PTPN6 encodes SHP-1, a cytosolic non-receptor protein tyrosine phosphatase with tandem SH2 domains and a catalytic PTP domain. Its core function is SH2-guided recruitment to phosphotyrosine-containing receptor/adaptor complexes followed by dephosphorylation of phosphotyrosine substrates, thereby tuning immune receptor, cytokine/JAK-STAT, TCR/CD27, B-cell, neutrophil, and inflammatory signaling thresholds.
| GO Term | Evidence | Action | Reason |
|---|---|---|---|
| GO:0001784 phosphotyrosine residue binding | IBA GO_REF:0000033 | ACCEPT | Summary: phosphotyrosine residue binding is central to SHP-1 SH2-mediated recruitment and substrate specificity. Reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic activity to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0030154 cell differentiation | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: cell differentiation is plausible downstream biology but not the core SHP-1 function. Reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect context-specific consequences of SHP-1 signaling regulation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0000278 mitotic cell cycle | IBA GO_REF:0000033 | KEEP AS NON CORE | Summary: mitotic cell cycle is plausible downstream biology but not the core SHP-1 function. Reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect context-specific consequences of SHP-1 signaling regulation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0005737 cytoplasm | IBA GO_REF:0000033 | ACCEPT | Summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0004726 non-membrane spanning protein tyrosine phosphatase activity | IBA GO_REF:0000033 | ACCEPT | Summary: non-membrane spanning protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0004721 phosphoprotein phosphatase activity | IEA GO_REF:0000043 | MODIFY | Summary: phosphoprotein phosphatase activity is directionally correct but less specific than SHP-1 protein tyrosine phosphatase activity. Reason: The supported activity is non-receptor protein tyrosine phosphatase activity rather than a generic phosphoprotein phosphatase or hydrolase term. Proposed replacements: non-membrane spanning protein tyrosine phosphatase activity protein tyrosine phosphatase activity Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0004725 protein tyrosine phosphatase activity | IEA GO_REF:0000120 | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005634 nucleus | IEA GO_REF:0000044 | KEEP AS NON CORE | Summary: nucleus localization is plausible but secondary to the main cytosolic/receptor-complex role. Reason: A nuclear localization signal and nuclear access are reported, but the best-supported core site of action is cytosolic and receptor-proximal signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0005737 cytoplasm | IEA GO_REF:0000120 | ACCEPT | Summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0016787 hydrolase activity | IEA GO_REF:0000043 | MODIFY | Summary: hydrolase activity is directionally correct but less specific than SHP-1 protein tyrosine phosphatase activity. Reason: The supported activity is non-receptor protein tyrosine phosphatase activity rather than a generic phosphoprotein phosphatase or hydrolase term. Proposed replacements: non-membrane spanning protein tyrosine phosphatase activity protein tyrosine phosphatase activity Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0031295 T cell costimulation | IEA GO_REF:0000117 | ACCEPT | Summary: T cell costimulation is supported in T-cell receptor/costimulation contexts. Reason: SHP-1 tunes T-cell activation and CD27/TCR signaling by dephosphorylating receptor-proximal substrates such as LCK. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Immunity study provides direct mechanistic evidence of substrate and site-level regulation: SHP-1 is associated with **Lck**, and receptor-driven signaling can lead to **SHP-1–dependent dephosphorylation of Lck at Y394** (the activating site), rather than the inhibitory Y505 site. file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IEA GO_REF:0000117 | MARK AS OVER ANNOTATED | Summary: Positive regulation of PI3K/AKT signaling is not well supported as a PTPN6/SHP-1 function. Reason: The strongest recent synthesis instead supports SHP-1 as a brake that can reduce AKT phosphorylation in receptor-signaling contexts; positive-direction annotations need context-specific support. Proposed replacements: T cell costimulation peptidyl-tyrosine dephosphorylation Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. |
| GO:0060338 regulation of type I interferon-mediated signaling pathway | IEA GO_REF:0000117 | ACCEPT | Summary: regulation of type I interferon-mediated signaling pathway is supported as a cytokine/JAK-STAT signaling context for SHP-1. Reason: SHP-1 negatively regulates cytokine signaling through JAK/STAT pathway dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. |
