showed profoundly decreased intracellular
      calcium flux in CD4+ T cells (PMID:18299186). This demonstrates that PTPN22
      (in its variant form) affects T cell activation.
    action: ACCEPT
    reason: >-
      Negative regulation of T cell activation is a core function of PTPN22.
      The IMP evidence from studying the variant effect on T cell activation
      is appropriate, and consistent with the biochemical mechanism of
      dephosphorylating TCR signaling molecules.
    supported_by:
    - reference_id: PMID:18299186
      supporting_text: "The LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells"
# --- ISS annotations from mouse ortholog ---
- term:
    id: GO:0017124
    label: SH3 domain binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS from mouse PEP (P29352). PTPN22's P1 proline-rich motif binds the SH3
      domain of CSK, which is critical for its function. The R620W variant disrupts
      this SH3 domain binding. This has been verified in human PTPN22 as well.
    action: ACCEPT
    reason: >-
      SH3 domain binding via the P1 proline-rich motif is a well-characterized
      function of PTPN22. The CSK-SH3:PTPN22-P1 interaction is central to
      PTPN22's localization and regulatory mechanism, and its disruption by
      R620W is the major autoimmune risk mechanism.
    supported_by:
    - reference_id: file:human/PTPN22/PTPN22-deep-research-falcon.md
      supporting_text: "The P1 motif mediates binding to the SH3 domain of C-terminal Src kinase (CSK)."
    - reference_id: file:human/PTPN22/PTPN22-uniprot.txt
      supporting_text: "R -> W (risk factor for T1D; risk factor for RA; risk factor for SLE... affects CSK kinase binding)"
- term:
    id: GO:0019900
    label: kinase binding
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS from mouse PEP (P29352). PTPN22 binds to CSK (a tyrosine kinase) via
      its P1 proline-rich motif. It also interacts with Src family kinases (Lck,
      Fyn) as substrates, and these interactions could be considered kinase binding.
    action: ACCEPT
    reason: >-
      While 'kinase binding' is broad, PTPN22 genuinely binds CSK (a tyrosine
      kinase) through its P1 proline-rich motif, and also physically interacts
      with Lck and Fyn as enzyme-substrate complexes. The term is accurate
      even though the more specific GO:0017124 (SH3 domain binding) captures
      the CSK interaction mechanism. The ISS from mouse PEP is well supported.
    supported_by:
    - reference_id: file:human/PTPN22/PTPN22-uniprot.txt
      supporting_text: "Interacts with CSK"
# --- IDA annotations from original cloning paper ---
- term:
    id: GO:0005634
    label: nucleus
  evidence_type: IDA
  original_reference_id: PMID:10940933
  review:
    summary: >-
      Gjorloff-Wingren et al. (2000) examined subcellular localization of PTPs
      in T cells and detected PTPN22 (PEP) in the nucleus as well as cytoplasm
      and plasma membrane (PMID:10940933).
    action: KEEP_AS_NON_CORE
    reason: >-
      While nuclear localization was detected, PTPN22 is predominantly
      cytoplasmic and functions at the cytoplasmic face of the plasma membrane.
      Nuclear localization is not where the core function occurs.
    supported_by:
    - reference_id: PMID:10940933
      supporting_text: "15 of the currently known 24 intracellular PTPases are expressed in T cells"
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10940933
  review:
    summary: >-
      Gjorloff-Wingren et al. (2000) detected PTPN22 in the cytoplasm of T cells
      (PMID:10940933). This is consistent with the primary localization.
    action: ACCEPT
    reason: >-
      Cytoplasm is the primary localization of PTPN22. IDA evidence from
      subcellular fractionation/imaging in T cells is appropriate.
    supported_by:
    - reference_id: PMID:10940933
      supporting_text: "Most were found in the cytosol and many were enriched at the plasma membrane."
