Affinage

PTPN6

Tyrosine-protein phosphatase non-receptor type 6 · UniProt P29350

Length
595 aa
Mass
67.6 kDa
Annotated
2026-04-28
100 papers in source corpus 42 papers cited in narrative 43 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

PTPN6 (SHP-1) is a cytoplasmic protein tyrosine phosphatase that functions as a master negative regulator of signaling downstream of immune receptors, cytokine receptors, integrins, and growth factor receptors in hematopoietic and non-hematopoietic cells. Structurally, SHP-1 is maintained in an autoinhibited conformation through intramolecular occlusion of its catalytic site by the N-SH2 domain; activation occurs via phosphotyrosine-mediated displacement of the N-SH2 block, C-terminal Tyr536 phosphorylation by Src family kinases, or phosphatidic acid binding, while PKCα-mediated Ser591 phosphorylation and THEMIS-promoted catalytic cysteine oxidation serve as inactivation mechanisms (PMID:12482860, PMID:21465528, PMID:12468540, PMID:10508402, PMID:15269224, PMID:28250424). Upon activation, SHP-1 dephosphorylates substrates including SLP-76, LAT, Vav1, JAK2, STAT3, TRPV1, alpha-actinin, and TonEBP/OREBP, thereby dampening TCR, BCR, KIR, FcγR, cytokine receptor, TLR, integrin, and VEGFR2 signaling pathways (PMID:9765283, PMID:11420038, PMID:10545526, PMID:22438258, PMID:25790452, PMID:15070900, PMID:20351292, PMID:23896411). In neutrophils, SHP-1 restrains p38 MAPK-dependent IL-1α/β production and maintains RIPK1 function to prevent caspase-8- and RIPK3/MLKL-dependent cell death, linking it to control of inflammatory tissue damage (PMID:31819256).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1997 High

    Whether SHP-1 and SHIP occupy distinct or overlapping roles in inhibitory receptor signaling was unknown; genetic deletion in B cells demonstrated that KIR-class receptors selectively recruit SHP-1 to block BCR-triggered apoptosis, while FcγRIIB requires SHIP, establishing non-redundant pathway specificity.

    Evidence SHP-1-deficient B cell lines with inhibitory receptor co-engagement functional assays

    PMID:9244303

    Open questions at the time
    • Direct SHP-1 substrate(s) mediating KIR-dependent apoptosis block not identified
    • Whether SHP-1 and SHIP cross-compensate in other cell types untested
  2. 1998 High

    The structural basis for SHP-1 catalytic mechanism and substrate specificity was unknown; crystal structures of the catalytic domain and its tungstate complex revealed an atypical WPD loop movement, and mutagenesis confirmed critical WPD-loop residues for catalysis, while SLP-76 was identified as a direct KIR-recruited substrate.

    Evidence X-ray crystallography with mutagenesis/kinetics (catalytic domain); direct binding and in vitro dephosphorylation assays (SLP-76 substrate identification); motheaten macrophages with PI3K inhibitor epistasis (integrin adhesion); H₂O₂/reductant treatment in vitro and in cells (redox regulation)

    PMID:9739453 PMID:9740804 PMID:9765283 PMID:9774441

    Open questions at the time
    • How WPD loop dynamics differ from PTP1B in a physiological context unclear
    • Redox regulation mechanism at the catalytic cysteine not structurally resolved
  3. 2000 High

    How SHP-1 achieves substrate selectivity and how dual SH2 domains cooperate in receptor recruitment were open questions; peptide-bound crystal structures identified the β5-loop-β6 motif as the specificity determinant, and quantitative ITIM-bead assays showed that simultaneous engagement of both SH2 domains with adjacent phospho-ITIMs is required for recruitment.

    Evidence SIRPα phosphopeptide-bound crystal structures; phospho-ITIM agarose bead density assays with in vivo Co-IP validation

    PMID:10660565 PMID:11099496

    Open questions at the time
    • No full-length structure with phosphopeptide-engaged SH2 domains
    • Quantitative affinity thresholds for in vivo recruitment not defined
  4. 2002 High

    The mechanism of autoinhibition was structurally defined but how C-terminal phosphorylation activates SHP-1 was unclear; the crystal structure confirmed N-SH2-mediated catalytic site occlusion, and semisynthetic phosphoproteins demonstrated that Tyr536 phosphorylation engages the N-SH2 domain intramolecularly to activate the enzyme ~8-fold.

