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.
|
The research report should be a detailed narrative explaining the function, biological processes, and localization of the gene product. Citations should be given for all claims.
You should prioritize authoritative reviews and primary scientific literature when conducting research. You can supplement
this with annotations you find in gene/protein databases, but these can be outdated or inaccurate.
We are specifically interested in the primary function of the gene - for enzymes, what reaction is catalyzed, and what is the substrate specificity? For transporters, what is the substrate? For structural proteins or adapters, what is the broader structural role? For signaling molecules, what is the role in the pathway.
We are interested in where in or outside the cell the gene product carries out its function.
We are also interested in the signaling or biochemical pathways in which the gene functions. We are less interested in broad pleiotropic effects, except where these elucidate the precise role.
Include evidence where possible. We are interested in both experimental evidence as well as inference from structure, evolution, or bioinformatic analysis. Precise studies should be prioritized over high-throughput, where available.
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. (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 1-2)
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. (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 1-2)
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). (lim2023considerationofshp1 pages 4-6)
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. (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 1-2)
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. This explains why substrates repeatedly observed in recent mechanistic studies include receptor-proximal kinases/adaptors such as LCK (pY394) in T-cell signaling and JAK/STAT pathway components in cytokine signaling. (poirier2024theinductionof pages 1-5, lim2023considerationofshp1 pages 4-6, jaegerruckstuhl2024signalingviaa pages 5-6)
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. (poirier2024theinductionof pages 1-5)
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. (jaegerruckstuhl2024signalingviaa pages 5-6, jaegerruckstuhl2024signalingviaa media de0c2553)
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. Functionally, this signaling favors memory-associated transcriptional/epigenetic programs rather than immediate effector differentiation. (jaegerruckstuhl2024signalingviaa pages 11-13, jaegerruckstuhl2024signalingviaa pages 5-6, jaegerruckstuhl2024signalingviaa media de0c2553)
Visual evidence for the recruitment and signaling logic of this axis is shown in the Immunity paper’s schematic and Figure panels (co-IP and phospho-signaling readouts). (jaegerruckstuhl2024signalingviaa media de0c2553, jaegerruckstuhl2024signalingviaa media d6d60109, jaegerruckstuhl2024signalingviaa media dd289f60)
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). Reviews also emphasize partial functional redundancy/overlap with SHP-2 in PD-1 signaling. (salmond2024targetingproteintyrosine pages 5-7, lim2023considerationofshp1 pages 17-17)
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. (lim2023considerationofshp1 pages 4-6)
In a metastatic melanoma study (Cancer Cell International, Dec 2024), PTPN6 overexpression in melanoma cell lines decreased p-JAK2 and p-STAT3 (without changing total JAK2/STAT3) and lowered PD-L1 protein, linking SHP-1 activity to JAK2–STAT3 and immune evasion phenotypes in that model. (sun2024prognosticvalueand pages 8-12, sun2024prognosticvalueand pages 12-14)
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. The presence of a C-terminal NLS is also reported in a 2023 review, suggesting potential regulated nuclear access in some contexts. (lim2023considerationofshp1 pages 4-6, jaegerruckstuhl2024signalingviaa pages 5-6)
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. (jaegerruckstuhl2024signalingviaa pages 5-6, jaegerruckstuhl2024signalingviaa pages 3-5)
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. (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 13-14)
Consistent with this, the 2024 Immunity study reports increased SHP-1 phosphorylation at Y564 following CD27 ligation in naïve T cells, coinciding with SHP-1–dependent modulation of Lck Y394 phosphorylation. (jaegerruckstuhl2024signalingviaa pages 5-6, jaegerruckstuhl2024signalingviaa media de0c2553)
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. Loss of TAOK3 increases SHP-1 abundance and activity and yields TCR desensitization (reduced TCR responsiveness), while pharmacologic SHP-1 inhibition can rescue activation in TAOK3-deficient T cells. (poirier2024theinductionof pages 1-5, poirier2024theinductionof pages 35-37)
This provides an updated conceptual frame: SHP-1 is not only regulated by conformational opening/closing and phosphorylation state, but also by regulated turnover that sets signaling thresholds. (poirier2024theinductionof pages 1-5)
PTPN6 is frequently described as epigenetically regulated. A 2023 review notes promoter hypermethylation as a mechanism suppressing SHP-1 expression in tumors, with promoter usage differing by cell type (epithelial-active promoter 1 vs hematopoietic-active promoter 2). (lim2023considerationofshp1 pages 1-2, lim2023considerationofshp1 pages 2-4)
Quantitatively, this review cites ~57% hypermethylation of promoter 2 in one diffuse large B cell lymphoma cohort. (lim2023considerationofshp1 pages 2-4)
The CD27–TRAF2–SHP-1 axis (Immunity 2024) provides a recent example where SHP-1 is not simply “inhibitory,” but is used to tune activation dynamics and bias differentiation programs toward memory-associated gene regulatory networks, with practical implications for CAR-T cell manufacturing strategies and persistence. (jaegerruckstuhl2024signalingviaa pages 11-13, jaegerruckstuhl2024signalingviaa pages 5-6, jaegerruckstuhl2024signalingviaa pages 1-3)
The TAOK3→SHP-1 Thr394 phosphorylation→ubiquitylation→proteasomal degradation pathway (Science Signaling 2024) adds a modern regulatory layer for SHP-1 abundance control in T cells, and highlights residue-level differences between SHP-1 and SHP-2 (SHP-2 lacks the corresponding Thr394). (poirier2024theinductionof pages 1-5)
A 2024 immunotherapy-focused review summarizes evidence that loss/inhibition of PTPN6 can enhance T-cell responses, including adoptive transfer settings, and that CRISPR-Cas9 deletion of PTPN6 can improve CAR-T cytolytic function, though tradeoffs exist (e.g., safety/purity and balancing toxicity vs efficacy). (salmond2024targetingproteintyrosine pages 5-7, salmond2024targetingproteintyrosine pages 13-14)
SHP-1 is presented as an actionable intracellular checkpoint in CAR-T contexts. Reviews describe (i) CRISPR-based PTPN6 knockout to enhance tumor killing and cytokine production in CAR-T systems and (ii) design strategies where recruiting inhibitory PTPs to CAR signaling can potentially mitigate cytokine release syndrome without fully losing antitumor activity—illustrating real engineering tradeoffs. (salmond2024targetingproteintyrosine pages 5-7, lim2023considerationofshp1 pages 9-10)
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. (moussaviharami2024neutrophilspecificshp1loss pages 5-7, moussaviharami2024neutrophilspecificshp1loss pages 1-2)
A phase I trial record (ClinicalTrials.gov) describes SC-43 as a compound that enhances SHP-1 activity by impairing N-SH2/PTP association (relieving autoinhibition) and proposed oral dose escalation, but this study was withdrawn before enrollment (0 participants). (NCT03443622 chunk 1)
In primary effusion lymphoma cells, a 2024 study reports that 5-azacytidine (5-AZA) upregulated PTPN6/SHP-1 and SOCS3, reduced STAT3 activation, and potentiated the cytotoxic effect of the STAT3-pathway inhibitor AG490, supporting a combined epigenetic + signaling inhibition approach. (crosta20245azaupregulatessocs3 pages 1-2)
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. This supports real-world use of PTPN6 as a candidate immune microenvironment biomarker, but also emphasizes heterogeneity and the risk of one-size-fits-all therapeutic targeting. (cui2024pancanceranalysisof pages 1-2)
A 2023 tumor-therapy review frames SHP-1 as a structurally regulated phosphatase whose “closed-to-open” switch is central for activity, and argues that SHP-1 targeting must consider context: SHP-1 can be tumor suppressive in some cancer cells (e.g., by restraining JAK/STAT3), while in immune cells it may suppress antitumor immunity. The review also notes that despite many candidate SHP-1 modulators, only a small number (e.g., sorafenib derivatives) have shown notable translational traction, highlighting ongoing druggability challenges and context dependence. (lim2023considerationofshp1 pages 1-2)
A 2024 immunotherapy review similarly positions PTPN6/SHP-1 among PTPs that act as intracellular checkpoints and discusses genetic deletion as a rational strategy to improve adoptive T-cell therapy, while acknowledging redundancy/complexity and safety concerns. (salmond2024targetingproteintyrosine pages 5-7, salmond2024targetingproteintyrosine pages 13-14)
Key quantitative/statistical findings extracted from 2023–2024 sources include:
| Group | Functional annotation point | Key evidence/details | Citation |
|---|---|---|---|
| Catalytic reaction / substrates | Enzyme identity and reaction | Human PTPN6 encodes SHP-1, a classical non-receptor protein tyrosine phosphatase (EC 3.1.3.48) that hydrolyzes phosphotyrosine on signaling proteins; it is a major negative regulator of hematopoietic signaling. | (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 1-2) |