| GO:1902564 negative regulation of neutrophil activation | IEA GO_REF:0000117 | ACCEPT | Summary: negative regulation of neutrophil activation is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0005515 protein binding | IPI PMID:10206955 The myeloid-specific sialic acid-binding receptor, CD33, ass... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:10556798 The sialoadhesin CD33 is a myeloid-specific inhibitory recep... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:10660620 PILRalpha, a novel immunoreceptor tyrosine-based inhibitory ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:10764762 Identification and characterization of leukocyte-associated ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:11266449 Negative regulation of Ros receptor tyrosine kinase signalin... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:11489943 NTB-A [correction of GNTB-A], a novel SH2D1A-associated surf... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:14652006 Characterization of phosphotyrosine binding motifs in the cy... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:17416557 Monitoring phosphatase reactions of multiple phosphorylated ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:17947393 ITIM-dependent endocytosis of CD33-related Siglecs: role of ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:18086677 Dynamic regulation of neutrophil survival through tyrosine p... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:18377662 Src homology 2 (SH2) domain containing protein tyrosine phos... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:18802077 Inhibitory immunoglobulin-like receptors LILRB and PIR-B neg... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:19167335 Large-scale structural analysis of the classical human prote... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:20351292 Contribution of SHP-1 protein tyrosine phosphatase to osmoti... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:22624718 Tetraspanin CD37 directly mediates transduction of survival ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:23001144 Inhibition of TLR signaling by a bacterial protein containin... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:24216507 Induction of myelodysplasia by myeloid-derived suppressor ce... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:24642916 Fine specificity and molecular competition in SLAM family re... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:25416956 A proteome-scale map of the human interactome network. | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:25535246 A THEMIS:SHP1 complex promotes T-cell survival. | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:25785436 Dissociation of SHP-1 from spinophilin during platelet activ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:28065597 A Global Analysis of the Receptor Tyrosine Kinase-Protein Ph... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:31980649 Extensive rewiring of the EGFR network in colorectal cancer ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:33961781 Dual proteome-scale networks reveal cell-specific remodeling... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:7228577 Cyclophosphamide, vincristine, and the blood testis barrier. | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:7528537 Intramolecular regulation of protein tyrosine phosphatase SH... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:7528577 Hematopoietic cell phosphatase associates with erythropoieti... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:8114715 Lck-dependent tyrosyl phosphorylation of the phosphotyrosine... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:8574854 Recruitment of tyrosine phosphatase HCP by the killer cell i... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:8577729 Differential functions of the two Src homology 2 domains in ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:8627166 CD22 associates with protein tyrosine phosphatase 1C, Syk, a... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:8648092 Human and mouse killer-cell inhibitory receptors recruit PTP... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:8691146 Phosphotyrosines in the killer cell inhibitory receptor moti... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:8691154 Tyrosine phosphorylation of a human killer inhibitory recept... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:9148918 A novel phosphotyrosine motif with a critical amino acid at ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:9603468 Thymocyte activation induces the association of the proto-on... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:9774457 Recruitment and activation of SHP-1 protein-tyrosine phospha... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0001784 phosphotyrosine residue binding | IEA GO_REF:0000107 | ACCEPT | Summary: phosphotyrosine residue binding is central to SHP-1 SH2-mediated recruitment and substrate specificity. Reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic activity to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005911 cell-cell junction | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: cell-cell junction is plausible as a receptor/complex localization context but not the dominant site of SHP-1 function. Reason: SHP-1 is recruited to immune receptor complexes, but its core function is cytosolic phosphotyrosine dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. |