    Evidence 2.8 Å crystal structure of autoinhibited SHP-1; expressed protein ligation with non-hydrolyzable phosphotyrosine mimetics at Tyr536/Tyr564

    PMID:12468540 PMID:12482860

    Open questions at the time
    • Whether Tyr536 phosphorylation fully displaces N-SH2 or adopts an intermediate state unknown
    • Contribution of Tyr564/Grb2 binding to downstream signaling unclear
  5. 2003 High

    The scope of SHP-1 negative regulation beyond lymphocytes and its ligand-discrimination role in TCR signaling were undefined; studies showed SHP-1 sets a signaling threshold by which weak TCR ligands trigger rapid SHP-1 recruitment and Lck inactivation while strong ligands evade this via ERK-dependent Lck modification, and SHP-1 was found to associate with FcγRIIa ITAM and suppress NF-κB.

    Evidence TCR stimulation with ERK inhibition in primary T cells; synthetic ITAM phosphopeptides with mutant FcγRIIa transfectants and NF-κB reporter; Src kinase phosphorylation of SHP-1 with substrate dephosphorylation assays

    PMID:12577055 PMID:12832410 PMID:14699166

    Open questions at the time
    • Structural basis for ERK-dependent Lck modification that prevents SHP-1 binding not resolved
    • Whether SHP-1/FcγRIIa ITAM interaction occurs under physiological phosphorylation levels uncertain
  6. 2004 High

    How SHP-1 activity is negatively regulated by serine phosphorylation and what non-immune substrates SHP-1 targets were unknown; PKCα was shown to phosphorylate SHP-1 at Ser591 to inhibit its activity toward Vav1 in platelets, and alpha-actinin was identified as a direct platelet substrate via biochemical purification and mass spectrometry.

    Evidence Co-IP/PKC inhibitor studies in human platelets (Ser591); sequential chromatography, electrospray MS, in vitro dephosphorylation, and COS-7 triple transfection (alpha-actinin)

    PMID:15070900 PMID:15269224

    Open questions at the time
    • Whether Ser591 phosphorylation alters SHP-1 conformation or protein interactions not structurally resolved
    • Full platelet SHP-1 substrate repertoire not catalogued
  7. 2006 High

    Whether SHP-1 regulates metabolic signaling was untested; motheaten viable mice and hepatocyte-specific SHP-1 silencing demonstrated that SHP-1 negatively regulates the insulin receptor–IRS–PI3K–Akt axis and modulates hepatic insulin clearance via CEACAM1.

    Evidence Motheaten viable mouse model, adenoviral shRNA and dominant-negative SHP-1 in mouse liver, [125I]-insulin clearance assays

    PMID:16617349

    Open questions at the time
    • Direct dephosphorylation site on insulin receptor or IRS by SHP-1 not mapped
    • Contribution of SHP-1 in muscle versus liver not dissected with tissue-specific knockouts
  8. 2010 High

    The substrate specificity of SHP-1 in osmotic stress and macrophage activation contexts was unclear; TonEBP/OREBP Tyr143 was identified as a direct dephosphorylation site controlling nuclear localization, and Vav1 was confirmed as a macrophage SHP-1 substrate that couples to LPS-driven TNF and iNOS.

    Evidence siRNA screen, in vitro/in vivo dephosphorylation of TonEBP Y143, Co-IP; inducible SHP-1 overexpression in RAW macrophages with Vav1 phosphorylation, TNF, and iNOS readouts

    PMID:16487932 PMID:20351292

    Open questions at the time
    • Whether SHP-1 dephosphorylates TonEBP directly at the chromatin level unknown
    • Vav1 dephosphorylation site by SHP-1 not mapped
  9. 2011 High

    The structural transition from autoinhibited to active SHP-1 lacked direct visualization; a full-length crystal structure at 3.1 Å captured the open conformation with N-SH2 displaced from the active site, completing the two-state structural model of SHP-1 regulation.

    Evidence X-ray crystallography of full-length SHP-1 in open conformation

    PMID:21465528

    Open questions at the time
    • Intermediate conformational states during activation not captured
    • No structure of SHP-1 bound to a physiological phospho-ITIM peptide in the open state
  10. 2015 High

    Whether SHP-1 has roles outside the immune system in sensory neuron physiology was unknown; SHP-1 was shown to directly bind and dephosphorylate TRPV1 in DRG neurons, bidirectionally modulating thermal nociception and inflammatory pain.