| Catalytic reaction / substrates | Proximal TCR substrates | In T cells, SHP-1 dephosphorylates TCR ITAMs, LCK and ZAP-70, thereby dampening proximal TCR signaling, MAPK output, and IL-2 production. A 2024 study specifically highlights dephosphorylation of Lck Y394. | (poirier2024theinductionof pages 1-5, poirier2024theinductionof pages 35-37, jaegerruckstuhl2024signalingviaa pages 5-6) |
| Catalytic reaction / substrates | Cytokine/JAK substrates | SHP-1 suppresses cytokine signaling by dephosphorylating JAK family kinases; examples noted include JAK2 downstream of EPOR and JAK1 in IFN-α signaling, with downstream restraint of STAT3 activation. | (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 13-14, sun2024prognosticvalueand pages 12-14) |
| Domain architecture / autoinhibition | Domain organization | SHP-1 contains tandem N-SH2 and C-SH2 domains, a central catalytic PTP domain, and a C-terminal tail containing regulatory phosphorylation sites plus a nuclear localization signal. | (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 1-2) |
| Domain architecture / autoinhibition | Closed-to-open regulation | Autoinhibition is mediated by N-SH2–PTP intramolecular interaction that occludes the catalytic cysteine-containing active site; phosphopeptide binding to SH2 domains relieves this and stabilizes an open, active conformation. | (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 1-2) |
| Domain / PTM regulation | Tyrosine and serine phosphorylation | Tyr536 and Tyr564 phosphorylation increase SHP-1 activity, whereas Ser591 phosphorylation inhibits phosphatase activity and affects localization after TCR engagement. | (lim2023considerationofshp1 pages 4-6, lim2023considerationofshp1 pages 13-14) |
| Key pathway: TCR | TCR signaling brake | SHP-1 is a central inhibitory phosphatase in TCR signaling, lowering activation thresholds by counteracting LCK/ZAP-70 and related proximal effectors. | (poirier2024theinductionof pages 1-5, lim2023considerationofshp1 pages 9-10) |
| Key pathway: PD-1 / inhibitory receptors | Immune checkpoint signaling | SHP-1 can be recruited to inhibitory receptor motifs, including PD-1 ITSM, where it contributes to dephosphorylation events such as CD28 and proximal TCR components; reviews emphasize partial redundancy with SHP-2. | (lim2023considerationofshp1 pages 16-17, salmond2024targetingproteintyrosine pages 5-7, lim2023considerationofshp1 pages 17-17) |
| Key pathway: CD27 axis | 2024 CD27–TRAF2–SHP-1 pathway | During naïve T-cell activation, CD27 ligation triggers receptor internalization, recruitment of TRAF2 and SHP-1, increased SHP-1 Y564 phosphorylation, and selective dephosphorylation of Lck Y394, reducing ERK1/2 and AKT signaling and biasing cells toward memory-associated programs. | (jaegerruckstuhl2024signalingviaa pages 11-13, jaegerruckstuhl2024signalingviaa pages 5-6, jaegerruckstuhl2024signalingviaa media de0c2553) |
| Key pathway: JAK/STAT3 | Tumor and cytokine contexts | Across multiple cancer studies, SHP-1 restrains JAK2-STAT3 signaling; restored or increased PTPN6 expression decreases p-JAK2/p-STAT3, suppresses tumor growth, and can lower PD-L1 in melanoma models. | (lim2023considerationofshp1 pages 4-6, crosta20245azaupregulatessocs3 pages 1-2, sun2024prognosticvalueand pages 8-12, sun2024prognosticvalueand pages 12-14) |
| Localization / recruitment | Basal subcellular localization | SHP-1 is primarily a cytosolic phosphatase but is recruited to activated receptor complexes through SH2-mediated recognition of phosphotyrosine motifs; the C-terminus also contains a nuclear localization signal. | (lim2023considerationofshp1 pages 4-6, cui2024pancanceranalysisof pages 1-2) |
| Localization / recruitment | Receptor-complex recruitment | Recruitment occurs at immune receptor complexes such as PD-1, TCR-associated complexes, and internalized CD27 endocytic complexes via TRAF2. | (lim2023considerationofshp1 pages 13-14, salmond2024targetingproteintyrosine pages 5-7, jaegerruckstuhl2024signalingviaa pages 5-6, jaegerruckstuhl2024signalingviaa pages 1-3) |
| 2024 regulation discovery | TAOK3-driven degradation rheostat | A 2024 Science Signaling study showed TAOK3 phosphorylates SHP-1 at Thr394 in the phosphatase domain, promoting ubiquitylation and proteasomal degradation. Loss of TAOK3 increases SHP-1 abundance/activity and desensitizes TCR signaling; SHP-2 is not affected because it lacks the corresponding residue. | (poirier2024theinductionof pages 1-5, poirier2024theinductionof pages 35-37) |
| Translational / therapeutic | SHP-1 activation with SC43 | The small molecule SC43 is described as a SHP-1 activator that relieves autoinhibition by impairing N-SH2/PTP association. In neutrophil-driven ALI models, SC43 reduced ROS, alveolar neutrophilia, and NET-associated readouts; a phase I SC-43 solid-tumor trial was registered but withdrawn before enrollment. | (moussaviharami2024neutrophilspecificshp1loss pages 5-7, moussaviharami2024neutrophilspecificshp1loss pages 1-2, NCT03443622 chunk 1) |
| Translational / therapeutic | Adoptive cell therapy / CAR-T | SHP-1 acts as an intracellular immune checkpoint. Genetic loss or inhibition can enhance antitumor T-cell function; CRISPR/Cas9 PTPN6 knockout increased cytolytic activity of CD133 CAR-T cells in vitro and antitumor activity in vivo, though reviews note safety and context trade-offs. | (lim2023considerationofshp1 pages 16-17, salmond2024targetingproteintyrosine pages 5-7, lim2023considerationofshp1 pages 9-10, salmond2024targetingproteintyrosine pages 13-14) |
| Translational / therapeutic | Epigenetic re-expression | 5-Azacytidine (5-AZA) upregulated PTPN6/SHP-1 and SOCS3 in primary effusion lymphoma cells, reduced STAT3 activation, and potentiated the cytotoxic effect of the JAK2/STAT3 inhibitor AG490. | (crosta20245azaupregulatessocs3 pages 1-2, lim2023considerationofshp1 pages 2-4) |
| Translational / therapeutic | Cancer biomarker / target complexity | SHP-1 can behave as tumor suppressor or tumor-supportive factor depending on cancer type and microenvironment; pan-cancer data indicate strong links to immune infiltration, methylation state, and prognosis. | (lim2023considerationofshp1 pages 1-2, cui2024pancanceranalysisof pages 1-2) |
| Quantitative statistics | Somatic alteration frequency | Review-level compilation reports somatic PTPN6 mutations in ~2.7% of cancers, with higher frequency in uterine carcinosarcoma (7.01%). | (lim2023considerationofshp1 pages 1-2) |
| Quantitative statistics | Epigenetic silencing frequency | PTPN6 promoter 2 hypermethylation was reported in about 57% of a diffuse large B-cell lymphoma cohort. | (lim2023considerationofshp1 pages 2-4) |
| Quantitative statistics | CD27-axis perturbation efficiency | In the 2024 Immunity study, CRISPR-Cas9 SHP-1 knockout efficiency reached ~88%, and single-cell multiome experiments retained 7,862 and 11,063 cells after QC. | (jaegerruckstuhl2024signalingviaa pages 5-6, jaegerruckstuhl2024signalingviaa pages 20-21) |
| Quantitative statistics | SKM-1 knockdown phenotypes | In SKM-1 cells, stable PTPN6 knockdown reduced apoptosis from 2.7% to 0.8% and reduced CD235a+ erythroid differentiation from 25.0% to 13.2%. | (yu2024effectsofptpn6 pages 8-11) |
| Quantitative statistics | Melanoma cohort sizes and significance | The metastatic melanoma study analyzed 368 MM samples and 1405 normal skin samples; PTPN6 was lower in MM (p < 0.001), higher PTPN6 associated with improved OS (p < 0.001) and PFS (p = 0.008). Xenograft experiments used 5 mice/group with 4 × 10^6 cells injected and tumor measurement every 3 days for 4 weeks. | (sun2024prognosticvalueand pages 1-2, sun2024prognosticvalueand pages 4-5) |
| Quantitative statistics | Neutrophil ALI experimental thresholds | In the JCI 2024 lung-injury work, intratracheal LPS dose was 5 μg/g body weight; large intravascular neutrophil clusters were defined as >5,000 μm^3; Pseudomonas inoculum was 5 × 10^5 CFU/mouse. | (moussaviharami2024neutrophilspecificshp1loss pages 7-9, moussaviharami2024lossofneutrophil pages 5-8, moussaviharami2024neutrophilspecificshp1loss pages 2-5) |
| Quantitative statistics | Clinical-trial implementation details | Historical translational trials targeting SHP-1/2 phosphatase activity with sodium stibogluconate enrolled 33 patients (M.D. Anderson phase I) and 22 patients (Case Comprehensive phase I). The registered SC-43 phase I study planned dose escalation from 100 to 1200 mg/day but enrolled 0 patients due to withdrawal. | (NCT00629200 chunk 1, NCT00498979 chunk 1, NCT03443622 chunk 1) |
Table: This table summarizes core functional annotation points for human PTPN6/SHP-1, including enzymatic role, regulatory domains and PTMs, signaling pathways, localization mechanisms, recent 2024 discoveries, translational relevance, and key quantitative findings. It is designed as a compact evidence map for downstream narrative reporting.
Some included studies (e.g., AML targeting) were only accessible in excerpted form here; therefore, precise quantitative effect sizes (IC50, hazard ratios, combination indices) could not be extracted from those particular texts despite qualitative claims. (wang2024targetingproteintyrosine pages 1-3, wang2024targetingproteintyrosine pages 14-16)
References
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(lim2023considerationofshp1 pages 17-17): Seyeon Lim, Ki Won Lee, Jeong Yoon Kim, and Kwang Dong Kim. Consideration of shp-1 as a molecular target for tumor therapy. International Journal of Molecular Sciences, 25:331, Dec 2023. URL: https://doi.org/10.3390/ijms25010331, doi:10.3390/ijms25010331. This article has 18 citations.