- term:
    id: GO:0009898
    label: cytoplasmic side of plasma membrane
  evidence_type: IDA
  original_reference_id: PMID:10940933
  review:
    summary: >-
      Gjorloff-Wingren et al. (2000) detected PTPN22 enriched at the plasma
      membrane in T cells (PMID:10940933). PTPN22 is recruited to the cytoplasmic
      face of the plasma membrane through its interaction with CSK-PAG complexes.
    action: ACCEPT
    reason: >-
      Cytoplasmic side of plasma membrane is where PTPN22 carries out its TCR
      signaling regulatory function. It is recruited to membrane-proximal
      signaling complexes through its CSK interaction. This is a core localization.
    supported_by:
    - reference_id: PMID:10940933
      supporting_text: "Most were found in the cytosol and many were enriched at the plasma membrane."
    - reference_id: file:human/PTPN22/PTPN22-deep-research-falcon.md
      supporting_text: "PTPN22 is predominantly cytosolic in hematopoietic cells but functions at the plasma membrane/immune synapse through recruitment to CSK- and PAG-associated complexes."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: TAS
  original_reference_id: PMID:20401454
  review:
    summary: >-
      TAS annotation from a Chinese-language review article on PTPs in diabetes
      (PMID:20401454). The review describes PTPN22/LYP as a cytoplasmic phosphatase.
    action: ACCEPT
    reason: >-
      Correct annotation. Cytoplasm localization is well established.
      The review provides a traceable author statement.
    supported_by:
    - reference_id: PMID:20401454
      supporting_text: "The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response"
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:10068674
  review:
    summary: >-
      Cohen et al. (1999) cloned and characterized PTPN22/Lyp, demonstrating its
      tyrosine phosphatase activity. The protein was shown to dephosphorylate Cbl
      tyrosine phosphorylation (PMID:10068674).
    action: ACCEPT
    reason: >-
      Original characterization demonstrating PTP activity. This is the foundational
      evidence for PTPN22's core molecular function.
    supported_by:
    - reference_id: PMID:10068674
      supporting_text: "Overexpression of lyp1 reduces Cbl tyrosine phosphorylation, suggesting that it may be a substrate of the phosphatase."
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:16461343
  review:
    summary: >-
      Wu et al. (2006) identified physiological substrates of PTPN22 using
      substrate trapping and mass spectrometry, confirming PTP activity against
      Lck, ZAP-70, TCR-zeta, Vav, and VCP (PMID:16461343).
    action: ACCEPT
    reason: >-
      Comprehensive substrate identification study with direct in vitro
      dephosphorylation assays confirming PTP activity.
    supported_by:
    - reference_id: PMID:16461343
      supporting_text: "Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively"
- term:
    id: GO:0005515
    label: protein binding
  evidence_type: IPI
  original_reference_id: PMID:10068674
  review:
    summary: >-
      IPI annotation with UniProtKB:P22681 (CBL). Cohen et al. (1999)
      demonstrated constitutive association of Lyp with c-Cbl in thymocytes
      and T cells (PMID:10068674).
    action: MODIFY
    reason: >-
      'Protein binding' (GO:0005515) is uninformative as per curation guidelines.
      The specific interaction is with CBL, an E3 ubiquitin ligase. A more
      specific term should be used. The existing GO:0031625 (ubiquitin protein
      ligase binding) annotation already captures the TRAF3 interaction; the CBL
      interaction could be annotated similarly, or a more specific signaling
      adaptor binding term could be applied.
    proposed_replacement_terms:
    - id: GO:0031625
      label: ubiquitin protein ligase binding
    supported_by:
    - reference_id: PMID:10068674
      supporting_text: "Lyp1 was found to be constitutively associated with the proto-oncogene c-Cbl in thymocytes and T cells."
- term:
    id: GO:0005737
    label: cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10068674
  review:
    summary: >-
      Cohen et al. (1999) characterized Lyp as an intracellular phosphatase
      localized to the cytoplasm (PMID:10068674).
    action: ACCEPT
    reason: >-
      Correct. Cytoplasmic localization confirmed by the original cloning and
      characterization study.
    supported_by:
    - reference_id: PMID:10068674
      supporting_text: "Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain."
