PTPN22

Existing Annotations Review

GO Term	Evidence	Action	Reason
GO:0045088 regulation of innate immune response	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:23871208 Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells. PMID:23991106 PTPN22 controls NOD2 signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products
GO:1901222 regulation of non-canonical NF-kappaB signal transduction	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:23991106 Further, we could not detect altered phosphorylation of the non-canonically activated NF-κB p52 form (Figure S3D) by MDP-treatment or PTPN22 knockdown file:human/PTPN22/PTPN22-deep-research-falcon.md PTPN22 dampens early signal propagation, curbing LAT/SLP-76 signalosome assembly, downstream MAPK and mTOR activation
GO:0005634 nucleus	IBA GO_REF:0000033	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:10940933 15 of the currently known 24 intracellular PTPases are expressed in T cells
GO:0004725 protein tyrosine phosphatase activity	IBA GO_REF:0000033	ACCEPT	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). 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. Supporting Evidence: PMID:16461343 Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively PMID:10068674 We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain.
GO:0050852 T cell receptor signaling pathway	IBA GO_REF:0000033	ACCEPT	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). 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. Supporting Evidence: PMID:16461343 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. PMID:18056643 Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling.
GO:0050868 negative regulation of T cell activation	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:18299186 The LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells among T1D patients. PMID:16461343 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
GO:0005737 cytoplasm	IBA GO_REF:0000033	ACCEPT	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. 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. Supporting Evidence: PMID:10068674 We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain. PMID:10940933 Most were found in the cytosol and many were enriched at the plasma membrane.
GO:0002376 immune system process	IEA GO_REF:0000043	ACCEPT	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. 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. Supporting Evidence: PMID:16461343 PTPN22 (Lyp), a non-receptor protein-tyrosine phosphatase, is expressed exclusively in cells of hematopoietic origin
GO:0004721 phosphoprotein phosphatase activity	IEA GO_REF:0000120	ACCEPT	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. 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. Supporting Evidence: PMID:16461343 Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively
GO:0004725 protein tyrosine phosphatase activity	IEA GO_REF:0000120	ACCEPT	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. 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. Supporting Evidence: PMID:16461343 Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues
GO:0004726 non-membrane spanning protein tyrosine phosphatase activity	IEA GO_REF:0000002	ACCEPT	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. 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. Supporting Evidence: PMID:10068674 Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain.
GO:0005737 cytoplasm	IEA GO_REF:0000120	ACCEPT	Summary: IEA annotation from automated methods mapping UniProt subcellular location. Consistent with multiple IDA annotations for cytoplasm. Reason: Correct IEA annotation. Cytoplasmic localization is well established by multiple experimental studies. This is redundant with IBA and IDA annotations but not incorrect. Supporting Evidence: PMID:10940933 Most were found in the cytosol and many were enriched at the plasma membrane.
GO:0006629 lipid metabolic process	IEA GO_REF:0000043	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/PTPN22/PTPN22-uniprot.txt Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide... (By similarity)
GO:0006914 autophagy	IEA GO_REF:0000043	ACCEPT	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. 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. Supporting Evidence: PMID:23991106 Additionally, loss of PTPN22 resulted in increased, MDP-mediated autophagy in human and mouse cells.
GO:0016787 hydrolase activity	IEA GO_REF:0000043	ACCEPT	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. 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. Supporting Evidence: PMID:16461343 Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues
GO:0050856 regulation of T cell receptor signaling pathway	IEA GO_REF:0000002	ACCEPT	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). 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. Supporting Evidence: PMID:18056643 Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling.
GO:0050852 T cell receptor signaling pathway	TAS Reactome:R-HSA-202403	ACCEPT	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. 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. Supporting Evidence: PMID:16461343 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
GO:0004725 protein tyrosine phosphatase activity	TAS Reactome:R-HSA-8852200	ACCEPT	Summary: TAS from Reactome (Inactivation of LCK by PTPN22). This reflects the specific dephosphorylation of LCK by PTPN22 in the context of TCR signaling. Reason: Correct. PTPN22 dephosphorylates LCK at its activating Tyr-394, which is a key step in negative regulation of TCR signaling. Supporting Evidence: PMID:16461343 Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively
GO:0004725 protein tyrosine phosphatase activity	TAS Reactome:R-HSA-8855381	ACCEPT	Summary: TAS from Reactome (PTPN22 dephosphorylates ZAP70). This reflects the specific dephosphorylation of ZAP-70 at Tyr-493 by PTPN22. Reason: Correct. PTPN22 dephosphorylates ZAP-70 at its activating Tyr-493, another key step in negative regulation of TCR signaling. Supporting Evidence: PMID:16461343 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)
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:27043286 NLRP3 tyrosine phosphorylation is controlled by protein tyro...	ACCEPT	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). 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. Supporting Evidence: PMID:27043286 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
GO:1900227 positive regulation of NLRP3 inflammasome complex assembly	IDA PMID:27043286 NLRP3 tyrosine phosphorylation is controlled by protein tyro...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:27043286 PTPN22 deficiency resulted in pronounced colitis, increased NLRP3 phosphorylation, but reduced levels of mature IL-1β
GO:0032717 negative regulation of interleukin-8 production	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23991106 PTPN22 deficiency finally resulted in enhanced secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF in human THP-1 monocytes
GO:0005829 cytosol	TAS Reactome:R-HSA-8852200	ACCEPT	Summary: TAS from Reactome (Inactivation of LCK by PTPN22). PTPN22 is a cytosolic phosphatase that is recruited to membrane-proximal signaling complexes. 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. Supporting Evidence: PMID:10940933 Most were found in the cytosol and many were enriched at the plasma membrane.
GO:0005829 cytosol	TAS Reactome:R-HSA-8855375	ACCEPT	Summary: TAS from Reactome (PTPN22 dissociates from CSK). Consistent with cytosolic localization of PTPN22. Reason: Duplicate cytosol annotation from a different Reactome event. Correct. Supporting Evidence: PMID:10940933 Most were found in the cytosol and many were enriched at the plasma membrane.
GO:0005829 cytosol	TAS Reactome:R-HSA-8855381	ACCEPT	Summary: TAS from Reactome (PTPN22 dephosphorylates ZAP70). Consistent with cytosolic localization. Reason: Duplicate cytosol annotation from a different Reactome event. Correct. Supporting Evidence: PMID:10940933 Most were found in the cytosol and many were enriched at the plasma membrane.
GO:0010507 negative regulation of autophagy	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:23991106 Additionally, loss of PTPN22 resulted in increased, MDP-mediated autophagy in human and mouse cells.
GO:0010628 positive regulation of gene expression	IMP PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23871208 Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells.
GO:0010629 negative regulation of gene expression	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	MARK AS OVER ANNOTATED	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. 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. Supporting Evidence: PMID:23991106 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
GO:0016791 phosphatase activity	IDA PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	ACCEPT	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. 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. Supporting Evidence: PMID:23991106 PTPN22 phosphatase activity was increased in response to MDP reaching its maximum only after 48 h
GO:0032496 response to lipopolysaccharide	IMP PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23871208 Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells.
GO:0032720 negative regulation of tumor necrosis factor production	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23991106 PTPN22 deficiency finally resulted in enhanced secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF in human THP-1 monocytes
GO:0032729 positive regulation of type II interferon production	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23991106 PTPN22 knockdown prevented the MDP-induced rise in IFN-γ secretion in THP-1 monocytes
GO:0043508 negative regulation of JUN kinase activity	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	Summary: Spalinger et al. (2013) showed that PTPN22 knockdown enhanced JNK phosphorylation upon MDP treatment (PMID:23991106), indicating PTPN22 negatively regulates JNK activity. 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. Supporting Evidence: PMID:23991106 Loss of PTPN22 enhanced basal and MDP-induced phosphorylation of p38 and MDP-induced JNK phosphorylation.
GO:0070374 positive regulation of ERK1 and ERK2 cascade	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:23991106 ERK activation was delayed and significantly reduced in MDP-treated PTPN22 knockdown cells
GO:0070433 negative regulation of nucleotide-binding oligomerization domain containing 2 signaling pathway	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	ACCEPT	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). 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. Supporting Evidence: PMID:23991106 PTPN22 controls NOD2 signaling, and loss of PTPN22 renders monocytes more reactive towards bacterial products
GO:1901222 regulation of non-canonical NF-kappaB signal transduction	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	ACCEPT	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). 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. Supporting Evidence: PMID:23991106 Further, we could not detect altered phosphorylation of the non-canonically activated NF-κB p52 form (Figure S3D) by MDP-treatment or PTPN22 knockdown