(sun2024prognosticvalueand pages 8-12): Rongyao Sun, Shuqiang Wei, Ying Yu, Zhuo Wang, Tonghao Yao, Yining Zhang, Luping Cui, and Xu Ma. Prognostic value and immune infiltration of a tumor microenvironment-related ptpn6 in metastatic melanoma. Cancer Cell International, Dec 2024. URL: https://doi.org/10.1186/s12935-024-03625-6, doi:10.1186/s12935-024-03625-6. This article has 7 citations and is from a peer-reviewed journal.
(sun2024prognosticvalueand pages 12-14): Rongyao Sun, Shuqiang Wei, Ying Yu, Zhuo Wang, Tonghao Yao, Yining Zhang, Luping Cui, and Xu Ma. Prognostic value and immune infiltration of a tumor microenvironment-related ptpn6 in metastatic melanoma. Cancer Cell International, Dec 2024. URL: https://doi.org/10.1186/s12935-024-03625-6, doi:10.1186/s12935-024-03625-6. This article has 7 citations and is from a peer-reviewed journal.
(jaegerruckstuhl2024signalingviaa pages 3-5): Carla A. Jaeger-Ruckstuhl, Yun Lo, Elena Fulton, Olivia G. Waltner, Tamer B. Shabaneh, Sylvain Simon, Pranav V. Muthuraman, Colin E. Correnti, Oliver J. Newsom, Ian A. Engstrom, Sami B. Kanaan, Shruti S. Bhise, Jobelle M.C. Peralta, Raymond Ruff, Jason P. Price, Sylvia M. Stull, Andrew R. Stevens, Grace Bugos, Mitchell G. Kluesner, Valentin Voillet, Vishaka Muhunthan, Fionnuala Morrish, James M. Olson, Raphaël Gottardo, Jay F. Sarthy, Steven Henikoff, Lucas B. Sullivan, Scott N. Furlan, and Stanley R. Riddell. Signaling via a cd27-traf2-shp-1 axis during naive t cell activation promotes memory-associated gene regulatory networks. Immunity, 57:287-302.e12, Feb 2024. URL: https://doi.org/10.1016/j.immuni.2024.01.011, doi:10.1016/j.immuni.2024.01.011. This article has 48 citations and is from a highest quality peer-reviewed journal.
(lim2023considerationofshp1 pages 13-14): Seyeon Lim, Ki Won Lee, Jeong Yoon Kim, and Kwang Dong Kim. Consideration of shp-1 as a molecular target for tumor therapy. International Journal of Molecular Sciences, 25:331, Dec 2023. URL: https://doi.org/10.3390/ijms25010331, doi:10.3390/ijms25010331. This article has 18 citations.
(poirier2024theinductionof pages 35-37): Alexandre Poirier, João Vitor Silva Ormonde, Isabelle Aubry, Belma Melda Abidin, Chu-Han Feng, Zuzet Martinez-Cordova, Ana Maria Hincapie, Chenyue Wu, Luis Alberto Pérez-Quintero, Chia-Lin Wang, Anne Claude Gingras, Joaquín Madrenas, and Michel L. Tremblay. The induction of shp-1 degradation by taok3 ensures the responsiveness of t cells to tcr stimulation. Science Signaling, Jan 2024. URL: https://doi.org/10.1126/scisignal.adg4422, doi:10.1126/scisignal.adg4422. This article has 7 citations and is from a domain leading peer-reviewed journal.
(lim2023considerationofshp1 pages 2-4): Seyeon Lim, Ki Won Lee, Jeong Yoon Kim, and Kwang Dong Kim. Consideration of shp-1 as a molecular target for tumor therapy. International Journal of Molecular Sciences, 25:331, Dec 2023. URL: https://doi.org/10.3390/ijms25010331, doi:10.3390/ijms25010331. This article has 18 citations.
(jaegerruckstuhl2024signalingviaa pages 1-3): Carla A. Jaeger-Ruckstuhl, Yun Lo, Elena Fulton, Olivia G. Waltner, Tamer B. Shabaneh, Sylvain Simon, Pranav V. Muthuraman, Colin E. Correnti, Oliver J. Newsom, Ian A. Engstrom, Sami B. Kanaan, Shruti S. Bhise, Jobelle M.C. Peralta, Raymond Ruff, Jason P. Price, Sylvia M. Stull, Andrew R. Stevens, Grace Bugos, Mitchell G. Kluesner, Valentin Voillet, Vishaka Muhunthan, Fionnuala Morrish, James M. Olson, Raphaël Gottardo, Jay F. Sarthy, Steven Henikoff, Lucas B. Sullivan, Scott N. Furlan, and Stanley R. Riddell. Signaling via a cd27-traf2-shp-1 axis during naive t cell activation promotes memory-associated gene regulatory networks. Immunity, 57:287-302.e12, Feb 2024. URL: https://doi.org/10.1016/j.immuni.2024.01.011, doi:10.1016/j.immuni.2024.01.011. This article has 48 citations and is from a highest quality peer-reviewed journal.
(salmond2024targetingproteintyrosine pages 13-14): Robert J. Salmond. Targeting protein tyrosine phosphatases to improve cancer immunotherapies. Cells, 13:231, Jan 2024. URL: https://doi.org/10.3390/cells13030231, doi:10.3390/cells13030231. This article has 6 citations.
(lim2023considerationofshp1 pages 9-10): Seyeon Lim, Ki Won Lee, Jeong Yoon Kim, and Kwang Dong Kim. Consideration of shp-1 as a molecular target for tumor therapy. International Journal of Molecular Sciences, 25:331, Dec 2023. URL: https://doi.org/10.3390/ijms25010331, doi:10.3390/ijms25010331. This article has 18 citations.
(moussaviharami2024neutrophilspecificshp1loss pages 5-7): S. Farshid Moussavi-Harami, Simon J Cleary, Mélia Magnen, Yurim Seo, Catharina Conrad, Bevin C. English, Longhui Qiu, Kristin M. Wang, Clare L. Abram, Clifford A. Lowell, and Mark R. Looney. Neutrophil-specific shp1 loss results in lethal pulmonary hemorrhage in mouse models of acute lung injury. The Journal of Clinical Investigation, Oct 2024. URL: https://doi.org/10.1172/jci183161, doi:10.1172/jci183161. This article has 9 citations.
(moussaviharami2024neutrophilspecificshp1loss pages 1-2): S. Farshid Moussavi-Harami, Simon J Cleary, Mélia Magnen, Yurim Seo, Catharina Conrad, Bevin C. English, Longhui Qiu, Kristin M. Wang, Clare L. Abram, Clifford A. Lowell, and Mark R. Looney. Neutrophil-specific shp1 loss results in lethal pulmonary hemorrhage in mouse models of acute lung injury. The Journal of Clinical Investigation, Oct 2024. URL: https://doi.org/10.1172/jci183161, doi:10.1172/jci183161. This article has 9 citations.
(NCT03443622 chunk 1): Phase I Study of SC-43 Oral Solution in Subjects With Refractory Solid Tumors. SupremeCure Pharma Inc.. 2021. ClinicalTrials.gov Identifier: NCT03443622
(crosta20245azaupregulatessocs3 pages 1-2): Michele Di Crosta, Andrea Arena, Rossella Benedetti, Maria Saveria Gilardini Montani, and Mara Cirone. 5-aza upregulates socs3 and ptpn6/shp1, inhibiting stat3 and potentiating the effects of ag490 against primary effusion lymphoma cells. Current Issues in Molecular Biology, 46:2468-2479, Mar 2024. URL: https://doi.org/10.3390/cimb46030156, doi:10.3390/cimb46030156. This article has 4 citations.
(cui2024pancanceranalysisof pages 1-2): Ping Cui, Jie Lian, Yang Liu, Dongsheng Zhang, Yao Lin, Lili Lu, Li Ye, Hui Chen, Sanqi An, Jiegang Huang, and Hao Liang. Pan-cancer analysis of the prognostic and immunological roles of shp-1/ptpn6. Scientific Reports, Oct 2024. URL: https://doi.org/10.1038/s41598-024-74037-9, doi:10.1038/s41598-024-74037-9. This article has 6 citations and is from a peer-reviewed journal.
(sun2024prognosticvalueand pages 4-5): Rongyao Sun, Shuqiang Wei, Ying Yu, Zhuo Wang, Tonghao Yao, Yining Zhang, Luping Cui, and Xu Ma. Prognostic value and immune infiltration of a tumor microenvironment-related ptpn6 in metastatic melanoma. Cancer Cell International, Dec 2024. URL: https://doi.org/10.1186/s12935-024-03625-6, doi:10.1186/s12935-024-03625-6. This article has 7 citations and is from a peer-reviewed journal.
(yu2024effectsofptpn6 pages 8-11): Li Yu, Xiaoli Gu, Pengjie Chen, Rui Yang, Yonggang Xu, and Xiupeng Yang. Effects of ptpn6 gene knockdown in skm-1 cells on apoptosis, erythroid differentiation and inflammations. Current Issues in Molecular Biology, 46:12061-12074, Oct 2024. URL: https://doi.org/10.3390/cimb46110715, doi:10.3390/cimb46110715. This article has 0 citations.