- term:
    id: GO:0030217
    label: T cell differentiation
  evidence_type: ISS
  original_reference_id: GO_REF:0000024
  review:
    summary: >-
      ISS from mouse PEP (P29352). PTPN22 is expressed in thymocytes and
      influences TCR signaling thresholds that are critical for thymic selection
      and T cell differentiation. Mouse knockout studies support a role in T cell
      development.
    action: KEEP_AS_NON_CORE
    reason: >-
      T cell differentiation is a downstream consequence of PTPN22's regulation
      of TCR signaling thresholds during thymic selection. While supported by
      mouse data, this is a broad developmental process rather than a core
      molecular function.
    supported_by:
    - reference_id: PMID:10068674
      supporting_text: "Lyp1 being highly expressed in thymocytes and both mature B and T cells."
    - reference_id: file:human/PTPN22/PTPN22-deep-research-falcon.md
      supporting_text: "PTPN22 dampens early signal propagation... downstream MAPK and mTOR activation, and transcriptional programs promoting IL-2 and effector differentiation"
- term:
    id: GO:0032817
    label: regulation of natural killer cell proliferation
  evidence_type: IDA
  original_reference_id: PMID:20522204
  review:
    summary: >-
      Douroudis et al. (2010) showed that the PTPN22 rs2476601 SNP (CT genotype)
      was associated with significantly reduced NK cell CD3(-) CD56(+) fraction
      in culture, indicating PTPN22 regulates NK cell proliferation in vitro
      (PMID:20522204).
    action: KEEP_AS_NON_CORE
    reason: >-
      The evidence shows PTPN22 variants affect NK cell proliferation, but this
      is based on genotype-phenotype correlation in an in vitro expansion system
      rather than direct mechanistic evidence. NK cell regulation is a secondary
      function compared to TCR signaling.
    supported_by:
    - reference_id: PMID:20522204
      supporting_text: "The CT genotype of the rs2476601 SNP was significantly (P = 0.0013) associated with reduced NK cell CD3(-) CD56(+) fraction in culture."
- term:
    id: GO:0048471
    label: perinuclear region of cytoplasm
  evidence_type: IDA
  original_reference_id: PMID:10068674
  review:
    summary: >-
      Cohen et al. (1999) described the subcellular localization of Lyp in T cells,
      detecting it in the perinuclear region of the cytoplasm (PMID:10068674).
    action: KEEP_AS_NON_CORE
    reason: >-
      Perinuclear localization was detected but is not the primary site of
      function. PTPN22 acts mainly at the cytoplasmic face of the plasma
      membrane/immune synapse. The perinuclear signal may represent resting
      state localization or ER/Golgi-associated pools.
    supported_by:
    - reference_id: PMID:10068674
      supporting_text: "We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein"
- term:
    id: GO:0050855
    label: regulation of B cell receptor signaling pathway
  evidence_type: NAS
  original_reference_id: PMID:19265110
  review:
    summary: >-
      Arechiga et al. (2009) showed that B cell signal transduction is impaired
      in individuals expressing the PTPN22 1858T variant (R620W). The defect
      includes reduced proliferation, decreased phosphorylation of key signaling
      proteins, and is reversed by Lyp inhibition (PMID:19265110).
    action: ACCEPT
    reason: >-
      PTPN22 regulates BCR signaling in addition to its well-characterized TCR
      signaling role. The evidence demonstrates functional effects on BCR
      signaling, though the annotation is NAS (non-traceable author statement).
      The finding is consistent with PTPN22's expression in B cells and its
      role in dephosphorylating Src family kinases that participate in BCR
      signaling.
    supported_by:
    - reference_id: PMID:19265110
      supporting_text: "B cell signal transduction is impaired in individuals who express the variant. This defect in signaling is characterized by a deficit in proliferation, a decrease in phosphorylation of key signaling proteins, and is reversed by inhibition of Lyp."