GO:1902523 positive regulation of protein K63-linked ubiquitination	IMP PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik...	ACCEPT	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). 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. Supporting Evidence: PMID:23871208 PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination.
GO:0010628 positive regulation of gene expression	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23991106 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
GO:0071225 cellular response to muramyl dipeptide	IDA PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	ACCEPT	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). 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. Supporting Evidence: PMID:23991106 MDP-treatment induced PTPN22 expression and activity in human and mouse cells.
GO:0031663 lipopolysaccharide-mediated signaling pathway	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23991106 While stimulation with LPS also led to a significant increase in PTPN22 expression after 24 h
GO:0032715 negative regulation of interleukin-6 production	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23991106 PTPN22 deficiency finally resulted in enhanced secretion of the pro-inflammatory cytokines IL-6, IL-8 and TNF in human THP-1 monocytes
GO:1903753 negative regulation of p38MAPK cascade	IMP PMID:23991106 Protein tyrosine phosphatase non-receptor type 22 modulates ...	KEEP AS NON CORE	Summary: Spalinger et al. (2013) showed that PTPN22 knockdown enhanced p38 phosphorylation in MDP-stimulated THP-1 cells and PTPN22 KO BMDC (PMID:23991106). 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. Supporting Evidence: PMID:23991106 Loss of PTPN22 enhanced basal and MDP-induced phosphorylation of p38
GO:0031625 ubiquitin protein ligase binding	IPI PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik...	ACCEPT	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. 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. Supporting Evidence: PMID:23871208 PTPN22 directly associated with TNF receptor-associated factor 3 (TRAF3) and promotes TRAF3 lysine 63-linked ubiquitination.
GO:0032481 positive regulation of type I interferon production	IMP PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik...	ACCEPT	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). 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. Supporting Evidence: PMID:23871208 Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells. Ptpn22 promoted host antiviral responses
GO:0034141 positive regulation of toll-like receptor 3 signaling pathway	IMP PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:23871208 Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells.
GO:0034145 positive regulation of toll-like receptor 4 signaling pathway	IMP PMID:23871208 The autoimmunity-associated gene PTPN22 potentiates toll-lik...	KEEP AS NON CORE	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). Reason: Same reasoning as TLR3. PTPN22 modulates TLR4 signaling as a secondary innate immune function through the TRAF3 mechanism. Supporting Evidence: PMID:23871208 Ptpn22 selectively regulated type 1 IFN production after TLR engagement in myeloid cells.
GO:0045088 regulation of innate immune response	IC PMID:20522204 PTPN22 gene regulates natural killer cell proliferation duri...	ACCEPT	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. 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. Supporting Evidence: PMID:20522204 The CT genotype of the rs2476601 SNP was significantly (P = 0.0013) associated with reduced NK cell CD3(-) CD56(+) fraction in culture.
GO:0035644 phosphoanandamide dephosphorylation	ISS GO_REF:0000024	KEEP AS NON CORE	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. 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. Supporting Evidence: file:human/PTPN22/PTPN22-uniprot.txt Dephosphorylates phospho-anandamide (p-AEA), an endocannabinoid to anandamide (also called N-arachidonoylethanolamide) (By similarity).
GO:0050868 negative regulation of T cell activation	IMP PMID:18299186 Reduced CD4+T cell activation in children with type 1 diabet...	ACCEPT	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. 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. Supporting Evidence: PMID:18299186 The LYP 620Trp variant is associated with reduced activation, proliferation and IL-2 production in CD4(+)T cells
GO:0017124 SH3 domain binding	ISS GO_REF:0000024	ACCEPT	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. 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. Supporting Evidence: file:human/PTPN22/PTPN22-deep-research-falcon.md The P1 motif mediates binding to the SH3 domain of C-terminal Src kinase (CSK). file:human/PTPN22/PTPN22-uniprot.txt R -> W (risk factor for T1D; risk factor for RA; risk factor for SLE... affects CSK kinase binding)
GO:0019900 kinase binding	ISS GO_REF:0000024	ACCEPT	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. 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. Supporting Evidence: file:human/PTPN22/PTPN22-uniprot.txt Interacts with CSK
GO:0005634 nucleus	IDA PMID:10940933 Subcellular localization of intracellular protein tyrosine p...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:10940933 15 of the currently known 24 intracellular PTPases are expressed in T cells
GO:0005737 cytoplasm	IDA PMID:10940933 Subcellular localization of intracellular protein tyrosine p...	ACCEPT	Summary: Gjorloff-Wingren et al. (2000) detected PTPN22 in the cytoplasm of T cells (PMID:10940933). This is consistent with the primary localization. Reason: Cytoplasm is the primary localization of PTPN22. IDA evidence from subcellular fractionation/imaging in T cells is appropriate. Supporting Evidence: PMID:10940933 Most were found in the cytosol and many were enriched at the plasma membrane.