(moussaviharami2024neutrophilspecificshp1loss pages 2-5): S. Farshid Moussavi-Harami, Simon J Cleary, Mélia Magnen, Yurim Seo, Catharina Conrad, Bevin C. English, Longhui Qiu, Kristin M. Wang, Clare L. Abram, Clifford A. Lowell, and Mark R. Looney. Neutrophil-specific shp1 loss results in lethal pulmonary hemorrhage in mouse models of acute lung injury. The Journal of Clinical Investigation, Oct 2024. URL: https://doi.org/10.1172/jci183161, doi:10.1172/jci183161. This article has 9 citations.
(lim2023considerationofshp1 pages 16-17): Seyeon Lim, Ki Won Lee, Jeong Yoon Kim, and Kwang Dong Kim. Consideration of shp-1 as a molecular target for tumor therapy. International Journal of Molecular Sciences, 25:331, Dec 2023. URL: https://doi.org/10.3390/ijms25010331, doi:10.3390/ijms25010331. This article has 18 citations.
(jaegerruckstuhl2024signalingviaa pages 20-21): Carla A. Jaeger-Ruckstuhl, Yun Lo, Elena Fulton, Olivia G. Waltner, Tamer B. Shabaneh, Sylvain Simon, Pranav V. Muthuraman, Colin E. Correnti, Oliver J. Newsom, Ian A. Engstrom, Sami B. Kanaan, Shruti S. Bhise, Jobelle M.C. Peralta, Raymond Ruff, Jason P. Price, Sylvia M. Stull, Andrew R. Stevens, Grace Bugos, Mitchell G. Kluesner, Valentin Voillet, Vishaka Muhunthan, Fionnuala Morrish, James M. Olson, Raphaël Gottardo, Jay F. Sarthy, Steven Henikoff, Lucas B. Sullivan, Scott N. Furlan, and Stanley R. Riddell. Signaling via a cd27-traf2-shp-1 axis during naive t cell activation promotes memory-associated gene regulatory networks. Immunity, 57:287-302.e12, Feb 2024. URL: https://doi.org/10.1016/j.immuni.2024.01.011, doi:10.1016/j.immuni.2024.01.011. This article has 48 citations and is from a highest quality peer-reviewed journal.
(sun2024prognosticvalueand pages 1-2): Rongyao Sun, Shuqiang Wei, Ying Yu, Zhuo Wang, Tonghao Yao, Yining Zhang, Luping Cui, and Xu Ma. Prognostic value and immune infiltration of a tumor microenvironment-related ptpn6 in metastatic melanoma. Cancer Cell International, Dec 2024. URL: https://doi.org/10.1186/s12935-024-03625-6, doi:10.1186/s12935-024-03625-6. This article has 7 citations and is from a peer-reviewed journal.
(moussaviharami2024neutrophilspecificshp1loss pages 7-9): S. Farshid Moussavi-Harami, Simon J Cleary, Mélia Magnen, Yurim Seo, Catharina Conrad, Bevin C. English, Longhui Qiu, Kristin M. Wang, Clare L. Abram, Clifford A. Lowell, and Mark R. Looney. Neutrophil-specific shp1 loss results in lethal pulmonary hemorrhage in mouse models of acute lung injury. The Journal of Clinical Investigation, Oct 2024. URL: https://doi.org/10.1172/jci183161, doi:10.1172/jci183161. This article has 9 citations.
(moussaviharami2024lossofneutrophil pages 5-8): S. Moussavi-Harami, SJ Cleary, M. Magnen, Y. Seo, C. Conrad, BC English, L. Qiu, KM Wang, CL Abram, CA Lowell, and M. Looney. Loss of neutrophil shp1 produces hemorrhagic and lethal acute lung injury. bioRxiv, May 2024. URL: https://doi.org/10.1101/2024.05.23.595575, doi:10.1101/2024.05.23.595575. This article has 3 citations.
(NCT00629200 chunk 1): Sodium Stibogluconate With Interferon Alpha-2b for Patients With Advanced Malignancies. M.D. Anderson Cancer Center. 2006. ClinicalTrials.gov Identifier: NCT00629200
(NCT00498979 chunk 1): Sodium Stibogluconate and IFNa-2b Followed By CDDP, VLB and DTIC Treating Pts.With Advanced Melanoma or Other Cancers. Case Comprehensive Cancer Center. 2007. ClinicalTrials.gov Identifier: NCT00498979
(wang2024targetingproteintyrosine pages 1-3): Xiaoou Wang, Zhenggang Li, Jing Shen, and Lin Liu. Targeting protein tyrosine phosphatase non-receptor type 6 (ptpn6) as a therapeutic strategy in acute myeloid leukemia. Cell Biology and Toxicology, Dec 2024. URL: https://doi.org/10.1007/s10565-024-09965-3, doi:10.1007/s10565-024-09965-3. This article has 2 citations and is from a peer-reviewed journal.
(wang2024targetingproteintyrosine pages 14-16): Xiaoou Wang, Zhenggang Li, Jing Shen, and Lin Liu. Targeting protein tyrosine phosphatase non-receptor type 6 (ptpn6) as a therapeutic strategy in acute myeloid leukemia. Cell Biology and Toxicology, Dec 2024. URL: https://doi.org/10.1007/s10565-024-09965-3, doi:10.1007/s10565-024-09965-3. This article has 2 citations and is from a peer-reviewed journal.
id: P29350
gene_symbol: PTPN6
product_type: PROTEIN
status: COMPLETE
taxon:
id: NCBITaxon:9606
label: Homo sapiens
description: '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.'
existing_annotations:
- term:
id: GO:0001784
label: phosphotyrosine residue binding
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: phosphotyrosine residue binding is central to SHP-1 SH2-mediated recruitment and
substrate specificity.
action: ACCEPT
reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic
activity to receptor/adaptor signaling complexes.
supported_by: &id004
- &id008
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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)**.
- &id009
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- &id010
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0030154
label: cell differentiation
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: cell differentiation is plausible downstream biology but not the core SHP-1 function.
action: KEEP_AS_NON_CORE
reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect
context-specific consequences of SHP-1 signaling regulation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0000278
label: mitotic cell cycle
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: mitotic cell cycle is plausible downstream biology but not the core SHP-1 function.
action: KEEP_AS_NON_CORE
reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect
context-specific consequences of SHP-1 signaling regulation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: &id002
- &id005
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- &id006
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0004726
label: non-membrane spanning protein tyrosine phosphatase activity
evidence_type: IBA
original_reference_id: GO_REF:0000033
review:
summary: non-membrane spanning protein tyrosine phosphatase activity is the core catalytic
activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: &id001
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0004721
label: phosphoprotein phosphatase activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: phosphoprotein phosphatase activity is directionally correct but less specific than
SHP-1 protein tyrosine phosphatase activity.
action: MODIFY
reason: The supported activity is non-receptor protein tyrosine phosphatase activity rather than
a generic phosphoprotein phosphatase or hydrolase term.
proposed_replacement_terms: &id003
- id: GO:0004726
label: non-membrane spanning protein tyrosine phosphatase activity
- id: GO:0004725
label: protein tyrosine phosphatase activity
supported_by: *id001
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0005634
label: nucleus
evidence_type: IEA
original_reference_id: GO_REF:0000044
review:
summary: nucleus localization is plausible but secondary to the main cytosolic/receptor-complex
role.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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)**.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IEA
original_reference_id: GO_REF:0000120
review:
summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0016787
label: hydrolase activity
evidence_type: IEA
original_reference_id: GO_REF:0000043
review:
summary: hydrolase activity is directionally correct but less specific than SHP-1 protein
tyrosine phosphatase activity.
action: MODIFY
reason: The supported activity is non-receptor protein tyrosine phosphatase activity rather than
a generic phosphoprotein phosphatase or hydrolase term.
proposed_replacement_terms: *id003
supported_by: *id001
- term:
id: GO:0031295
label: T cell costimulation
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: T cell costimulation is supported in T-cell receptor/costimulation contexts.
action: ACCEPT
reason: SHP-1 tunes T-cell activation and CD27/TCR signaling by dephosphorylating
receptor-proximal substrates such as LCK.
supported_by: &id014
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: Positive regulation of PI3K/AKT signaling is not well supported as a PTPN6/SHP-1
function.
action: MARK_AS_OVER_ANNOTATED
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_replacement_terms:
- id: GO:0031295
label: T cell costimulation
- id: GO:0035335
label: peptidyl-tyrosine dephosphorylation
supported_by:
- &id016
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0060338
label: regulation of type I interferon-mediated signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: regulation of type I interferon-mediated signaling pathway is supported as a
cytokine/JAK-STAT signaling context for SHP-1.
action: ACCEPT
reason: SHP-1 negatively regulates cytokine signaling through JAK/STAT pathway
dephosphorylation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:1902564
label: negative regulation of neutrophil activation
evidence_type: IEA
original_reference_id: GO_REF:0000117
review:
summary: negative regulation of neutrophil activation is supported as an immune/inflammatory
signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- &id007
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- &id011
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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).