    Evidence Co-IP and co-localization in DRG neurons, SHP-1 inhibitors and adenoviral overexpression in vivo, TRPV1 current measurements

    PMID:25790452

    Open questions at the time
    • Specific TRPV1 phosphotyrosine site(s) dephosphorylated by SHP-1 not identified
    • Whether SHP-1 regulates other TRP channels unknown
  11. 2017 High

    How SHP-1 activity is regulated during thymocyte development was mechanistically unclear; THEMIS was found to directly interact with the SHP-1 phosphatase domain via CABIT modules and promote oxidation of the catalytic cysteine, inactivating SHP-1, with genetic epistasis showing SHP-1 deletion rescues thymocyte development in Themis−/− mice.

    Evidence Direct binding assays (CABIT–PTP domain), catalytic cysteine oxidation analysis, Themis−/− × SHP-1−/− double knockout genetic epistasis

    PMID:28250424

    Open questions at the time
    • Whether THEMIS-mediated oxidation involves ROS generation or direct electron transfer unresolved
    • Structural basis of CABIT–PTP domain interaction not determined
  12. 2019 High

    How neutrophil SHP-1 controls inflammatory tissue pathology was undefined; conditional Ptpn6 deletion in neutrophils revealed dual roles — restraining p38 MAPK-dependent cytokine production and maintaining RIPK1 function to prevent caspase-8/RIPK3/MLKL-dependent cell death and IL-1 release.

    Evidence Conditional Ptpn6 deletion in neutrophils with genetic epistasis using Ripk1, caspase-8, Ripk3, and Mlkl knockout mice, p38 inhibition, cytokine and cell death assays

    PMID:31819256

    Open questions at the time
    • Direct SHP-1 substrate in the RIPK1-protective pathway not identified
    • Whether the dual mechanism operates in other myeloid cells untested
  13. 2020 High

    Whether SHP-1 mediates PD-1 checkpoint signaling in sensory neurons was unknown; conditional SHP-1 deletion in NaV1.8+ neurons abolished PD-L1/PD-1-mediated TRPV1 current inhibition and aggravated bone cancer pain, placing SHP-1 as the effector phosphatase in neuronal PD-1 signaling.

    Evidence Conditional SHP-1 knockout (NaV1.8-Cre), TRPV1 electrophysiology, PD-1/SHP-1 co-localization, in vivo bone cancer pain model

    PMID:32960817

    Open questions at the time
    • Whether SHP-1 dephosphorylates TRPV1 directly downstream of PD-1 or acts on an intermediate unknown
    • Relevance to human sensory neuron PD-1 biology not confirmed
  14. 2022 Medium

    Whether SHP-1 regulates innate immune DNA-sensing pathways was untested; SHP-1 was found to physically interact with STING and suppress its K63-linked ubiquitination and activation, linking SHP-1 to control of the cGAS-STING pathway.

    Evidence Co-IP of SHP-1 and STING, K63-ubiquitination assay, STING antagonist rescue, lentiviral SHP-1 knockdown in RPE cells

    PMID:36273174

    Open questions at the time
    • Whether SHP-1 dephosphorylates STING directly or acts on an upstream kinase/ubiquitin ligase unknown
    • Not confirmed in immune cells
    • Single-lab finding awaits independent replication

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the full structural basis of SHP-1 activation in the context of membrane-bound receptor complexes, the complete phosphoproteomic substrate repertoire across cell types, and how mechanotransduction (β-actin/actomyosin flow) regulates SHP-1 conformation and activity in vivo.
  • No cryo-EM or crystallographic structure of SHP-1 bound to a full-length inhibitory receptor complex
  • Comprehensive phosphoproteomics of SHP-1-dependent substrates lacking
  • Mechanotransduction-based conformational regulation reported by single lab only

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140096 catalytic activity, acting on a protein 10
Localization
GO:0005829 cytosol 3 GO:0005886 plasma membrane 3
Pathway
R-HSA-168256 Immune System 9 R-HSA-162582 Signal Transduction 7 R-HSA-1430728 Metabolism 2 R-HSA-5357801 Programmed Cell Death 2
Partners
ACTN1JAK2LATSLP76STAT3THEMISTRPV1VAV1