| GO:0017124 SH3 domain binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SH3 domain binding is a specific interaction context but secondary to SH2-mediated phosphotyrosine recruitment and phosphatase activity. Reason: Partner binding helps localize SHP-1 in signaling complexes, but the core molecular function is phosphotyrosine dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0031665 negative regulation of lipopolysaccharide-mediated signaling pathway | IEA GO_REF:0000107 | ACCEPT | Summary: negative regulation of lipopolysaccharide-mediated signaling pathway is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0032715 negative regulation of interleukin-6 production | IEA GO_REF:0000107 | ACCEPT | Summary: negative regulation of interleukin-6 production is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0032720 negative regulation of tumor necrosis factor production | IEA GO_REF:0000107 | ACCEPT | Summary: negative regulation of tumor necrosis factor production is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0033007 negative regulation of mast cell activation involved in immune response | IEA GO_REF:0000107 | ACCEPT | Summary: negative regulation of mast cell activation involved in immune response is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0042105 alpha-beta T cell receptor complex | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: alpha-beta T cell receptor complex is plausible as a receptor/complex localization context but not the dominant site of SHP-1 function. Reason: SHP-1 is recruited to immune receptor complexes, but its core function is cytosolic phosphotyrosine dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. |
| GO:0042169 SH2 domain binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: SH2 domain binding is a specific interaction context but secondary to SH2-mediated phosphotyrosine recruitment and phosphatase activity. Reason: Partner binding helps localize SHP-1 in signaling complexes, but the core molecular function is phosphotyrosine dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0050839 cell adhesion molecule binding | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: cell adhesion molecule binding is a specific interaction context but secondary to SH2-mediated phosphotyrosine recruitment and phosphatase activity. Reason: Partner binding helps localize SHP-1 in signaling complexes, but the core molecular function is phosphotyrosine dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0106015 negative regulation of inflammatory response to wounding | IEA GO_REF:0000107 | ACCEPT | Summary: negative regulation of inflammatory response to wounding is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:1905867 epididymis development | IEA GO_REF:0000107 | KEEP AS NON CORE | Summary: epididymis development is plausible downstream biology but not the core SHP-1 function. Reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect context-specific consequences of SHP-1 signaling regulation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0005654 nucleoplasm | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: nucleoplasm localization is plausible but secondary to the main cytosolic/receptor-complex role. Reason: A nuclear localization signal and nuclear access are reported, but the best-supported core site of action is cytosolic and receptor-proximal signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0005730 nucleolus | IDA GO_REF:0000052 | KEEP AS NON CORE | Summary: nucleolus localization is plausible but secondary to the main cytosolic/receptor-complex role. Reason: A nuclear localization signal and nuclear access are reported, but the best-supported core site of action is cytosolic and receptor-proximal signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0004725 protein tyrosine phosphatase activity | IDA PMID:29925997 The E3 ligases Itch and WWP2 cooperate to limit T(H)2 differ... | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0019221 cytokine-mediated signaling pathway | TAS Reactome:R-HSA-512988 | ACCEPT | Summary: cytokine-mediated signaling pathway is supported as a cytokine/JAK-STAT signaling context for SHP-1. Reason: SHP-1 negatively regulates cytokine signaling through JAK/STAT pathway dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. |
| GO:0031295 T cell costimulation | TAS Reactome:R-HSA-388841 | ACCEPT | Summary: T cell costimulation is supported in T-cell receptor/costimulation contexts. Reason: SHP-1 tunes T-cell activation and CD27/TCR signaling by dephosphorylating receptor-proximal substrates such as LCK. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Immunity study provides direct mechanistic evidence of substrate and site-level regulation: SHP-1 is associated with **Lck**, and receptor-driven signaling can lead to **SHP-1–dependent dephosphorylation of Lck at Y394** (the activating site), rather than the inhibitory Y505 site. file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. |
| GO:0060338 regulation of type I interferon-mediated signaling pathway | TAS Reactome:R-HSA-912694 | ACCEPT | Summary: regulation of type I interferon-mediated signaling pathway is supported as a cytokine/JAK-STAT signaling context for SHP-1. Reason: SHP-1 negatively regulates cytokine signaling through JAK/STAT pathway dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. |