- &id012
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- &id013
reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10206955
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10556798
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10660620
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10764762
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11266449
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11489943
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:14652006
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17416557
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17947393
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18086677
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18377662
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18802077
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19167335
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20351292
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:22624718
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23001144
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24216507
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:24642916
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25416956
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25535246
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:25785436
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:28065597
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:31980649
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:33961781
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:7228577
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:7528537
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:7528577
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8114715
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8574854
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8577729
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8627166
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8648092
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8691146
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:8691154
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9148918
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9603468
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9774457
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0001784
label: phosphotyrosine residue binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: phosphotyrosine residue binding is central to SHP-1 SH2-mediated recruitment and
substrate specificity.
action: ACCEPT
reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic
activity to receptor/adaptor signaling complexes.
supported_by: *id004
- term:
id: GO:0005911
label: cell-cell junction
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: cell-cell junction is plausible as a receptor/complex localization context but not the
dominant site of SHP-1 function.
action: KEEP_AS_NON_CORE
reason: SHP-1 is recruited to immune receptor complexes, but its core function is cytosolic
phosphotyrosine dephosphorylation.
supported_by:
- *id005
- *id006
- *id007
- term:
id: GO:0017124
label: SH3 domain binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SH3 domain binding is a specific interaction context but secondary to SH2-mediated
phosphotyrosine recruitment and phosphatase activity.
action: KEEP_AS_NON_CORE
reason: Partner binding helps localize SHP-1 in signaling complexes, but the core molecular
function is phosphotyrosine dephosphorylation.
supported_by:
- *id008
- *id009
- *id010
- *id005
- term:
id: GO:0031665
label: negative regulation of lipopolysaccharide-mediated signaling pathway
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: negative regulation of lipopolysaccharide-mediated signaling pathway is supported as an
immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0032715
label: negative regulation of interleukin-6 production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: negative regulation of interleukin-6 production is supported as an immune/inflammatory
signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0032720
label: negative regulation of tumor necrosis factor production
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: negative regulation of tumor necrosis factor production is supported as an
immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0033007
label: negative regulation of mast cell activation involved in immune response
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
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.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0042105
label: alpha-beta T cell receptor complex
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: alpha-beta T cell receptor complex is plausible as a receptor/complex localization
context but not the dominant site of SHP-1 function.
action: KEEP_AS_NON_CORE
reason: SHP-1 is recruited to immune receptor complexes, but its core function is cytosolic
phosphotyrosine dephosphorylation.
supported_by:
- *id005
- *id006
- *id007
- term:
id: GO:0042169
label: SH2 domain binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: SH2 domain binding is a specific interaction context but secondary to SH2-mediated
phosphotyrosine recruitment and phosphatase activity.
action: KEEP_AS_NON_CORE
reason: Partner binding helps localize SHP-1 in signaling complexes, but the core molecular
function is phosphotyrosine dephosphorylation.
supported_by:
- *id008
- *id009
- *id010
- *id005
- term:
id: GO:0050839
label: cell adhesion molecule binding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: cell adhesion molecule binding is a specific interaction context but secondary to
SH2-mediated phosphotyrosine recruitment and phosphatase activity.
action: KEEP_AS_NON_CORE
reason: Partner binding helps localize SHP-1 in signaling complexes, but the core molecular
function is phosphotyrosine dephosphorylation.
supported_by:
- *id008
- *id009
- *id010
- *id005
- term:
id: GO:0106015
label: negative regulation of inflammatory response to wounding
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: negative regulation of inflammatory response to wounding is supported as an
immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:1905867
label: epididymis development
evidence_type: IEA
original_reference_id: GO_REF:0000107
review:
summary: epididymis development is plausible downstream biology but not the core SHP-1 function.
action: KEEP_AS_NON_CORE
reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect
context-specific consequences of SHP-1 signaling regulation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: nucleoplasm localization is plausible but secondary to the main
cytosolic/receptor-complex role.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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)**.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0005730
label: nucleolus
evidence_type: IDA
original_reference_id: GO_REF:0000052
review:
summary: nucleolus localization is plausible but secondary to the main
cytosolic/receptor-complex role.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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)**.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: IDA
original_reference_id: PMID:29925997
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0019221
label: cytokine-mediated signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-512988
review:
summary: cytokine-mediated signaling pathway is supported as a cytokine/JAK-STAT signaling
context for SHP-1.
action: ACCEPT
reason: SHP-1 negatively regulates cytokine signaling through JAK/STAT pathway
dephosphorylation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0031295
label: T cell costimulation
evidence_type: TAS
original_reference_id: Reactome:R-HSA-388841
review:
summary: T cell costimulation is supported in T-cell receptor/costimulation contexts.
action: ACCEPT
reason: SHP-1 tunes T-cell activation and CD27/TCR signaling by dephosphorylating
receptor-proximal substrates such as LCK.
supported_by: *id014
- term:
id: GO:0060338
label: regulation of type I interferon-mediated signaling pathway
evidence_type: TAS
original_reference_id: Reactome:R-HSA-912694
review:
summary: regulation of type I interferon-mediated signaling pathway is supported as a
cytokine/JAK-STAT signaling context for SHP-1.
action: ACCEPT
reason: SHP-1 negatively regulates cytokine signaling through JAK/STAT pathway
dephosphorylation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389758
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-914036
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9701507
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: TAS
original_reference_id: Reactome:R-HSA-997314
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: IMP
original_reference_id: PMID:19749791
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0031665
label: negative regulation of lipopolysaccharide-mediated signaling pathway
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: negative regulation of lipopolysaccharide-mediated signaling pathway is supported as an
immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:1902564
label: negative regulation of neutrophil activation
evidence_type: IDA
original_reference_id: PMID:34234773
review:
summary: negative regulation of neutrophil activation is supported as an immune/inflammatory
signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:12051764
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:9065461
review:
summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0042110
label: T cell activation
evidence_type: IDA
original_reference_id: PMID:38354704
review:
summary: T cell activation is supported in T-cell receptor/costimulation contexts.
action: ACCEPT
reason: SHP-1 tunes T-cell activation and CD27/TCR signaling by dephosphorylating
receptor-proximal substrates such as LCK.
supported_by: *id014
- term:
id: GO:0160162
label: CD27 signaling pathway
evidence_type: IDA
original_reference_id: PMID:38354704
review:
summary: CD27 signaling pathway is supported in T-cell receptor/costimulation contexts.
action: ACCEPT
reason: SHP-1 tunes T-cell activation and CD27/TCR signaling by dephosphorylating
receptor-proximal substrates such as LCK.
supported_by: *id014
- term:
id: GO:0045824
label: negative regulation of innate immune response
evidence_type: IDA
original_reference_id: PMID:34811497
review:
summary: negative regulation of innate immune response is supported as an immune/inflammatory
signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0050859
label: negative regulation of B cell receptor signaling pathway
evidence_type: IDA
original_reference_id: PMID:35941532
review:
summary: negative regulation of B cell receptor signaling pathway is supported as an
immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0005886
label: plasma membrane
evidence_type: IDA
original_reference_id: PMID:23896411
review:
summary: Plasma membrane localization is supported as a receptor-proximal signaling context.
action: ACCEPT
reason: SHP-1 acts locally at plasma membrane or internalized receptor complexes after
SH2-mediated recruitment.
supported_by: *id002
- term:
id: GO:0016525
label: negative regulation of angiogenesis
evidence_type: IDA
original_reference_id: PMID:23896411
review:
summary: negative regulation of angiogenesis is a context-specific downstream phenotype, not the
core SHP-1 molecular function.
action: KEEP_AS_NON_CORE
reason: These phenotypes are secondary to SHP-1-mediated dephosphorylation of receptor-proximal
and JAK/STAT signaling components.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0106015
label: negative regulation of inflammatory response to wounding
evidence_type: IDA
original_reference_id: PMID:27830702
review:
summary: negative regulation of inflammatory response to wounding is supported as an
immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16493035
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0140031
label: phosphorylation-dependent protein binding
evidence_type: IPI
original_reference_id: PMID:11162587
review:
summary: phosphorylation-dependent protein binding is central to SHP-1 SH2-mediated recruitment
and substrate specificity.
action: ACCEPT
reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic
activity to receptor/adaptor signaling complexes.
supported_by: *id004
- term:
id: GO:0042981
label: regulation of apoptotic process
evidence_type: TAS
original_reference_id: PMID:10506221
review:
summary: regulation of apoptotic process is a context-specific downstream phenotype, not the
core SHP-1 molecular function.
action: KEEP_AS_NON_CORE
reason: These phenotypes are secondary to SHP-1-mediated dephosphorylation of receptor-proximal
and JAK/STAT signaling components.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: IMP
original_reference_id: PMID:10206955
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10887109
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0032715
label: negative regulation of interleukin-6 production
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: negative regulation of interleukin-6 production is supported as an immune/inflammatory
signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0032720
label: negative regulation of tumor necrosis factor production
evidence_type: ISS
original_reference_id: GO_REF:0000024
review:
summary: negative regulation of tumor necrosis factor production is supported as an
immune/inflammatory signaling brake downstream of SHP-1 phosphatase activity.
action: ACCEPT
reason: SHP-1 restrains immune receptor, cytokine, innate immune, B-cell, T-cell, and neutrophil
signaling thresholds.
supported_by:
- *id007
- *id011
- *id012
- *id013
- term:
id: GO:0001784
label: phosphotyrosine residue binding
evidence_type: IPI
original_reference_id: PMID:11986327
review:
summary: phosphotyrosine residue binding is central to SHP-1 SH2-mediated recruitment and
substrate specificity.
action: ACCEPT
reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic
activity to receptor/adaptor signaling complexes.