Evidence

Reading pass · 43 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2002 Crystal structure of human SHP-1 (C-terminal truncated) at 2.8 Å resolution reveals an autoinhibited conformation in which the N-SH2 domain blocks the catalytic domain, demonstrating that phosphatase activity is primarily regulated by the N-SH2 domain. X-ray crystallography The Journal of biological chemistry High 12482860
2011 Crystal structure of full-length SHP-1 at 3.1 Å reveals an open (active) conformation in which the N-SH2 domain is shifted away from the active site, defining the structural basis for SHP-1 activation by release of autoinhibition. X-ray crystallography Journal of cellular biochemistry High 21465528
1998 Crystal structure of the SHP-1 catalytic domain and its tungstate complex at 2.5–2.8 Å resolution reveals that the WPD loop moves away from the substrate-binding pocket upon tungstate binding (opposite to PTP1B), and mutagenesis of WPD-loop residues confirms their critical role in substrate binding and catalytic activity. X-ray crystallography and site-directed mutagenesis with kinetic measurements The Journal of biological chemistry High 9774441
2000 Crystal structures of the SHP-1 catalytic domain complexed with two SIRPα-derived phosphopeptides reveal that the variable β5-loop-β6 motif confers substrate specificity at the P-4 and further N-terminal subpockets, explaining SHP-1 substrate selectivity. X-ray crystallography (substrate-bound structures) The Journal of biological chemistry High 10660565
2002 Using expressed protein ligation to install non-hydrolyzable phosphotyrosine mimetics at Tyr536 and Tyr564, phosphorylation at Tyr536 (but not Tyr564) was shown to engage the N-SH2 domain intramolecularly and activate SHP-1 ~8-fold, while both sites promote Grb2 binding. Expressed protein ligation (semisynthetic phosphoproteins), size exclusion chromatography, phosphotyrosine peptide stimulation, site-directed mutagenesis The Journal of biological chemistry High 12468540
2003 Src phosphorylates SHP-1 at C-terminal sites (Tyr538 and Tyr566 in mouse), activating SHP-1; SHP-1 in turn effectively dephosphorylates Src substrates via its catalytic domain (not SH2 domains), with acidic residues N-terminal of phosphotyrosine being critical for substrate interaction. In vitro kinase assay with recombinant proteins, mutagenesis of SHP-1 phosphorylation sites, GST-pulldown of Src-generated phosphoproteins, molecular modeling The Journal of biological chemistry High 14699166
2004 In human platelets, SHP-1 is constitutively associated with Vav1 and protein kinase Cα through its SH2 domains; upon PAR1/PAR4 activation, PKCα phosphorylates SHP-1 on Ser591, which inhibits SHP-1 phosphatase activity toward Vav1, establishing a serine-phosphorylation-based negative regulatory mechanism. Co-immunoprecipitation, in vitro phosphatase assay, PKC inhibitor studies in human platelets The Journal of biological chemistry High 15269224
1999 Phosphatidic acid (PA) directly binds SHP-1 at a high-affinity site within the 41 C-terminal amino acids (absent from SHP-2) and activates SHP-1 phosphatase activity; a second low-affinity PA binding site is located in the N-terminal SH2 domain region. 14C-PA binding chromatographic assay, ELISA plate binding, silica bead (TRANSIL) assay, fluorescently labeled PA liposome spectroscopy, in vitro phosphatase activity assays Biochemistry High 10508402
1997 Genetic deletion experiments in B cell lines established two distinct inhibitory signaling pathways: KIR-class inhibitory receptors selectively recruit SHP-1 to block BCR-triggered apoptosis, while FcγRIIB-class requires SHIP and not SHP-1. SHP-1-deficient B cell lines (genetic deletion), inhibitory receptor co-engagement functional assays Cell High 9244303
1998 SLP-76 is a direct substrate of SHP-1 recruited to killer cell inhibitory receptors (KIRs) in T cells and NK cells; dephosphorylation of SLP-76 by SHP-1 mediates inhibitory receptor negative regulation of immune cell activation. Direct binding assays, in vitro dephosphorylation assays, functional inhibition assays in T cells and NK cells The Journal of biological chemistry High 9765283