| GO:0004725 protein tyrosine phosphatase activity | TAS Reactome:R-HSA-389758 | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0004725 protein tyrosine phosphatase activity | TAS Reactome:R-HSA-914036 | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0004725 protein tyrosine phosphatase activity | TAS Reactome:R-HSA-9701507 | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0004725 protein tyrosine phosphatase activity | TAS Reactome:R-HSA-997314 | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0004725 protein tyrosine phosphatase activity | IMP PMID:19749791 Repression of SHP-1 expression by p53 leads to trkA tyrosine... | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0031665 negative regulation of lipopolysaccharide-mediated signaling pathway | ISS GO_REF:0000024 | ACCEPT | Summary: negative regulation of lipopolysaccharide-mediated signaling pathway is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:1902564 negative regulation of neutrophil activation | IDA PMID:34234773 The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling... | ACCEPT | Summary: negative regulation of neutrophil activation is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0005515 protein binding | IPI PMID:12051764 SPAP2, an Ig family receptor containing both ITIMs and ITAMs... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005737 cytoplasm | IDA PMID:9065461 Interleukin-4 (IL-4) induces phosphatidylinositol 3-kinase (... | ACCEPT | Summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0042110 T cell activation | IDA PMID:38354704 Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell ac... | ACCEPT | Summary: T cell activation is supported in T-cell receptor/costimulation contexts. Reason: SHP-1 tunes T-cell activation and CD27/TCR signaling by dephosphorylating receptor-proximal substrates such as LCK. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Immunity study provides direct mechanistic evidence of substrate and site-level regulation: SHP-1 is associated with **Lck**, and receptor-driven signaling can lead to **SHP-1–dependent dephosphorylation of Lck at Y394** (the activating site), rather than the inhibitory Y505 site. file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. |
| GO:0160162 CD27 signaling pathway | IDA PMID:38354704 Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell ac... | ACCEPT | Summary: CD27 signaling pathway is supported in T-cell receptor/costimulation contexts. Reason: SHP-1 tunes T-cell activation and CD27/TCR signaling by dephosphorylating receptor-proximal substrates such as LCK. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Immunity study provides direct mechanistic evidence of substrate and site-level regulation: SHP-1 is associated with **Lck**, and receptor-driven signaling can lead to **SHP-1–dependent dephosphorylation of Lck at Y394** (the activating site), rather than the inhibitory Y505 site. file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. |
| GO:0045824 negative regulation of innate immune response | IDA PMID:34811497 HIV-1 Vif suppresses antiviral immunity by targeting STING. | ACCEPT | Summary: negative regulation of innate immune response is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0050859 negative regulation of B cell receptor signaling pathway | IDA PMID:35941532 Interfering B cell receptor signaling via SHP-1/p-Lyn axis s... | ACCEPT | Summary: negative regulation of B cell receptor signaling pathway is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0005886 plasma membrane | IDA PMID:23896411 Thrombospondin-1 modulates VEGF signaling via CD36 by recrui... | ACCEPT | Summary: Plasma membrane localization is supported as a receptor-proximal signaling context. Reason: SHP-1 acts locally at plasma membrane or internalized receptor complexes after SH2-mediated recruitment. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0016525 negative regulation of angiogenesis | IDA PMID:23896411 Thrombospondin-1 modulates VEGF signaling via CD36 by recrui... | KEEP AS NON CORE | Summary: negative regulation of angiogenesis is a context-specific downstream phenotype, not the core SHP-1 molecular function. Reason: These phenotypes are secondary to SHP-1-mediated dephosphorylation of receptor-proximal and JAK/STAT signaling components. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0106015 negative regulation of inflammatory response to wounding | IDA PMID:27830702 Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-... | ACCEPT | Summary: negative regulation of inflammatory response to wounding is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0005515 protein binding | IPI PMID:16493035 Recombinant Ig-like transcript 3-Fc modulates T cell respons... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0140031 phosphorylation-dependent protein binding | IPI PMID:11162587 Molecular cloning and characterization of SPAP1, an inhibito... | ACCEPT | Summary: phosphorylation-dependent protein binding is central to SHP-1 SH2-mediated recruitment and substrate specificity. Reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic activity to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0042981 regulation of apoptotic process | TAS PMID:10506221 Regulation of acidification and apoptosis by SHP-1 and Bcl-2... | KEEP AS NON CORE | Summary: regulation of apoptotic process is a context-specific downstream phenotype, not the core SHP-1 molecular function. Reason: These phenotypes are secondary to SHP-1-mediated dephosphorylation of receptor-proximal and JAK/STAT signaling components. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0004725 protein tyrosine phosphatase activity | IMP PMID:10206955 The myeloid-specific sialic acid-binding receptor, CD33, ass... | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:10887109 Myeloid specific human CD33 is an inhibitory receptor with d... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0032715 negative regulation of interleukin-6 production | ISS GO_REF:0000024 | ACCEPT | Summary: negative regulation of interleukin-6 production is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0032720 negative regulation of tumor necrosis factor production | ISS GO_REF:0000024 | ACCEPT | Summary: negative regulation of tumor necrosis factor production is supported as an immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity. Reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil signaling thresholds. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md Multiple 2023–2024 reviews characterize PTPN6/SHP-1 as an **intracellular immune checkpoint**, in part because it can be recruited to inhibitory receptor motifs (notably **PD-1 ITSM**) and dampen costimulatory/proximal signaling (e.g., CD28 and proximal TCR signaling). file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md In inflammatory disease modeling, a 2024 JCI study of acute lung injury (ALI) demonstrates that neutrophil-specific loss of Shp1 causes hyperinflammation and lethal hemorrhagic phenotypes that are SYK-dependent, and reports that a **SHP-1 activator (SC43)** can reduce neutrophil ROS in vitro and mitigate neutrophilic inflammation/NET-associated outcomes in vivo. |
| GO:0001784 phosphotyrosine residue binding | IPI PMID:11986327 Cloning and characterization of human Siglec-11. A recently ... | ACCEPT | Summary: phosphotyrosine residue binding is central to SHP-1 SH2-mediated recruitment and substrate specificity. Reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic activity to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0140031 phosphorylation-dependent protein binding | IPI PMID:12163025 Cloning of two new splice variants of Siglec-10 and mapping ... | ACCEPT | Summary: phosphorylation-dependent protein binding is central to SHP-1 SH2-mediated recruitment and substrate specificity. Reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic activity to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:19843936 FCRL3, an autoimmune susceptibility gene, has inhibitory pot... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:20933011 FCRL6 receptor: expression and associated proteins. | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:26755705 Identification of CD112R as a novel checkpoint for human T c... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0004725 protein tyrosine phosphatase activity | IMP PMID:17562706 Identification of CLEC12B, an inhibitory receptor on myeloid... | ACCEPT | Summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1. Reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from phosphotyrosine residues in signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:17562706 Identification of CLEC12B, an inhibitory receptor on myeloid... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0032991 protein-containing complex | IMP PMID:17562706 Identification of CLEC12B, an inhibitory receptor on myeloid... | KEEP AS NON CORE | Summary: protein-containing complex is plausible as a receptor/complex localization context but not the dominant site of SHP-1 function. Reason: SHP-1 is recruited to immune receptor complexes, but its core function is cytosolic phosphotyrosine dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. |
| GO:0035335 peptidyl-tyrosine dephosphorylation | IMP PMID:17562706 Identification of CLEC12B, an inhibitory receptor on myeloid... | ACCEPT | Summary: peptidyl-tyrosine dephosphorylation is the direct catalytic process mediated by SHP-1. Reason: SHP-1 dephosphorylates phosphotyrosine residues on signaling proteins such as LCK, TCR ITAMs, ZAP-70, and JAK family proteins. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Immunity study provides direct mechanistic evidence of substrate and site-level regulation: SHP-1 is associated with **Lck**, and receptor-driven signaling can lead to **SHP-1–dependent dephosphorylation of Lck at Y394** (the activating site), rather than the inhibitory Y505 site. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. |
| GO:0005654 nucleoplasm | TAS Reactome:R-HSA-9008894 | KEEP AS NON CORE | Summary: nucleoplasm localization is plausible but secondary to the main cytosolic/receptor-complex role. Reason: A nuclear localization signal and nuclear access are reported, but the best-supported core site of action is cytosolic and receptor-proximal signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0005515 protein binding | IPI PMID:23112346 Mice lacking the ITIM-containing receptor G6b-B exhibit macr... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798745 | MARK AS OVER ANNOTATED | Summary: extracellular region is likely a context-specific or high-throughput localization and not a core SHP-1 site of action. Reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and possible nuclear localization rather than extracellular/granule lumen function. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005576 extracellular region | TAS Reactome:R-HSA-6798749 | MARK AS OVER ANNOTATED | Summary: extracellular region is likely a context-specific or high-throughput localization and not a core SHP-1 site of action. Reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and possible nuclear localization rather than extracellular/granule lumen function. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0035580 specific granule lumen | TAS Reactome:R-HSA-6798749 | MARK AS OVER ANNOTATED | Summary: specific granule lumen is likely a context-specific or high-throughput localization and not a core SHP-1 site of action. Reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and possible nuclear localization rather than extracellular/granule lumen function. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:1904724 tertiary granule lumen | TAS Reactome:R-HSA-6798745 | MARK AS OVER ANNOTATED | Summary: tertiary granule lumen is likely a context-specific or high-throughput localization and not a core SHP-1 site of action. Reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and possible nuclear localization rather than extracellular/granule lumen function. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005515 protein binding | IPI PMID:23696226 CEACAM1 on activated NK cells inhibits NKG2D-mediated cytoly... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:18424730 Carcinoembryonic antigen-related cell adhesion molecule 1 in... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:10540326 Molecular and functional characterization of IRp60, a member... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:16254138 The inhibitory receptor IRp60 (CD300a) suppresses the effect... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:16339535 The inhibitory receptor IRp60 (CD300a) is expressed and func... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0070062 extracellular exosome | HDA PMID:19056867 Large-scale proteomics and phosphoproteomics of urinary exos... | MARK AS OVER ANNOTATED | Summary: extracellular exosome is likely a context-specific or high-throughput localization and not a core SHP-1 site of action. Reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and possible nuclear localization rather than extracellular/granule lumen function. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0070062 extracellular exosome | HDA PMID:20458337 MHC class II-associated proteins in B-cell exosomes and pote... | MARK AS OVER ANNOTATED | Summary: extracellular exosome is likely a context-specific or high-throughput localization and not a core SHP-1 site of action. Reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and possible nuclear localization rather than extracellular/granule lumen function. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-205306 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-210277 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-389758 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-389759 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-389941 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5684169 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-5690701 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-909738 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-913424 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-914036 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9701507 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-9851072 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005829 cytosol | TAS Reactome:R-HSA-997314 | ACCEPT | Summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0005515 protein binding | IPI PMID:11907092 Mutational analysis of immunoreceptor tyrosine-based inhibit... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:9285411 A novel immunoglobulin superfamily receptor for cellular and... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005515 protein binding | IPI PMID:9842885 The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0018108 peptidyl-tyrosine phosphorylation | IDA PMID:9285411 A novel immunoglobulin superfamily receptor for cellular and... | REMOVE | Summary: Peptidyl-tyrosine phosphorylation is not a process catalyzed by PTPN6. Reason: The cited biology describes SHP-1 phosphorylation or kinase substrates, but PTPN6/SHP-1 is a phosphatase that dephosphorylates tyrosine-phosphorylated proteins. Proposed replacements: peptidyl-tyrosine dephosphorylation protein dephosphorylation Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2023 review summarizes phosphorylation-based regulation: **Tyr536 and Tyr564** phosphorylation can increase SHP-1 activity, whereas **Ser591** phosphorylation inhibits activity and is associated with regulation of localization and function after TCR engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A key 2024 development is the discovery that SHP-1 can be regulated at the protein level by phosphorylation-triggered degradation. Poirier et al. (Science Signaling, Jan 2024) report that **TAOK3 phosphorylates SHP-1 at Thr394** in the phosphatase domain, promoting **ubiquitylation and proteasomal degradation**. |
| GO:0018108 peptidyl-tyrosine phosphorylation | IDA PMID:18802077 Inhibitory immunoglobulin-like receptors LILRB and PIR-B neg... | REMOVE | Summary: Peptidyl-tyrosine phosphorylation is not a process catalyzed by PTPN6. Reason: The cited biology describes SHP-1 phosphorylation or kinase substrates, but PTPN6/SHP-1 is a phosphatase that dephosphorylates tyrosine-phosphorylated proteins. Proposed replacements: peptidyl-tyrosine dephosphorylation protein dephosphorylation Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2023 review summarizes phosphorylation-based regulation: **Tyr536 and Tyr564** phosphorylation can increase SHP-1 activity, whereas **Ser591** phosphorylation inhibits activity and is associated with regulation of localization and function after TCR engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A key 2024 development is the discovery that SHP-1 can be regulated at the protein level by phosphorylation-triggered degradation. Poirier et al. (Science Signaling, Jan 2024) report that **TAOK3 phosphorylates SHP-1 at Thr394** in the phosphatase domain, promoting **ubiquitylation and proteasomal degradation**. |