supported_by: *id004
- term:
id: GO:0140031
label: phosphorylation-dependent protein binding
evidence_type: IPI
original_reference_id: PMID:12163025
review:
summary: phosphorylation-dependent protein binding is central to SHP-1 SH2-mediated recruitment
and substrate specificity.
action: ACCEPT
reason: SHP-1 uses tandem SH2 domains to bind phosphotyrosine motifs and localize catalytic
activity to receptor/adaptor signaling complexes.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19843936
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:20933011
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:26755705
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0004725
label: protein tyrosine phosphatase activity
evidence_type: IMP
original_reference_id: PMID:17562706
review:
summary: protein tyrosine phosphatase activity is the core catalytic activity of PTPN6/SHP-1.
action: ACCEPT
reason: SHP-1 is a non-receptor protein tyrosine phosphatase that removes phosphate from
phosphotyrosine residues in signaling complexes.
supported_by: *id001
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:17562706
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0032991
label: protein-containing complex
evidence_type: IMP
original_reference_id: PMID:17562706
review:
summary: protein-containing complex is plausible as a receptor/complex localization context but
not the dominant site of SHP-1 function.
action: KEEP_AS_NON_CORE
reason: SHP-1 is recruited to immune receptor complexes, but its core function is cytosolic
phosphotyrosine dephosphorylation.
supported_by:
- *id005
- *id006
- *id007
- term:
id: GO:0035335
label: peptidyl-tyrosine dephosphorylation
evidence_type: IMP
original_reference_id: PMID:17562706
review:
summary: peptidyl-tyrosine dephosphorylation is the direct catalytic process mediated by SHP-1.
action: ACCEPT
reason: SHP-1 dephosphorylates phosphotyrosine residues on signaling proteins such as LCK, TCR
ITAMs, ZAP-70, and JAK family proteins.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005654
label: nucleoplasm
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9008894
review:
summary: nucleoplasm localization is plausible but secondary to the main
cytosolic/receptor-complex role.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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)**.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23112346
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6798745
review:
summary: extracellular region is likely a context-specific or high-throughput localization and
not a core SHP-1 site of action.
action: MARK_AS_OVER_ANNOTATED
reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and
possible nuclear localization rather than extracellular/granule lumen function.
supported_by: *id002
- term:
id: GO:0005576
label: extracellular region
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6798749
review:
summary: extracellular region is likely a context-specific or high-throughput localization and
not a core SHP-1 site of action.
action: MARK_AS_OVER_ANNOTATED
reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and
possible nuclear localization rather than extracellular/granule lumen function.
supported_by: *id002
- term:
id: GO:0035580
label: specific granule lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6798749
review:
summary: specific granule lumen is likely a context-specific or high-throughput localization and
not a core SHP-1 site of action.
action: MARK_AS_OVER_ANNOTATED
reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and
possible nuclear localization rather than extracellular/granule lumen function.
supported_by: *id002
- term:
id: GO:1904724
label: tertiary granule lumen
evidence_type: TAS
original_reference_id: Reactome:R-HSA-6798745
review:
summary: tertiary granule lumen is likely a context-specific or high-throughput localization and
not a core SHP-1 site of action.
action: MARK_AS_OVER_ANNOTATED
reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and
possible nuclear localization rather than extracellular/granule lumen function.
supported_by: *id002
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:23696226
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18424730
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:10540326
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16254138
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:16339535
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0070062
label: extracellular exosome
evidence_type: HDA
original_reference_id: PMID:19056867
review:
summary: extracellular exosome is likely a context-specific or high-throughput localization and
not a core SHP-1 site of action.
action: MARK_AS_OVER_ANNOTATED
reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and
possible nuclear localization rather than extracellular/granule lumen function.
supported_by: *id002
- term:
id: GO:0070062
label: extracellular exosome
evidence_type: HDA
original_reference_id: PMID:20458337
review:
summary: extracellular exosome is likely a context-specific or high-throughput localization and
not a core SHP-1 site of action.
action: MARK_AS_OVER_ANNOTATED
reason: The literature synthesis supports cytosolic, receptor-complex, plasma membrane, and
possible nuclear localization rather than extracellular/granule lumen function.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-205306
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-210277
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389758
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389759
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-389941
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5684169
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-5690701
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-909738
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-913424
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-914036
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9701507
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-9851072
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005829
label: cytosol
evidence_type: TAS
original_reference_id: Reactome:R-HSA-997314
review:
summary: cytosol is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:11907092
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9285411
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:9842885
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0018108
label: peptidyl-tyrosine phosphorylation
evidence_type: IDA
original_reference_id: PMID:9285411
review:
summary: Peptidyl-tyrosine phosphorylation is not a process catalyzed by PTPN6.
action: REMOVE
reason: The cited biology describes SHP-1 phosphorylation or kinase substrates, but PTPN6/SHP-1
is a phosphatase that dephosphorylates tyrosine-phosphorylated proteins.
proposed_replacement_terms: &id015
- id: GO:0035335
label: peptidyl-tyrosine dephosphorylation
- id: GO:0006470
label: protein dephosphorylation
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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**.
- term:
id: GO:0018108
label: peptidyl-tyrosine phosphorylation
evidence_type: IDA
original_reference_id: PMID:18802077
review:
summary: Peptidyl-tyrosine phosphorylation is not a process catalyzed by PTPN6.
action: REMOVE
reason: The cited biology describes SHP-1 phosphorylation or kinase substrates, but PTPN6/SHP-1
is a phosphatase that dephosphorylates tyrosine-phosphorylated proteins.
proposed_replacement_terms: *id015
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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**.
- term:
id: GO:0005001
label: transmembrane receptor protein tyrosine phosphatase activity
evidence_type: IDA
original_reference_id: PMID:11266449
review:
summary: Transmembrane receptor protein tyrosine phosphatase activity is inconsistent with
PTPN6/SHP-1.
action: MODIFY
reason: PTPN6 encodes a cytosolic non-receptor tyrosine phosphatase, not a transmembrane
receptor phosphatase.
proposed_replacement_terms: *id003
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0006470
label: protein dephosphorylation
evidence_type: IDA
original_reference_id: PMID:11266449
review:
summary: protein dephosphorylation is the direct catalytic process mediated by SHP-1.
action: ACCEPT
reason: SHP-1 dephosphorylates phosphotyrosine residues on signaling proteins such as LCK, TCR
ITAMs, ZAP-70, and JAK family proteins.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0019901
label: protein kinase binding
evidence_type: IPI
original_reference_id: PMID:11266449
review:
summary: protein kinase binding is a specific interaction context but secondary to SH2-mediated
phosphotyrosine recruitment and phosphatase activity.
action: KEEP_AS_NON_CORE
reason: Partner binding helps localize SHP-1 in signaling complexes, but the core molecular
function is phosphotyrosine dephosphorylation.
supported_by:
- *id008
- *id009
- *id010
- *id005
- term:
id: GO:0030154
label: cell differentiation
evidence_type: IDA
original_reference_id: PMID:11266449
review:
summary: cell differentiation is plausible downstream biology but not the core SHP-1 function.
action: KEEP_AS_NON_CORE
reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect
context-specific consequences of SHP-1 signaling regulation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0070372
label: regulation of ERK1 and ERK2 cascade
evidence_type: IDA
original_reference_id: PMID:11266449
review:
summary: regulation of ERK1 and ERK2 cascade is plausible downstream biology but not the core
SHP-1 function.
action: KEEP_AS_NON_CORE
reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect
context-specific consequences of SHP-1 signaling regulation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:10940933
review:
summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0008284
label: positive regulation of cell population proliferation
evidence_type: IMP
original_reference_id: PMID:19749791
review:
summary: positive regulation of cell population proliferation is plausible downstream biology
but not the core SHP-1 function.
action: KEEP_AS_NON_CORE
reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect
context-specific consequences of SHP-1 signaling regulation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:19838216
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0005634
label: nucleus
evidence_type: IDA
original_reference_id: PMID:19838216
review:
summary: nucleus localization is plausible but secondary to the main cytosolic/receptor-complex
role.
action: KEEP_AS_NON_CORE
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.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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)**.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- term:
id: GO:0005737
label: cytoplasm
evidence_type: IDA
original_reference_id: PMID:19838216
review:
summary: cytoplasm is a core localization for cytosolic non-receptor SHP-1 activity.
action: ACCEPT
reason: SHP-1 is primarily cytosolic and is recruited dynamically to receptor/adaptor signaling
complexes.
supported_by: *id002
- term:
id: GO:0008284
label: positive regulation of cell population proliferation
evidence_type: IMP
original_reference_id: PMID:19838216
review:
summary: positive regulation of cell population proliferation is plausible downstream biology
but not the core SHP-1 function.
action: KEEP_AS_NON_CORE
reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect
context-specific consequences of SHP-1 signaling regulation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0051897
label: positive regulation of phosphatidylinositol 3-kinase/protein kinase B signal transduction
evidence_type: IMP
original_reference_id: PMID:19838216
review:
summary: Positive regulation of PI3K/AKT signaling is not well supported as a PTPN6/SHP-1
function.
action: MARK_AS_OVER_ANNOTATED
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_replacement_terms:
- id: GO:0031295
label: T cell costimulation
- id: GO:0035335
label: peptidyl-tyrosine dephosphorylation
supported_by:
- *id016
- term:
id: GO:2000045
label: regulation of G1/S transition of mitotic cell cycle
evidence_type: IMP
original_reference_id: PMID:19838216
review:
summary: regulation of G1/S transition of mitotic cell cycle is plausible downstream biology but
not the core SHP-1 function.