2003 In T lymphocytes, weakly binding TCR ligands trigger a negative feedback loop involving rapid recruitment of SHP-1 followed by Lck kinase inactivation and receptor desensitization, while strongly binding ligands activate ERK-dependent Lck modification that prevents SHP-1 recruitment. ERK inhibition, TCR stimulation assays, phosphorylation analysis of Lck and SHP-1 recruitment in T cells Nature immunology High 12577055
1999 SHP-1 is constitutively associated with JAK2 in pituitary corticotroph cells; LIF stimulation induces recruitment of phosphorylated STAT3 to this SHP-1/JAK2 complex, and SHP-1 dephosphorylates JAK2 and STAT3, terminating LIF-induced POMC gene transcription. Co-immunoprecipitation, overexpression of WT and dominant-negative SHP-1, promoter activity assays The Journal of clinical investigation High 10545526
2001 SHP-1 dephosphorylates LAT in lipid rafts after TCR engagement; raft-targeted constitutively active SHP-1 completely blocks TCR-induced CD69 expression and transcription factor activation by rapidly dephosphorylating phospho-LAT, without affecting TCRζ, ZAP-70 phosphorylation, or Lck kinase activity. Chimeric raft-targeting SHP-1 construct in Jurkat transfectants, immunoprecipitation, kinase assays Immunity High 11420038
2006 SHP-1 negatively regulates insulin receptor signaling (IRS-PI3K-Akt pathway) in liver and muscle; SHP-1-deficient (motheaten viable) mice show enhanced insulin sensitivity, and adenoviral SHP-1 silencing or dominant-negative SHP-1 in normal mouse liver phenocopies this; SHP-1 also modulates hepatic insulin clearance via CEACAM1 tyrosine phosphorylation. Motheaten viable mouse model, adenoviral shRNA and dominant-negative expression, in vitro hepatocyte assays with [125I]-insulin clearance Nature medicine High 16617349
2013 TSP-1/CD36 interaction recruits SHP-1 to the VEGFR2 signaling complex, increasing SHP-1 phosphatase activity within the complex and suppressing VEGFR2 phosphorylation; CD36 is required for this complex formation, and SHP-1 mediates TSP-1 antiangiogenic effects on endothelial cell migration and tube formation. Co-immunoprecipitation, SHP-1 phosphatase activity assays on immunoprecipitated complexes, siRNA knockdown, cd36-/- mouse endothelial cells Blood High 23896411
2017 THEMIS directly interacts with the phosphatase domain of SHP-1 via its CABIT modules, promoting or stabilizing oxidation of SHP-1's catalytic cysteine residue to inhibit SHP-1 tyrosine-phosphatase activity; deletion of SHP-1 rescues the developmental block in Themis-/- thymocytes. Direct binding assays (CABIT–SHP-1 phosphatase domain), oxidation state analysis of catalytic cysteine, genetic epistasis (Themis-/- × SHP-1-/- double mutant) Nature immunology High 28250424
2002 Death domain-containing receptors (TNF/NGF family) contain a conserved phosphotyrosine motif in their death domain that recruits SHP-1 in a caspase-independent manner; receptor-associated activated SHP-1 prevents Lyn kinase activation, blocking cytokine-induced anti-apoptotic signaling in neutrophils. Co-immunoprecipitation, SHP-1 activity assays, mutational analysis of death-domain phosphotyrosine motif Nature medicine High 11786908
1998 SHP-1 reversible oxidative inactivation: H2O2 inactivates SHP-1 in vitro and in SHP-1-transfected HeLa cells; activity is fully recovered by dithiothreitol, glutathione, or N-acetylcysteine, establishing redox regulation as a reversible mechanism controlling SHP-1 activity. In vitro PTPase assay with H2O2 and reducing agents, cellular SHP-1 activity measurement after H2O2 stimulation Biochemistry and molecular biology international Medium 9739453
2003 SHP-1 associates with the phosphorylated N-terminal ITAM tyrosine of FcγRIIa (while Syk binds the C-terminal ITAM tyrosine), activates phosphatase activity upon FcγRIIa clustering, and associates with Syk, p85-PI3K, and p62dok as substrates; catalytically active SHP-1 suppresses NF-κB-dependent transcription downstream of FcγRIIa. Synthetic phosphopeptides, ITAM tyrosine mutant stable transfectants, Co-immunoprecipitation, NF-κB reporter assay, SHP-1 activity assay The Journal of biological chemistry High 12832410