| GO:0005001 transmembrane receptor protein tyrosine phosphatase activity | IDA PMID:11266449 Negative regulation of Ros receptor tyrosine kinase signalin... | MODIFY | Summary: Transmembrane receptor protein tyrosine phosphatase activity is inconsistent with PTPN6/SHP-1. Reason: PTPN6 encodes a cytosolic non-receptor tyrosine phosphatase, not a transmembrane receptor phosphatase. Proposed replacements: non-membrane spanning protein tyrosine phosphatase activity protein tyrosine phosphatase activity Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md The UniProt accession **P29350** corresponds to **human PTPN6**, encoding **Src homology region 2 (SH2) domain-containing phosphatase-1 (SHP-1)**, also known as **hematopoietic cell protein-tyrosine phosphatase (HCP)** and **PTP1C**. Recent reviews and primary studies consistently describe this protein as a **non-receptor (cytosolic) protein tyrosine phosphatase** with tandem SH2 domains and a catalytic PTP domain, aligning with the UniProt description and domain expectations for PTPN6/SHP-1. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. |
| GO:0006470 protein dephosphorylation | IDA PMID:11266449 Negative regulation of Ros receptor tyrosine kinase signalin... | ACCEPT | Summary: protein dephosphorylation is the direct catalytic process mediated by SHP-1. Reason: SHP-1 dephosphorylates phosphotyrosine residues on signaling proteins such as LCK, TCR ITAMs, ZAP-70, and JAK family proteins. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Immunity study provides direct mechanistic evidence of substrate and site-level regulation: SHP-1 is associated with **Lck**, and receptor-driven signaling can lead to **SHP-1–dependent dephosphorylation of Lck at Y394** (the activating site), rather than the inhibitory Y505 site. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. |
| GO:0019901 protein kinase binding | IPI PMID:11266449 Negative regulation of Ros receptor tyrosine kinase signalin... | KEEP AS NON CORE | Summary: protein kinase binding is a specific interaction context but secondary to SH2-mediated phosphotyrosine recruitment and phosphatase activity. Reason: Partner binding helps localize SHP-1 in signaling complexes, but the core molecular function is phosphotyrosine dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0030154 cell differentiation | IDA PMID:11266449 Negative regulation of Ros receptor tyrosine kinase signalin... | KEEP AS NON CORE | Summary: cell differentiation is plausible downstream biology but not the core SHP-1 function. Reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect context-specific consequences of SHP-1 signaling regulation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0070372 regulation of ERK1 and ERK2 cascade | IDA PMID:11266449 Negative regulation of Ros receptor tyrosine kinase signalin... | KEEP AS NON CORE | Summary: regulation of ERK1 and ERK2 cascade is plausible downstream biology but not the core SHP-1 function. Reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect context-specific consequences of SHP-1 signaling regulation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0005737 cytoplasm | IDA PMID:10940933 Subcellular localization of intracellular protein tyrosine p... | ACCEPT | Summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:19749791 Repression of SHP-1 expression by p53 leads to trkA tyrosine... | KEEP AS NON CORE | Summary: positive regulation of cell population proliferation is plausible downstream biology but not the core SHP-1 function. Reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect context-specific consequences of SHP-1 signaling regulation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0005515 protein binding | IPI PMID:19838216 Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0005634 nucleus | IDA PMID:19838216 Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/... | KEEP AS NON CORE | Summary: nucleus localization is plausible but secondary to the main cytosolic/receptor-complex role. Reason: A nuclear localization signal and nuclear access are reported, but the best-supported core site of action is cytosolic and receptor-proximal signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. |
| GO:0005737 cytoplasm | IDA PMID:19838216 Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/... | ACCEPT | Summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity. Reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling complexes. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. |
| GO:0008284 positive regulation of cell population proliferation | IMP PMID:19838216 Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/... | KEEP AS NON CORE | Summary: positive regulation of cell population proliferation is plausible downstream biology but not the core SHP-1 function. Reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect context-specific consequences of SHP-1 signaling regulation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0051897 positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction | IMP PMID:19838216 Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/... | MARK AS OVER ANNOTATED | Summary: Positive regulation of PI3K/AKT signaling is not well supported as a PTPN6/SHP-1 function. Reason: The strongest recent synthesis instead supports SHP-1 as a brake that can reduce AKT phosphorylation in receptor-signaling contexts; positive-direction annotations need context-specific support. Proposed replacements: T cell costimulation peptidyl-tyrosine dephosphorylation Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. |