action: KEEP_AS_NON_CORE
reason: Cell differentiation, cell-cycle, proliferation, ERK, and PI3K/AKT annotations reflect
context-specific consequences of SHP-1 signaling regulation.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0005515
label: protein binding
evidence_type: IPI
original_reference_id: PMID:18604210
review:
summary: Protein binding is supported but too generic for SHP-1 curation.
action: MARK_AS_OVER_ANNOTATED
reason: PTPN6 has specific SH2-mediated phosphotyrosine recruitment and catalytic phosphatase
activity; generic protein binding obscures the mechanism.
supported_by: *id004
- term:
id: GO:0007186
label: G protein-coupled receptor signaling pathway
evidence_type: TAS
original_reference_id: PMID:7781604
review:
summary: G protein-coupled receptor signaling pathway is a context-specific downstream
phenotype, not the core SHP-1 molecular function.
action: KEEP_AS_NON_CORE
reason: These phenotypes are secondary to SHP-1-mediated dephosphorylation of receptor-proximal
and JAK/STAT signaling components.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- term:
id: GO:0016020
label: membrane
evidence_type: TAS
original_reference_id: PMID:10506221
review:
summary: membrane is plausible as a receptor/complex localization context but not the dominant
site of SHP-1 function.
action: KEEP_AS_NON_CORE
reason: SHP-1 is recruited to immune receptor complexes, but its core function is cytosolic
phosphotyrosine dephosphorylation.
supported_by:
- *id005
- *id006
- *id007
- term:
id: GO:0008285
label: negative regulation of cell population proliferation
evidence_type: NAS
original_reference_id: PMID:10497187
review:
summary: negative regulation of cell population proliferation is a context-specific downstream
phenotype, not the core SHP-1 molecular function.
action: KEEP_AS_NON_CORE
reason: These phenotypes are secondary to SHP-1-mediated dephosphorylation of receptor-proximal
and JAK/STAT signaling components.
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
references:
- id: GO_REF:0000024
title: Manual transfer of experimentally-verified manual GO annotation data to orthologs by
curator judgment of sequence similarity
findings: []
- id: GO_REF:0000033
title: Annotation inferences using phylogenetic trees
findings: []
- id: GO_REF:0000043
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot keyword mapping
findings: []
- id: GO_REF:0000044
title: Gene Ontology annotation based on UniProtKB/Swiss-Prot Subcellular Location vocabulary
mapping, accompanied by conservative changes to GO terms applied by UniProt
findings: []
- id: GO_REF:0000052
title: Gene Ontology annotation based on curation of immunofluorescence data
findings: []
- id: GO_REF:0000107
title: Automatic transfer of experimentally verified manual GO annotation data to orthologs using
Ensembl Compara
findings: []
- id: GO_REF:0000117
title: Electronic Gene Ontology annotations created by ARBA machine learning models
findings: []
- id: GO_REF:0000120
title: Combined Automated Annotation using Multiple IEA Methods
findings: []
- id: PMID:10206955
title: The myeloid-specific sialic acid-binding receptor, CD33, associates with the
protein-tyrosine phosphatases, SHP-1 and SHP-2.
findings: []
- id: PMID:10497187
title: Human 70-kDa SHP-1L differs from 68-kDa SHP-1 in its C-terminal structure and catalytic
activity.
findings: []
- id: PMID:10506221
title: Regulation of acidification and apoptosis by SHP-1 and Bcl-2.
findings: []
- id: PMID:10540326
title: Molecular and functional characterization of IRp60, a member of the immunoglobulin
superfamily that functions as an inhibitory receptor in human NK cells.
findings: []
- id: PMID:10556798
title: The sialoadhesin CD33 is a myeloid-specific inhibitory receptor.
findings: []
- id: PMID:10660620
title: PILRalpha, a novel immunoreceptor tyrosine-based inhibitory motif-bearing protein, recruits
SHP-1 upon tyrosine phosphorylation and is paired with the truncated counterpart PILRbeta.
findings: []
- id: PMID:10764762
title: Identification and characterization of leukocyte-associated Ig-like receptor-1 as a major
anchor protein of tyrosine phosphatase SHP-1 in hematopoietic cells.
findings: []
- id: PMID:10887109
title: Myeloid specific human CD33 is an inhibitory receptor with differential ITIM function in
recruiting the phosphatases SHP-1 and SHP-2.
findings: []
- id: PMID:10940933
title: Subcellular localization of intracellular protein tyrosine phosphatases in T cells.
findings: []
- id: PMID:11162587
title: Molecular cloning and characterization of SPAP1, an inhibitory receptor.
findings: []
- id: PMID:11266449
title: Negative regulation of Ros receptor tyrosine kinase signaling. An epithelial function of
the SH2 domain protein tyrosine phosphatase SHP-1.
findings: []
- id: PMID:11489943
title: NTB-A [correction of GNTB-A], a novel SH2D1A-associated surface molecule contributing to
the inability of natural killer cells to kill Epstein-Barr virus-infected B cells in X-linked
lymphoproliferative disease.
findings: []
- id: PMID:11907092
title: Mutational analysis of immunoreceptor tyrosine-based inhibition motifs of the Ig-like
transcript 2 (CD85j) leukocyte receptor.
findings: []
- id: PMID:11986327
title: Cloning and characterization of human Siglec-11. A recently evolved signaling molecule that
can interact with SHP-1 and SHP-2 and is expressed by tissue macrophages, including brain
microglia.
findings: []
- id: PMID:12051764
title: SPAP2, an Ig family receptor containing both ITIMs and ITAMs.
findings: []
- id: PMID:12163025
title: 'Cloning of two new splice variants of Siglec-10 and mapping of the interaction between Siglec-10
and SHP-1.'
findings: []
- id: PMID:14652006
title: Characterization of phosphotyrosine binding motifs in the cytoplasmic domain of B and T
lymphocyte attenuator required for association with protein tyrosine phosphatases SHP-1 and
SHP-2.
findings: []
- id: PMID:16254138
title: The inhibitory receptor IRp60 (CD300a) suppresses the effects of IL-5, GM-CSF, and eotaxin
on human peripheral blood eosinophils.
findings: []
- id: PMID:16339535
title: 'The inhibitory receptor IRp60 (CD300a) is expressed and functional on human mast cells.'
findings: []
- id: PMID:16493035
title: Recombinant Ig-like transcript 3-Fc modulates T cell responses via induction of Th anergy
and differentiation of CD8+ T suppressor cells.
findings: []
- id: PMID:17416557
title: 'Monitoring phosphatase reactions of multiple phosphorylated substrates by reversed-phase HPLC.'
findings: []
- id: PMID:17562706
title: Identification of CLEC12B, an inhibitory receptor on myeloid cells.
findings: []
- id: PMID:17947393
title: 'ITIM-dependent endocytosis of CD33-related Siglecs: role of intracellular domain, tyrosine phosphorylation,
and the tyrosine phosphatases, Shp1 and Shp2.'
findings: []
- id: PMID:18086677
title: Dynamic regulation of neutrophil survival through tyrosine phosphorylation or
dephosphorylation of caspase-8.
findings: []
- id: PMID:18377662
title: Src homology 2 (SH2) domain containing protein tyrosine phosphatase-1 (SHP-1)
dephosphorylates VEGF Receptor-2 and attenuates endothelial DNA synthesis, but not migration*.
findings: []
- id: PMID:18424730
title: Carcinoembryonic antigen-related cell adhesion molecule 1 inhibits proximal TCR signaling
by targeting ZAP-70.
findings: []
- id: PMID:18604210
title: An essential function for beta-arrestin 2 in the inhibitory signaling of natural killer
cells.
findings: []
- id: PMID:18802077
title: Inhibitory immunoglobulin-like receptors LILRB and PIR-B negatively regulate osteoclast
development.
findings: []
- id: PMID:19056867
title: Large-scale proteomics and phosphoproteomics of urinary exosomes.
findings: []
- id: PMID:19167335
title: Large-scale structural analysis of the classical human protein tyrosine phosphatome.
findings: []
- id: PMID:19749791
title: Repression of SHP-1 expression by p53 leads to trkA tyrosine phosphorylation and
suppression of breast cancer cell proliferation.
findings: []
- id: PMID:19838216
title: 'Knockdown of protein tyrosine phosphatase SHP-1 inhibits G1/S progression in prostate cancer
cells through the regulation of components of the cell-cycle machinery.'
findings: []
- id: PMID:19843936
title: FCRL3, an autoimmune susceptibility gene, has inhibitory potential on B-cell
receptor-mediated signaling.
findings: []
- id: PMID:20351292
title: Contribution of SHP-1 protein tyrosine phosphatase to osmotic regulation of the
transcription factor TonEBP/OREBP.
findings: []
- id: PMID:20458337
title: MHC class II-associated proteins in B-cell exosomes and potential functional implications
for exosome biogenesis.
findings: []
- id: PMID:20933011
title: 'FCRL6 receptor: expression and associated proteins.'
findings: []
- id: PMID:22624718
title: Tetraspanin CD37 directly mediates transduction of survival and apoptotic signals.
findings: []
- id: PMID:23001144
title: Inhibition of TLR signaling by a bacterial protein containing immunoreceptor tyrosine-based
inhibitory motifs.