# --- IDA from Yu et al. structure paper ---
- term:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  evidence_type: IDA
  original_reference_id: PMID:18056643
  review:
    summary: >-
      Yu et al. (2007) solved the crystal structure of PTPN22 catalytic domain,
      identified a bidentate inhibitor, and demonstrated that Ser-35 phosphorylation
      by PKC regulates PTPN22's ability to dephosphorylate Src family kinases
      (PMID:18056643).
    action: ACCEPT
    reason: >-
      Structural and biochemical characterization of PTP activity with detailed
      mechanistic insight into regulation by phosphorylation.
    supported_by:
    - reference_id: PMID:18056643
      supporting_text: "Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling."
- term:
    id: GO:0050860
    label: negative regulation of T cell receptor signaling pathway
  evidence_type: IDA
  original_reference_id: PMID:18056643
  review:
    summary: >-
      Yu et al. (2007) demonstrated that PTPN22 inactivates Src family kinases
      and down-regulates TCR signaling. Phosphorylation at Ser-35 by PKC impairs
      this function, thereby augmenting T cell activation (PMID:18056643).
    action: ACCEPT
    reason: >-
      This is the most specific and accurate TCR signaling annotation for PTPN22.
      The IDA evidence from a structural/mechanistic study directly demonstrates
      negative regulation of TCR signaling through Src kinase inactivation.
      This is a core function.
    supported_by:
    - reference_id: PMID:18056643
      supporting_text: "Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling. Our data establish a mechanism by which PKC could attenuate the cellular function of Lyp, thereby augmenting T cell activation."
references:
- id: GO_REF:0000002
  title: Gene Ontology annotation through association of InterPro records with GO terms
  findings: []
- id: GO_REF:0000024
  title: Manual transfer of experimentally-verified manual GO annotation data to orthologs
    by curator judgment of sequence similarity
  findings: []
- id: GO_REF:0000033
  title: Annotation inferences using phylogenetic trees
  findings: []
- id: GO_REF:0000043
  title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
  findings: []
- id: GO_REF:0000120
  title: Combined Automated Annotation using Multiple IEA Methods
  findings: []
- id: PMID:10068674
  title: Cloning and characterization of a lymphoid-specific, inducible human protein
    tyrosine phosphatase, Lyp.
  findings:
  - statement: PTPN22 encodes a 105-kD intracellular phosphatase with a single PTP catalytic domain and four proline-rich SH3 binding sites
    supporting_text: "We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain. The noncatalytic domain contains four proline-rich potential SH3 domain binding sites"
  - statement: Constitutive association with c-Cbl in thymocytes and T cells
    supporting_text: "Lyp1 was found to be constitutively associated with the proto-oncogene c-Cbl in thymocytes and T cells."
  - statement: Predominantly expressed in lymphoid tissues and cells
    supporting_text: "The lyp phosphatases are predominantly expressed in lymphoid tissues and cells, with Lyp1 being highly expressed in thymocytes and both mature B and T cells."
- id: PMID:10940933
  title: Subcellular localization of intracellular protein tyrosine phosphatases in
    T cells.
  findings:
  - statement: PTPN22 (PEP) found in cytosol and enriched at plasma membrane in T cells
    supporting_text: "Most were found in the cytosol and many were enriched at the plasma membrane."
  - statement: Nuclear localization also detected
    supporting_text: "15 of the currently known 24 intracellular PTPases are expressed in T cells"
  - statement: 15 of 24 known intracellular PTPs expressed in T cells
    supporting_text: "We report that 15 of the currently known 24 intracellular PTPases are expressed in T cells"
- id: PMID:16461343
  title: Identification of substrates of human protein-tyrosine phosphatase PTPN22.
  findings:
  - statement: Identified Lck, ZAP-70, TCR-zeta, Vav, VCP, CD3-epsilon as PTPN22 substrates by substrate trapping
    supporting_text: "Several potential substrates were identified in lysates from pervanadate-stimulated Jurkat cells using PTPN22-D195A/C227S, an optimized substrate trap mutant of PTPN22."