2000 SHP-1 requires both of its SH2 domains binding simultaneously to adjacent phospho-ITIMs for recruitment; FcγRIIB phosphorylation levels in vivo are insufficient for SHP-1 recruitment (only SHIP is recruited), but hyperphosphorylation with pervanadate enables SHP-1 association. Phospho-ITIM peptide-coated agarose beads at varying density, in vivo co-immunoprecipitation in B cells and mast cells, pervanadate treatment The Journal of biological chemistry High 11099496
2004 SHP-1 directly dephosphorylates alpha-actinin both in vitro and in vivo; SHP-1 co-purifies with alpha-actinin from platelets, and platelet adhesion to fibrinogen selectively reduces SHP-1 activity toward alpha-actinin without affecting its activity toward a synthetic substrate. Sequential column chromatography purification from platelets, electrospray MS identification, in vitro dephosphorylation by recombinant SHP-1, triple transfection COS-7 assays, platelet adhesion assays The Journal of biological chemistry High 15070900
2010 SHP-1 directly dephosphorylates TonEBP/OREBP at Tyr143, reducing nuclear localization and transactivating activity; SHP-1 co-immunoprecipitates with TonEBP/OREBP; high NaCl inhibits SHP-1 by promoting Ser591 phosphorylation, thereby disinhibiting TonEBP/OREBP activation. siRNA library screen, SHP-1 overexpression, in vivo and in vitro dephosphorylation at Y143, Co-immunoprecipitation, nuclear localization assays Proceedings of the National Academy of Sciences of the United States of America High 20351292
2018 SHP-1 interacts with the immunoreceptor tyrosine-based inhibition motif (ITIM) on TGF-β receptor 1 in hematopoietic stem cells (HSCs) and is required for TGF-β signaling activation; SHP-1-knockout HSCs fail to respond to TGF-β-enforced quiescence both in vitro and in vivo. Co-immunoprecipitation (SHP-1 with TGFβR1 ITIM), Shp-1 conditional knockout mice, HSC quiescence assays, in vitro and in vivo TGF-β signaling The Journal of experimental medicine High 29669741
2019 Ptpn6 in neutrophils negatively regulates p38 MAPK-dependent IL-1α/β and TNF production (Ripk1-independent pathway) and maintains Ripk1 function to prevent caspase-8- and Ripk3/Mlkl-dependent cell death and concomitant IL-1α/β release; combined deletion of caspase-8 and Ripk3 or Mlkl strongly protects Ptpn6ΔPMN mice from cutaneous inflammatory disease. Conditional Ptpn6 deletion in neutrophils, genetic epistasis with Ripk1-, caspase-8-, Ripk3-, Mlkl-deficient mice, p38 MAPK inhibition, cytokine assays, cell death assays Nature immunology High 31819256
2011 In B-CLL cells, Lyn phosphorylates ITIM motifs of CD5, creating an anchoring site for SHP-1; this recruits SHP-1 to CD5 in an active form, driving negative BCR signaling and contributing to resistance to apoptosis; SHP-1 knockdown or pharmacological inhibition reverses this survival advantage. Co-immunoprecipitation, SHP-1 activity assay, Lyn kinase assay, SHP-1 knockdown and inhibitor (PTP-I-I) treatment Leukemia High 21701493
2009 Endorepellin engagement of integrin α2β1 induces SHP-1 co-precipitation with integrin α2 and dynamic SHP-1 phosphorylation; SHP-1 is required for endorepellin-mediated reduction of angiogenic receptor phosphorylation; integrin α2 intracellular domain is needed to maintain SHP-1 levels and phosphatase activity. Antibody array, Co-immunoprecipitation, siRNA knockdown, integrin α2β1-/- mouse-derived endothelial cells, chimeric integrin constructs Blood High 19789387
2003 SHP-1 suppresses cancer cell growth in part by promoting proteasome-mediated degradation of activated JAK kinases (TYK2 in H9 cells; JAK1 in HTB26 cells); MG132 proteasome inhibitor blocks SHP-1-mediated JAK1 degradation. SHP-1 transfection into lymphoma/breast cancer cell lines, MG132 proteasome inhibitor treatment, western blotting of JAK kinase levels Journal of cellular biochemistry Medium 14624462