GO:0009898 cytoplasmic side of plasma membrane	IDA PMID:10940933 Subcellular localization of intracellular protein tyrosine p...	ACCEPT	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. 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. Supporting Evidence: PMID:10940933 Most were found in the cytosol and many were enriched at the plasma membrane. file:human/PTPN22/PTPN22-deep-research-falcon.md PTPN22 is predominantly cytosolic in hematopoietic cells but functions at the plasma membrane/immune synapse through recruitment to CSK- and PAG-associated complexes.
GO:0005737 cytoplasm	TAS PMID:20401454 Research progress of several protein tyrosine phosphatases i...	ACCEPT	Summary: TAS annotation from a Chinese-language review article on PTPs in diabetes (PMID:20401454). The review describes PTPN22/LYP as a cytoplasmic phosphatase. Reason: Correct annotation. Cytoplasm localization is well established. The review provides a traceable author statement. Supporting Evidence: PMID:20401454 The tyrosine phosphatase LYP, which down-regulates LCK activity in T cell response
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:10068674 Cloning and characterization of a lymphoid-specific, inducib...	ACCEPT	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). Reason: Original characterization demonstrating PTP activity. This is the foundational evidence for PTPN22's core molecular function. Supporting Evidence: PMID:10068674 Overexpression of lyp1 reduces Cbl tyrosine phosphorylation, suggesting that it may be a substrate of the phosphatase.
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:16461343 Identification of substrates of human protein-tyrosine phosp...	ACCEPT	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). Reason: Comprehensive substrate identification study with direct in vitro dephosphorylation assays confirming PTP activity. Supporting Evidence: PMID:16461343 Native PTPN22 dephosphorylated Lck and Zap70 at their activating tyrosine residues Tyr-394 and Tyr-493, respectively
GO:0005515 protein binding	IPI PMID:10068674 Cloning and characterization of a lymphoid-specific, inducib...	MODIFY	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). 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 replacements: ubiquitin protein ligase binding Supporting Evidence: PMID:10068674 Lyp1 was found to be constitutively associated with the proto-oncogene c-Cbl in thymocytes and T cells.
GO:0005737 cytoplasm	IDA PMID:10068674 Cloning and characterization of a lymphoid-specific, inducib...	ACCEPT	Summary: Cohen et al. (1999) characterized Lyp as an intracellular phosphatase localized to the cytoplasm (PMID:10068674). Reason: Correct. Cytoplasmic localization confirmed by the original cloning and characterization study. Supporting Evidence: PMID:10068674 Lyp, that encodes an intracellular 105-kD protein containing a single tyrosine phosphatase catalytic domain.
GO:0030217 T cell differentiation	ISS GO_REF:0000024	KEEP AS NON CORE	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. 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. Supporting Evidence: PMID:10068674 Lyp1 being highly expressed in thymocytes and both mature B and T cells. file:human/PTPN22/PTPN22-deep-research-falcon.md PTPN22 dampens early signal propagation... downstream MAPK and mTOR activation, and transcriptional programs promoting IL-2 and effector differentiation
GO:0032817 regulation of natural killer cell proliferation	IDA PMID:20522204 PTPN22 gene regulates natural killer cell proliferation duri...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:20522204 The CT genotype of the rs2476601 SNP was significantly (P = 0.0013) associated with reduced NK cell CD3(-) CD56(+) fraction in culture.
GO:0048471 perinuclear region of cytoplasm	IDA PMID:10068674 Cloning and characterization of a lymphoid-specific, inducib...	KEEP AS NON CORE	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). 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. Supporting Evidence: PMID:10068674 We have isolated a previously undescribed human phosphatase, Lyp, that encodes an intracellular 105-kD protein
GO:0050855 regulation of B cell receptor signaling pathway	NAS PMID:19265110 Cutting edge: the PTPN22 allelic variant associated with aut...	ACCEPT	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). 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. Supporting Evidence: PMID:19265110 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.
GO:0004725 protein tyrosine phosphatase activity	IDA PMID:18056643 Structure, inhibitor, and regulatory mechanism of Lyp, a lym...	ACCEPT	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). Reason: Structural and biochemical characterization of PTP activity with detailed mechanistic insight into regulation by phosphorylation. Supporting Evidence: PMID:18056643 Ser-35 phosphorylation impairs Lyp's ability to inactivate the Src family kinases and down-regulate T cell receptor signaling.
GO:0050860 negative regulation of T cell receptor signaling pathway	IDA PMID:18056643 Structure, inhibitor, and regulatory mechanism of Lyp, a lym...	ACCEPT	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). 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. Supporting Evidence: PMID:18056643 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.

Gene Description

Existing Annotations Review

Core Functions

References

Deep Research

Falcon

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