findings: []
- id: PMID:23112346
title: 'Mice lacking the ITIM-containing receptor G6b-B exhibit macrothrombocytopenia and aberrant platelet
function.'
findings: []
- id: PMID:23696226
title: CEACAM1 on activated NK cells inhibits NKG2D-mediated cytolytic function and signaling.
findings: []
- id: PMID:23896411
title: Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in
microvascular endothelial cells.
findings: []
- id: PMID:24216507
title: 'Induction of myelodysplasia by myeloid-derived suppressor cells.'
findings: []
- id: PMID:24642916
title: 'Fine specificity and molecular competition in SLAM family receptor signalling.'
findings: []
- id: PMID:25416956
title: A proteome-scale map of the human interactome network.
findings: []
- id: PMID:25535246
title: A THEMIS:SHP1 complex promotes T-cell survival.
findings: []
- id: PMID:25785436
title: Dissociation of SHP-1 from spinophilin during platelet activation exposes an inhibitory
binding site for protein phosphatase-1 (PP1).
findings: []
- id: PMID:26755705
title: Identification of CD112R as a novel checkpoint for human T cells.
findings: []
- id: PMID:27830702
title: Hyperglycaemia inhibits REG3A expression to exacerbate TLR3-mediated skin inflammation in
diabetes.
findings: []
- id: PMID:28065597
title: A Global Analysis of the Receptor Tyrosine Kinase-Protein Phosphatase Interactome.
findings: []
- id: PMID:29925997
title: The E3 ligases Itch and WWP2 cooperate to limit T(H)2 differentiation by enhancing
signaling through the TCR.
findings: []
- id: PMID:31980649
title: Extensive rewiring of the EGFR network in colorectal cancer cells expressing transforming
levels of KRAS(G13D).
findings: []
- id: PMID:33961781
title: Dual proteome-scale networks reveal cell-specific remodeling of the human interactome.
findings: []
- id: PMID:34234773
title: The Inhibitory Receptor CLEC12A Regulates PI3K-Akt Signaling to Inhibit Neutrophil
Activation and Cytokine Release.
findings: []
- id: PMID:34811497
title: HIV-1 Vif suppresses antiviral immunity by targeting STING.
findings: []
- id: PMID:35941532
title: Interfering B cell receptor signaling via SHP-1/p-Lyn axis shows therapeutic potential in
diffuse large B-cell lymphoma.
findings: []
- id: PMID:38354704
title: Signaling via a CD27-TRAF2-SHP-1 axis during naive T cell activation promotes
memory-associated gene regulatory networks.
findings: []
- id: PMID:7228577
title: Cyclophosphamide, vincristine, and the blood testis barrier.
findings: []
- id: PMID:7528537
title: 'Intramolecular regulation of protein tyrosine phosphatase SH-PTP1: a new function for Src homology
2 domains.'
findings: []
- id: PMID:7528577
title: 'Hematopoietic cell phosphatase associates with erythropoietin (Epo) receptor after Epo-induced
receptor tyrosine phosphorylation: identification of potential binding sites.'
findings: []
- id: PMID:7781604
title: Tyrosine phosphorylation of an SH2-containing protein tyrosine phosphatase is coupled to
platelet thrombin receptor via a pertussis toxin-sensitive heterotrimeric G-protein.
findings: []
- id: PMID:8114715
title: Lck-dependent tyrosyl phosphorylation of the phosphotyrosine phosphatase SH-PTP1 in murine
T cells.
findings: []
- id: PMID:8574854
title: Recruitment of tyrosine phosphatase HCP by the killer cell inhibitor receptor.
findings: []
- id: PMID:8577729
title: Differential functions of the two Src homology 2 domains in protein tyrosine phosphatase
SH-PTP1.
findings: []
- id: PMID:8627166
title: CD22 associates with protein tyrosine phosphatase 1C, Syk, and phospholipase C-gamma(1)
upon B cell activation.
findings: []
- id: PMID:8648092
title: Human and mouse killer-cell inhibitory receptors recruit PTP1C and PTP1D protein tyrosine
phosphatases.
findings: []
- id: PMID:8691146
title: Phosphotyrosines in the killer cell inhibitory receptor motif of NKB1 are required for
negative signaling and for association with protein tyrosine phosphatase 1C.
findings: []
- id: PMID:8691154
title: 'Tyrosine phosphorylation of a human killer inhibitory receptor recruits protein tyrosine phosphatase
1C.'
findings: []
- id: PMID:9065461
title: Interleukin-4 (IL-4) induces phosphatidylinositol 3-kinase (p85) dephosphorylation.
Implications for the role of SHP-1 in the IL-4-induced signals in human B cells.
findings: []
- id: PMID:9148918
title: A novel phosphotyrosine motif with a critical amino acid at position -2 for the SH2
domain-mediated activation of the tyrosine phosphatase SHP-1.
findings: []
- id: PMID:9285411
title: 'A novel immunoglobulin superfamily receptor for cellular and viral MHC class I molecules.'
findings: []
- id: PMID:9603468
title: Thymocyte activation induces the association of the proto-oncoprotein c-cbl and ras
GTPase-activating protein with CD5.
findings: []
- id: PMID:9774457
title: Recruitment and activation of SHP-1 protein-tyrosine phosphatase by human platelet
endothelial cell adhesion molecule-1 (PECAM-1). Identification of immunoreceptor tyrosine-based
inhibitory motif-like binding motifs and substrates.
findings: []
- id: PMID:9842885
title: The MHC class I binding proteins LIR-1 and LIR-2 inhibit Fc receptor-mediated signaling in
monocytes.
findings: []
- id: Reactome:R-HSA-205306
title: Interaction of SHP1 and KIT
findings: []
- id: Reactome:R-HSA-210277
title: Interaction of PECAM-1 and SHP-1
findings: []
- id: Reactome:R-HSA-388841
title: Regulation of T cell activation by CD28 family
findings: []
- id: Reactome:R-HSA-389758
title: Dephosphorylation of CD3-zeta by PD-1 bound phosphatases
findings: []
- id: Reactome:R-HSA-389759
title: Interaction of SHP-1 or SHP-2 with phospho PD-1
findings: []
- id: Reactome:R-HSA-389941
title: SHP-1 and SHP-2 bind pBTLA
findings: []
- id: Reactome:R-HSA-512988
title: Interleukin-3, Interleukin-5 and GM-CSF signaling
findings: []
- id: Reactome:R-HSA-5684169
title: G6B binds PTPN6,PTPN11
findings: []
- id: Reactome:R-HSA-5690701
title: SHP1 binds p-CD22
findings: []
- id: Reactome:R-HSA-6798745
title: Exocytosis of tertiary granule lumen proteins
findings: []
- id: Reactome:R-HSA-6798749
title: Exocytosis of specific granule lumen proteins
findings: []
- id: Reactome:R-HSA-9008894
title: PTPNs gene transcription and translation
findings: []
- id: Reactome:R-HSA-909738
title: SHP1 and SHP2 bind the common beta chain
findings: []
- id: Reactome:R-HSA-912694
title: Regulation of IFNA/IFNB signaling
findings: []
- id: Reactome:R-HSA-913424
title: The SHC1:SHIP1 complex is stabilized by GRB2
findings: []
- id: Reactome:R-HSA-914036
title: SHP1 and SHP2 dephosphorylate Y628 of IL3RB
findings: []
- id: Reactome:R-HSA-9701507
title: PTPN6 dephosphorylates JAK3
findings: []
- id: Reactome:R-HSA-9851072
title: DNMT1-dependent PTPN6 gene silencing
findings: []
- id: Reactome:R-HSA-997314
title: Dephosphorylation of JAK1 by SHP1
findings: []
- id: file:human/PTPN6/PTPN6-deep-research-falcon.md
title: Falcon deep research synthesis for PTPN6
findings: []
core_functions:
- description: Cytosolic non-receptor protein tyrosine phosphatase activity that dephosphorylates
phosphotyrosine residues on receptor-proximal and cytokine-signaling substrates.
molecular_function:
id: GO:0004726
label: non-membrane spanning protein tyrosine phosphatase activity
directly_involved_in:
- id: GO:0035335
label: peptidyl-tyrosine dephosphorylation
- id: GO:0006470
label: protein dephosphorylation
- id: GO:0031295
label: T cell costimulation
- id: GO:0060338
label: regulation of type I interferon-mediated signaling pathway
- id: GO:0050859
label: negative regulation of B cell receptor signaling pathway
locations:
- id: GO:0005737
label: cytoplasm
- id: GO:0005829
label: cytosol
- id: GO:0005886
label: plasma membrane
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- description: SH2-domain phosphotyrosine-dependent binding that recruits SHP-1 to receptor and
adaptor signaling complexes and confers pathway-specific substrate access.
molecular_function:
id: GO:0001784
label: phosphotyrosine residue binding
directly_involved_in:
- id: GO:0031295
label: T cell costimulation
- id: GO:0160162
label: CD27 signaling pathway
- id: GO:0045824
label: negative regulation of innate immune response
- id: GO:1902564
label: negative regulation of neutrophil activation
locations:
- id: GO:0005737
label: cytoplasm
- id: GO:0005829
label: cytosol
- id: GO:0005886
label: plasma membrane
supported_by:
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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)**.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: '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.'
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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.
- reference_id: file:human/PTPN6/PTPN6-deep-research-falcon.md
supporting_text: 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).
proposed_new_terms: []
suggested_questions: []
suggested_experiments: []