1998 SHP-1 deficiency in macrophages results in enhanced αmβ2 integrin-mediated adhesion and spreading, accompanied by 10–15-fold increase in PI 3-kinase-generated D-3 phospholipids and 2–5-fold increase in membrane-associated PI 3-kinase activity; PI 3-kinase inhibitors (wortmannin, LY294002) reverse the adhesion phenotype, placing SHP-1 upstream of PI 3-kinase in integrin adhesion regulation. Motheaten viable macrophages, adhesion/spreading assays, PI 3-kinase activity assay, PI 3-kinase inhibitor treatment Current biology : CB High 9740804
2015 SHP-1 co-localizes with and directly binds TRPV1 in nociceptive DRG neurons; SHP-1 dephosphorylates TRPV1 to inhibit its activity; pharmacological SHP-1 inhibition or SHP-1 overexpression in DRG neurons bi-directionally modulates thermal nociception and CFA-induced inflammatory pain. Co-immunoprecipitation, co-localization by immunofluorescence, SHP-1 inhibitors (sodium stibogluconate, PTP inhibitor III), intrathecal injection, adenoviral SHP-1 overexpression in vivo, TRPV1 current measurements Pain High 25790452
2020 PD-L1/PD-1 signaling activates SHP-1 in DRG TRPV1+ neurons; activated SHP-1 inhibits TRPV1 currents; conditional deletion of SHP-1 in NaV1.8+ sensory neurons aggravates bone cancer pain and abolishes PD-L1 inhibition of TRPV1 currents. Conditional SHP-1 knockout (NaV1.8-Cre), electrophysiology (TRPV1 current recording), co-localization of PD-1/TRPV1/SHP-1, SHP-1 phosphorylation assays JCI insight High 32960817
2012 SHP-1 negatively regulates Th17 development by decreasing STAT3 phosphorylation in response to IL-6 and IL-21; genetic deletion, dominant-negative transgene expression, or pharmacological SHP-1 inhibition each strongly promote Th17 differentiation. SHP-1 genetic knockout, dominant-negative SHP-1 transgenic mice, sodium stibogluconate pharmacological inhibition, ex vivo Th17 skewing with IL-6/IL-21, STAT3 phosphorylation assays Blood High 22438258
2018 β-actin directly interacts with SHP-1 in NK cells, and actomyosin retrograde flow (ARF) converts SHP-1 conformation state; this mechano-transduction mechanism via β-actin/SHP-1 interaction regulates SHP-1 catalytic activity and thereby controls NK cell cytotoxicity. Co-immunoprecipitation of β-actin and SHP-1, ARF perturbation, primary human NK cell cytotoxicity assays, conformational analysis The EMBO journal Medium 29449322
2008 Leishmania-induced SHP-1 directly binds IRAK-1 via an evolutionarily conserved ITIM-like motif in the IRAK-1 kinase domain (named KTIM), completely inactivating IRAK-1 kinase activity and blocking downstream TLR signaling (Erk1/2, IKKα/β also bear KTIMs and interact with SHP-1). Co-immunoprecipitation, IRAK-1 kinase activity assay, KTIM motif identification and mutagenesis, SHP-1-deficient macrophage cell line PLoS neglected tropical diseases High 19104650
2000 SHP-1 negatively regulates macrophage integrin-mediated adhesion; SHP-1-deficient (motheaten viable) macrophages show markedly enhanced αmβ2-dependent adhesion and spreading with increased PI 3-kinase activity and D-3 phospholipid products; PI 3-kinase inhibitors reverse the adhesion defect. Motheaten viable mouse macrophages, adhesion assays, PI 3-kinase activity and lipid product measurements, PI3K inhibitor treatment Current biology : CB High 9740804
1998 SHP-1 deficiency in SHP-1-/- astrocytes prolongs IFN-gamma-induced GAF (STAT1) activity and increases IRF-1 and MHC class I expression, establishing SHP-1 as a negative regulator of IFN-γ-JAK-STAT signaling in neural cells. Motheaten (SHP-1-deficient) astrocytes, EMSA (GAF activity), vanadate-treated cultures, MHC class I immunostaining Journal of immunology Medium 8943425
2006 Leishmania-induced SHP-1 activity inhibits nitric oxide production by inactivating JAK2 and ERK1/2 phosphorylation and preventing nuclear translocation of NF-κB and AP-1; SHP-1-deficient macrophages fail to inhibit JAK2/ERK1/2 upon infection. SHP-1-/- macrophage cell line from motheaten mice, phosphorylation assays (JAK2, ERK1/2), NF-κB/AP-1 nuclear translocation, nitric oxide measurements Infection and immunity High 17057094
