{"gene":"PTPN6","run_date":"2026-04-28T19:45:45","timeline":{"discoveries":[{"year":2002,"finding":"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.","method":"X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure with functional model proposed, replicated by open-conformation structure","pmids":["12482860"],"is_preprint":false},{"year":2011,"finding":"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.","method":"X-ray crystallography","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure complementing autoinhibited structure, provides mechanistic model","pmids":["21465528"],"is_preprint":false},{"year":1998,"finding":"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.","method":"X-ray crystallography and site-directed mutagenesis with kinetic measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — crystal structure plus mutagenesis and kinetic validation","pmids":["9774441"],"is_preprint":false},{"year":2000,"finding":"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.","method":"X-ray crystallography (substrate-bound structures)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — peptide-bound crystal structures defining substrate specificity determinants","pmids":["10660565"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Expressed protein ligation (semisynthetic phosphoproteins), size exclusion chromatography, phosphotyrosine peptide stimulation, site-directed mutagenesis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with phosphonate analogues, multiple orthogonal methods in one study","pmids":["12468540"],"is_preprint":false},{"year":2003,"finding":"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.","method":"In vitro kinase assay with recombinant proteins, mutagenesis of SHP-1 phosphorylation sites, GST-pulldown of Src-generated phosphoproteins, molecular modeling","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis and multiple orthogonal approaches","pmids":["14699166"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Co-immunoprecipitation, in vitro phosphatase assay, PKC inhibitor studies in human platelets","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus in vitro activity assay; multiple orthogonal methods","pmids":["15269224"],"is_preprint":false},{"year":1999,"finding":"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.","method":"14C-PA binding chromatographic assay, ELISA plate binding, silica bead (TRANSIL) assay, fluorescently labeled PA liposome spectroscopy, in vitro phosphatase activity assays","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 — direct binding demonstrated by multiple orthogonal biochemical methods with activity validation","pmids":["10508402"],"is_preprint":false},{"year":1997,"finding":"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.","method":"SHP-1-deficient B cell lines (genetic deletion), inhibitory receptor co-engagement functional assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — clean genetic KO with defined cellular and molecular phenotype, highly cited foundational study","pmids":["9244303"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Direct binding assays, in vitro dephosphorylation assays, functional inhibition assays in T cells and NK cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — direct substrate identified by binding and in vitro dephosphorylation assays with functional validation","pmids":["9765283"],"is_preprint":false},{"year":2003,"finding":"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.","method":"ERK inhibition, TCR stimulation assays, phosphorylation analysis of Lck and SHP-1 recruitment in T cells","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary approaches in primary T cells defining feedback pathway; highly cited","pmids":["12577055"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Co-immunoprecipitation, overexpression of WT and dominant-negative SHP-1, promoter activity assays","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP plus dominant-negative and WT overexpression with functional read-out","pmids":["10545526"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Chimeric raft-targeting SHP-1 construct in Jurkat transfectants, immunoprecipitation, kinase assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — targeted localization experiment with defined substrate (LAT) and specific cellular phenotype","pmids":["11420038"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Motheaten viable mouse model, adenoviral shRNA and dominant-negative expression, in vitro hepatocyte assays with [125I]-insulin clearance","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — multiple complementary in vivo and in vitro approaches, genetic and acute knockdown models","pmids":["16617349"],"is_preprint":false},{"year":2013,"finding":"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.","method":"Co-immunoprecipitation, SHP-1 phosphatase activity assays on immunoprecipitated complexes, siRNA