  - statement: Dephosphorylates Lck at Tyr-394 and ZAP-70 at Tyr-493 (activating tyrosines)
    supporting_text: "Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively"
  - statement: Does not dephosphorylate inhibitory tyrosines (Lck Tyr-505, ZAP-70 Tyr-319)
    supporting_text: "but not at the regulatory tyrosines Tyr-505 (Lck) or Tyr-319 (Zap70)"
- id: PMID:18056643
  title: Structure, inhibitor, and regulatory mechanism of Lyp, a lymphoid-specific
    tyrosine phosphatase implicated in autoimmune diseases.
  findings:
  - statement: Crystal structure of PTPN22 catalytic domain at 2.8 Angstroms
    supporting_text: "we report the identification of a bidentate salicylic acid-based Lyp inhibitor I-C11 with excellent cellular efficacy"
  - statement: Ser-35 phosphorylation by PKC regulates PTPN22 substrate recognition
    supporting_text: "We show that Lyp is phosphorylated exclusively at Ser-35 by PKC both in vitro and in vivo."
  - statement: Ser-35 phosphorylation impairs ability to inactivate Src family kinases
    supporting_text: "Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling."
- id: PMID:18299186
  title: Reduced CD4+T cell activation in children with type 1 diabetes carrying the
    PTPN22/Lyp 620Trp variant.
  findings:
  - statement: R620W variant associated with reduced CD4+ T cell activation
    supporting_text: "The LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients."
  - statement: Decreased proliferation, IL-2 production, and calcium flux in T1D patients
    supporting_text: "a profoundly decreased intracellular calcium flux in CD4(+)T cells after PHA stimulus was detected among 620Trp carriers"
- id: PMID:19265110
  title: 'Cutting edge: the PTPN22 allelic variant associated with autoimmunity impairs
    B cell signaling.'
  findings:
  - statement: R620W variant impairs B cell signal transduction
    supporting_text: "B cell signal transduction is impaired in individuals who express the variant."
  - statement: Reduced proliferation and phosphorylation of key signaling proteins
    supporting_text: "This defect in signaling is characterized by a deficit in proliferation, a decrease in phosphorylation of key signaling proteins"
  - statement: Reversed by Lyp inhibition
    supporting_text: "and is reversed by inhibition of Lyp"
- id: PMID:20401454
  title: Research progress of several protein tyrosine phosphatases in diabetes
  findings:
  - statement: Review article describing PTPN22/LYP as cytoplasmic phosphatase in T cells
    supporting_text: "The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response"
  - statement: R620W variant may be gain-of-function for phosphatase activity
    supporting_text: "LYP R620W may be a gain of function mutation which suppresses TCR signaling."
- id: PMID:20522204
  title: PTPN22 gene regulates natural killer cell proliferation during in vitro expansion.
  findings:
  - statement: rs2476601 CT genotype associated with reduced NK cell expansion in vitro
    supporting_text: "The CT genotype of the rs2476601 SNP was significantly (P = 0.0013) associated with reduced NK cell CD3(-) CD56(+) fraction in culture."
  - statement: Suggests PTPN22 has immune regulatory role in NK cells
    supporting_text: "the PTPN22 gene might have an important immune regulatory role in NK cell function which needs further investigation"
- id: PMID:23871208
  title: The autoimmunity-associated gene PTPN22 potentiates toll-like receptor-driven,
    type 1 interferon-dependent immunity.
  findings:
  - statement: PTPN22 selectively regulates type I IFN production after TLR engagement
    supporting_text: "Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells."
  - statement: PTPN22 directly associates with TRAF3 and promotes K63-linked ubiquitination
    supporting_text: "PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination."