2000 In platelets stimulated via glycoprotein VI (GPVI), SHP-1 associates with Lyn and Syk kinases through its SH2 domains; SHP-1-deficient (mev/mev) platelets show hypophosphorylation of Syk and Lyn and reduced P-selectin expression, establishing SHP-1's functional role in GPVI signaling. GST-SH2 domain pulldown, kinase assays, motheaten viable (mev/mev) platelet analysis, SHP-1 immunoprecipitation The Journal of biological chemistry Medium 10871605
2005 SHP-1 is a negative regulator of endothelial NAD(P)H-oxidase-dependent superoxide production by inhibiting PI3K-dependent Rac1 activation; SHP-1 knockdown by AS-ODN or siRNA increases NAD(P)H-oxidase activity 3.3-fold, elevates p85 (PI3K) tyrosine phosphorylation, and activates Rac1. AS-ODN and siRNA knockdown of SHP-1 in HUVEC, NAD(P)H-oxidase activity assay, Rac1 pull-down assay, PI3K activity assay, cytochrome c reduction for O2- Journal of the American College of Cardiology Medium 15893190
2010 SHP-1 is constitutively associated with Vav1 in RAW 264.7 macrophages; WT SHP-1 overexpression inhibits LPS-mediated Vav1 tyrosine phosphorylation and reduces TNF secretion and iNOS accumulation, establishing Vav1 as a SHP-1 substrate in macrophage activation. Repressible/inducible SHP-1 overexpression in RAW-TT10 macrophages, LPS stimulation, Vav1 phosphorylation analysis, TNF ELISA, iNOS western blot Biochemical and biophysical research communications Medium 16487932
2022 SHP-1 physically interacts with STING (ER-resident) and suppresses K63-linked ubiquitination and activation of STING; SHP-1 knockdown potentiates STING overactivation and blocks AMPK-dependent mitochondrial biogenesis in RPE cells. Co-immunoprecipitation of SHP-1 and STING, ubiquitination assay (K63-linkage), STING antagonist rescue, AMPK pathway analysis, SHP-1 knockdown via lentivirus Molecular medicine (Cambridge, Mass.) Medium 36273174
2024 SHP-1 inhibition in leukemia stem cells (LSCs) upregulates phosphofructokinase platelet (PFKP) through the AKT-β-catenin pathway, enhancing glycolysis and oxidative phosphorylation, increasing chemosensitivity, and promoting MYC degradation to reduce immune evasion. SHP-1 inhibition in LSCs, PFKP overexpression/knockdown, AKT-β-catenin pathway analysis, metabolic assays, MYC stability assays Nature cell biology Medium 38321204
2001 SHP-1 is found in a complex with both p210 Bcr-Abl and p190 Bcr-Abl in K562 cells, and exogenous SHP-1 expression inhibits K562 proliferation and alters adhesion properties; SHP-1 induction correlates with dephosphorylation of a specific set of tyrosyl phosphoproteins during differentiation. Co-immunoprecipitation, SHP-1 exogenous expression, proliferation assay, western blot of phosphotyrosyl proteins Leukemia Medium 11516103
1998 SHP-1 C-terminus interacts with novel substrate proteins p32/p30 (identified by co-immunoprecipitation and in vitro binding to synthetic C-terminal peptide but not SH2 domain fusion proteins); p32/p30 are hyperphosphorylated in SHP-1-deficient motheaten hematopoietic cells and during IL-3/Epo-driven cell cycle progression. Co-immunoprecipitation, GST-SH2 domain pulldown, synthetic peptide binding, hyperphosphorylated protein detection in motheaten cells Blood Low 9573011

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1997 Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 380 9244303
2003 TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways. Nature immunology 360 12577055
2000 Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling. Seminars in immunology 263 10995583
2003 The function of the protein tyrosine phosphatase SHP-1 in cancer. Gene 237 12657462
2002 Death receptors bind SHP-1 and block cytokine-induced anti-apoptotic signaling in neutrophils. Nature medicine 151 11786908
2002 Crystal structure of human protein-tyrosine phosphatase SHP-1. The Journal of biological chemistry 145 12482860
2013 Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial cells. Blood 130 23896411
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