knockdown, cd36-/- mouse endothelial cells","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, enzymatic activity assay in complex, genetic and siRNA validation","pmids":["23896411"],"is_preprint":false},{"year":2017,"finding":"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.","method":"Direct binding assays (CABIT–SHP-1 phosphatase domain), oxidation state analysis of catalytic cysteine, genetic epistasis (Themis-/- × SHP-1-/- double mutant)","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — direct binding + catalytic mechanism + genetic epistasis; multiple orthogonal approaches","pmids":["28250424"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Co-immunoprecipitation, SHP-1 activity assays, mutational analysis of death-domain phosphotyrosine motif","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — molecular binding characterized plus functional consequence in primary cells","pmids":["11786908"],"is_preprint":false},{"year":1998,"finding":"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.","method":"In vitro PTPase assay with H2O2 and reducing agents, cellular SHP-1 activity measurement after H2O2 stimulation","journal":"Biochemistry and molecular biology international","confidence":"Medium","confidence_rationale":"Tier 1 — in vitro and cellular assay, single lab, single paper","pmids":["9739453"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Synthetic phosphopeptides, ITAM tyrosine mutant stable transfectants, Co-immunoprecipitation, NF-κB reporter assay, SHP-1 activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — phosphopeptide binding specificity, IP, functional reporter, mutant transfectants — multiple orthogonal methods","pmids":["12832410"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Phospho-ITIM peptide-coated agarose beads at varying density, in vivo co-immunoprecipitation in B cells and mast cells, pervanadate treatment","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — mechanistic dissection with quantitative bead assay and cellular validation","pmids":["11099496"],"is_preprint":false},{"year":2004,"finding":"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.","method":"Sequential column chromatography purification from platelets, electrospray MS identification, in vitro dephosphorylation by recombinant SHP-1, triple transfection COS-7 assays, platelet adhesion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — substrate identified by biochemical purification, MS, in vitro assay, and cellular validation","pmids":["15070900"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA library screen, SHP-1 overexpression, in vivo and in vitro dephosphorylation at Y143, Co-immunoprecipitation, nuclear localization assays","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro and in vivo dephosphorylation at specific site, Co-IP, overexpression/knockdown with mechanistic detail","pmids":["20351292"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation (SHP-1 with TGFβR1 ITIM), Shp-1 conditional knockout mice, HSC quiescence assays, in vitro and in vivo TGF-β signaling","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — Co-IP plus conditional KO with defined cellular phenotype and in vitro/in vivo validation","pmids":["29669741"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Conditional Ptpn6 deletion in neutrophils, genetic epistasis with Ripk1-, caspase-8-, Ripk3-, Mlkl-deficient mice, p38 MAPK inhibition, cytokine assays, cell death assays","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 — multiple genetic epistasis experiments defining dual pathway role, rigorous controls","pmids":["31819256"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation, SHP-1 activity assay, Lyn kinase assay, SHP-1 knockdown and inhibitor (PTP-I-I) treatment","journal":"Leukemia","confidence":"High","confidence_rationale":"Tier 2 — reciprocal Co-IP, kinase assay establishing Lyn as SHP-1 recruiter, pharmacological and genetic validation","pmids":["21701493"],"is_preprint":false},{"year":2009,"finding":"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.","method":"Antibody array, Co-immunoprecipitation, siRNA knockdown, integrin α2β1-/- mouse-derived endothelial cells, chimeric integrin constructs","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — genetic and siRNA evidence, Co-IP, engineered receptor chimera — multiple orthogonal approaches","pmids":["19789387"],"is_preprint":false},{"year":2003,"finding":"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.","method":"SHP-1 transfection into lymphoma/breast cancer cell lines, MG132 proteasome inhibitor treatment, western blotting of JAK kinase levels","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function/gain-of-function with pharmacological rescue, single lab","pmids":["14624462"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Motheaten viable macrophages, adhesion/spreading assays, PI 3-kinase activity assay, PI 3-kinase inhibitor