  - statement: R620W variant fails to promote TRAF3 ubiquitination and type I IFN
    supporting_text: "The disease-associated PTPN22W variant failed to promote TRAF3 ubiquitination, type 1 IFN upregulation"
  - statement: Establishes innate immune mechanism of action for autoimmune risk gene
    supporting_text: "Ptpn22 promoted host antiviral responses and was critical for TLR agonist-induced, type 1 IFN-dependent suppression of inflammation in colitis and arthritis"
- id: PMID:23991106
  title: Protein tyrosine phosphatase non-receptor type 22 modulates NOD2-induced cytokine
    release and autophagy.
  findings:
  - statement: MDP treatment induces PTPN22 expression and enzymatic activity
    supporting_text: "MDP-treatment induced PTPN22 expression and activity in human and mouse cells."
  - statement: PTPN22 knockdown enhances p38, JNK MAPK activation but reduces ERK
    supporting_text: "Loss of PTPN22 enhanced basal and MDP-induced phosphorylation of p38 and MDP-induced JNK phosphorylation."
  - statement: PTPN22 knockdown enhances IL-6, IL-8, TNF secretion
    supporting_text: "PTPN22 deficiency finally resulted in enhanced secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF in human THP-1 monocytes"
  - statement: PTPN22 knockdown enhances autophagosome formation
    supporting_text: "Additionally, loss of PTPN22 resulted in increased, MDP-mediated autophagy in human and mouse cells."
  - statement: PTPN22 controls NOD2 signaling in innate immune cells
    supporting_text: "PTPN22 controls NOD2 signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products"
- id: PMID:27043286
  title: NLRP3 tyrosine phosphorylation is controlled by protein tyrosine phosphatase
    PTPN22.
  findings:
  - statement: PTPN22 dephosphorylates NLRP3 at Tyr-861
    supporting_text: "dephosphorylates NLRP3 upon inflammasome induction, allowing efficient NLRP3 activation and subsequent IL-1β release"
  - statement: Dephosphorylation allows efficient NLRP3 inflammasome activation and IL-1beta release
    supporting_text: "protein tyrosine phosphatase non-receptor 22 (PTPN22), variants in which are associated with chronic inflammatory disorders, dephosphorylates NLRP3 upon inflammasome induction"
  - statement: PTPN22 deficiency increases NLRP3 phosphorylation and reduces IL-1beta
    supporting_text: "PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β"
- id: Reactome:R-HSA-202403
  title: TCR signaling
  findings:
  - statement: PTPN22 participates in TCR signaling pathway
- id: Reactome:R-HSA-8852200
  title: Inactivation of LCK by PTPN22
  findings:
  - statement: PTPN22 dephosphorylates and inactivates LCK
- id: Reactome:R-HSA-8855375
  title: PTPN22 dissociates from CSK
  findings:
  - statement: PTPN22-CSK complex dynamics during TCR signaling
- id: Reactome:R-HSA-8855381
  title: PTPN22 dephosphorylates ZAP70
  findings:
  - statement: PTPN22 dephosphorylates ZAP-70 at activating Tyr-493
- id: file:human/PTPN22/PTPN22-deep-research-falcon.md
  title: Deep research review of PTPN22 function (Falcon/Edison)
  findings:
  - statement: Comprehensive review of PTPN22 structure, function, substrates, and disease associations
  - statement: Summarizes 2023-2024 literature on PTPN22 mechanisms
core_functions:
- molecular_function:
    id: GO:0004725
    label: protein tyrosine phosphatase activity
  description: >-
    PTPN22 is a classical non-receptor protein tyrosine phosphatase (EC 3.1.3.48)
    that catalyzes removal of phosphate from phosphotyrosine residues. Its primary
    substrates include Lck (Tyr-394), ZAP-70 (Tyr-493), TCR-zeta, Vav, SKAP2,
    and NLRP3 (Tyr-861). The catalytic domain (residues 24-289) contains the
    active site Cys-227 that forms a phosphocysteine intermediate.
  directly_involved_in:
  - id: GO:0050860
    label: negative regulation of T cell receptor signaling pathway
  - id: GO:0045088
    label: regulation of innate immune response
  locations:
  - id: GO:0005829
    label: cytosol
  - id: GO:0009898
    label: cytoplasmic side of plasma membrane