| GO:2000045 regulation of G1/S transition of mitotic cell cycle | IMP PMID:19838216 Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/... | KEEP AS NON CORE | Summary: regulation of G1/S transition of mitotic cell cycle is plausible downstream biology but not the core SHP-1 function. Reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect context-specific consequences of SHP-1 signaling regulation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md Jaeger-Ruckstuhl et al. (Immunity, Feb 2024) describe a **CD27–TRAF2–SHP-1 signaling axis** during naïve T-cell activation. Strong CD27 ligation triggers **clathrin-mediated internalization** of CD27, recruitment of **TRAF2** and **SHP-1**, increased SHP-1 phosphorylation at **Y564**, and SHP-1–dependent dephosphorylation of **Lck Y394**, resulting in reduced ERK1/2 and AKT phosphorylation in the context of CD28 co-engagement. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0005515 protein binding | IPI PMID:18604210 An essential function for beta-arrestin 2 in the inhibitory ... | MARK AS OVER ANNOTATED | Summary: Protein binding is supported but too generic for SHP-1 curation. Reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase activity; generic protein binding obscures the mechanism. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md SHP-1 contains **two N-terminal SH2 domains (N-SH2, C-SH2)** and a **catalytic PTP domain**, plus a **C-terminal tail** bearing multiple regulatory phosphorylation sites and a reported **nuclear localization signal (NLS)**. file:human/PTPN6/PTPN6-deep-research-falcon.md A core organizing principle is **autoinhibition**: intramolecular interaction between the **N-SH2 and PTP domains** occludes the active site (including the catalytic cysteine), producing a “closed” inactive conformation. Binding of phosphotyrosine-containing ligands to SH2 domains can promote a conformational change to an “open” active state. file:human/PTPN6/PTPN6-deep-research-falcon.md Like other classical PTPs, SHP-1 catalysis is directed toward pTyr residues within signaling complexes. Functionally, “substrate specificity” is largely conferred by **spatiotemporal recruitment** via SH2 domains to **phosphotyrosine motifs** on receptors/adaptors, rather than by broad free-diffusion activity. |
| GO:0007186 G protein-coupled receptor signaling pathway | TAS PMID:7781604 Tyrosine phosphorylation of an SH2-containing protein tyrosi... | KEEP AS NON CORE | Summary: G protein-coupled receptor signaling pathway is a context-specific downstream phenotype, not the core SHP-1 molecular function. Reason: These phenotypes are secondary to SHP-1-mediated dephosphorylation of receptor-proximal and JAK/STAT signaling components. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
| GO:0016020 membrane | TAS PMID:10506221 Regulation of acidification and apoptosis by SHP-1 and Bcl-2... | KEEP AS NON CORE | Summary: membrane is plausible as a receptor/complex localization context but not the dominant site of SHP-1 function. Reason: SHP-1 is recruited to immune receptor complexes, but its core function is cytosolic phosphotyrosine dephosphorylation. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is primarily described as a **cytosolic (non-receptor) PTP**, but its functional “localization” is dynamic: it is **recruited to receptor/adaptor signaling complexes** through SH2 binding to phosphotyrosine motifs, thereby acting locally at the plasma membrane or at internalized receptor complexes. file:human/PTPN6/PTPN6-deep-research-falcon.md The CD27 axis provides a clear example of compartmentalized action: CD27 internalization is required for recruiting TRAF2 and SHP-1 into a signaling complex that modulates Lck phosphorylation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 Science Signaling study synthesizes SHP-1’s role as a **major negative regulator of proximal TCR signaling** by dephosphorylating multiple TCR-proximal substrates, including **TCR ITAMs**, **LCK**, and **ZAP-70**, thereby limiting downstream MAPK/transcriptional outputs such as IL-2 production. |
| GO:0008285 negative regulation of cell population proliferation | NAS PMID:10497187 Human 70-kDa SHP-1L differs from 68-kDa SHP-1 in its C-termi... | KEEP AS NON CORE | Summary: negative regulation of cell population proliferation is a context-specific downstream phenotype, not the core SHP-1 molecular function. Reason: These phenotypes are secondary to SHP-1-mediated dephosphorylation of receptor-proximal and JAK/STAT signaling components. Supporting Evidence: file:human/PTPN6/PTPN6-deep-research-falcon.md PTPN6/SHP-1 is a **classical protein tyrosine phosphatase** (EC 3.1.3.48) that removes phosphate from **phosphotyrosine (pTyr)** residues on signaling proteins, thereby counterbalancing tyrosine kinases and tuning receptor-proximal signaling thresholds—especially in hematopoietic/immune contexts. file:human/PTPN6/PTPN6-deep-research-falcon.md A recurring functional theme—highlighted in 2023 and 2024 oncology-focused literature—is SHP-1 as a **negative regulator of the JAK/STAT3 pathway**, via dephosphorylation/inactivation of **JAKs** and reduced STAT3 activation. file:human/PTPN6/PTPN6-deep-research-falcon.md A 2024 pan-cancer analysis reports that PTPN6 expression differs between tumor and adjacent tissues across many cancers, associates with prognosis in a cancer-type–dependent manner, correlates with immune infiltration, and shows tumor-type–specific methylation and phosphorylation differences. |
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