treatment","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — genetic model with biochemical pathway placement and pharmacological epistasis","pmids":["9740804"],"is_preprint":false},{"year":2015,"finding":"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.","method":"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","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 — Co-IP demonstrating direct interaction, pharmacological and viral overexpression in vivo, electrophysiology","pmids":["25790452"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Conditional SHP-1 knockout (NaV1.8-Cre), electrophysiology (TRPV1 current recording), co-localization of PD-1/TRPV1/SHP-1, SHP-1 phosphorylation assays","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 — conditional KO with electrophysiological and in vivo pain phenotype, mechanistic pathway established","pmids":["32960817"],"is_preprint":false},{"year":2012,"finding":"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.","method":"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","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — three complementary approaches (genetic, transgenic DN, pharmacological) defining STAT3 as target","pmids":["22438258"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-immunoprecipitation of β-actin and SHP-1, ARF perturbation, primary human NK cell cytotoxicity assays, conformational analysis","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus functional cytotoxicity assay, single lab, novel mechanism","pmids":["29449322"],"is_preprint":false},{"year":2008,"finding":"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).","method":"Co-immunoprecipitation, IRAK-1 kinase activity assay, KTIM motif identification and mutagenesis, SHP-1-deficient macrophage cell line","journal":"PLoS neglected tropical diseases","confidence":"High","confidence_rationale":"Tier 2 — binding motif identified, kinase activity assay, SHP-1-deficient validation — multiple approaches","pmids":["19104650"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Motheaten viable mouse macrophages, adhesion assays, PI 3-kinase activity and lipid product measurements, PI3K inhibitor treatment","journal":"Current biology : CB","confidence":"High","confidence_rationale":"Tier 2 — genetic model plus biochemical and pharmacological pathway analysis","pmids":["9740804"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Motheaten (SHP-1-deficient) astrocytes, EMSA (GAF activity), vanadate-treated cultures, MHC class I immunostaining","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic model with signaling and transcriptional readout in neural cells","pmids":["8943425"],"is_preprint":false},{"year":2006,"finding":"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.","method":"SHP-1-/- macrophage cell line from motheaten mice, phosphorylation assays (JAK2, ERK1/2), NF-κB/AP-1 nuclear translocation, nitric oxide measurements","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 — SHP-1-deficient cell line with biochemical pathway analysis at multiple signaling nodes","pmids":["17057094"],"is_preprint":false},{"year":2000,"finding":"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.","method":"GST-SH2 domain pulldown, kinase assays, motheaten viable (mev/mev) platelet analysis, SHP-1 immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — GST pulldown plus genetic model, but substrate identity not fully defined","pmids":["10871605"],"is_preprint":false},{"year":2005,"finding":"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.","method":"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":"Journal of the American College of Cardiology","confidence":"Medium","confidence_rationale":"Tier 2 — RNAi knockdown with biochemical pathway validation in endothelial cells","pmids":["15893190"],"is_preprint":false},{"year":2010,"finding":"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.","method":"Repressible/inducible SHP-1 overexpression in RAW-TT10 macrophages, LPS stimulation, Vav1 phosphorylation analysis, TNF ELISA, iNOS western blot","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 — overexpression with substrate-level readout, single lab","pmids":["16487932"],"is_preprint":false},{"year":2022,"finding":"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.","method":"Co-immunoprecipitation of SHP-1 and STING, ubiquitination assay (K63-linkage), STING antagonist rescue, AMPK pathway analysis, SHP-1 knockdown via lentivirus","journal":"Molecular medicine (Cambridge, Mass.)","confidence":"Medium","confidence_rationale":"Tier 2 — Co-IP plus ubiquitination assay and pharmacological rescue, single lab","pmids":["36273174"],"is_preprint":false},{"year":2024,"finding":"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.","method":"SHP-1 inhibition in LSCs, PFKP overexpression/knockdown, AKT-β-catenin pathway analysis, metabolic assays, MYC stability assays","journal":"Nature cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — defined mechanism through identified intermediate (PFKP), multiple orthogonal approaches, single lab","pmids":["38321204"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Co-immunoprecipitation, SHP-1 exogenous expression, proliferation assay, western blot of phosphotyrosyl proteins","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 3 — single Co-IP, correlative dephosphorylation, no direct substrate identification","pmids":["11516103"],"is_preprint":false},{"year":1998,"finding":"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.","method":"Co-immunoprecipitation, GST-SH2 domain pulldown, synthetic peptide binding, hyperphosphorylated protein detection in motheaten cells","journal":"Blood","confidence":"Low","confidence_rationale":"Tier 3 — binding demonstrated but substrates not fully identified; single lab, single approach","pmids":["9573011"],"is_preprint":false}],"current_model":"PTPN6 (SHP-1) is an SH2 domain-containing cytoplasmic protein tyrosine phosphatase that is maintained in an autoinhibited conformation through intramolecular occlusion of its catalytic domain by the N-SH2 domain; activation occurs by phosphotyrosine-mediated displacement of this N-SH2 block (or by C-terminal Tyr536 phosphorylation by Src, phosphatidic acid binding, or THEMIS-mediated catalytic cysteine oxidation), after which SHP-1 dephosphorylates substrates including SLP-76, LAT, TRPV1, alpha-actinin, TonEBP/OREBP, and JAK/STAT components to dampen immune receptor (TCR, BCR, KIR, FcγR, cytokine receptor), integrin, growth-factor-receptor, and ion-channel signaling; its activity is further regulated by PKCα-mediated Ser591 phosphorylation (inhibitory) and reversible oxidation of its catalytic cysteine."},"narrative":{"teleology":[{"year":1997,"claim":"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","pmids":["9244303"],"confidence":"High","gaps":["Direct SHP-1 substrate(s) mediating KIR-dependent apoptosis block not identified","Whether SHP-1 and SHIP cross-compensate in other cell types untested"]},{"year":1998,"claim":"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)","pmids":["9774441","9765283","9740804","9739453"],"confidence":"High","gaps":["How WPD loop dynamics differ from PTP1B in a physiological context unclear","Redox regulation mechanism at the catalytic cysteine not structurally resolved"]},{"year":2000,"claim":"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","pmids":["10660565","11099496"],"confidence":"High","gaps":["No full-length structure with phosphopeptide-engaged SH2 domains","Quantitative affinity thresholds for in vivo recruitment not defined"]},{"year":2002,"claim":"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","pmids":["12482860","12468540"],"confidence":"High","gaps":["Whether Tyr536 phosphorylation fully displaces N-SH2 or adopts an intermediate state unknown","Contribution of Tyr564/Grb2 binding to downstream signaling unclear"]},{"year":2003,"claim":"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","pmids":["12577055","12832410","14699166"],"confidence":"High","gaps":["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"]},{"year":2004,"claim":"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)","pmids":["15269224","15070900"],"confidence":"High","gaps":["Whether Ser591 phosphorylation alters SHP-1 conformation or protein interactions not structurally resolved","Full platelet SHP-1 substrate repertoire not catalogued"]},{"year":2006,"claim":"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","pmids":["16617349"],"confidence":"High","gaps":["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"]},{"year":2010,"claim":"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","pmids":["20351292","16487932"],"confidence":"High","gaps":["Whether SHP-1 dephosphorylates TonEBP directly at the chromatin level unknown","Vav1 dephosphorylation site by SHP-1 not mapped"]},{"year":2011,"claim":"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","pmids":["21465528"],"confidence":"High","gaps":["Intermediate conformational states during activation not captured","No structure of SHP-1 bound to a physiological phospho-ITIM peptide in the open state"]},{"year":2015,"claim":"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","pmids":["25790452"],"confidence":"High","gaps":["Specific TRPV1 phosphotyrosine site(s) dephosphorylated by SHP-1 not identified","Whether SHP-1 regulates other TRP channels unknown"]},{"year":2017,"claim":"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","pmids":["28250424"],"confidence":"High","gaps":["Whether THEMIS-mediated oxidation involves ROS generation or direct electron transfer unresolved","Structural basis of CABIT–PTP domain interaction not determined"]},{"year":2019,"claim":"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","pmids":["31819256"],"confidence":"High","gaps":["Direct SHP-1 substrate in the RIPK1-protective pathway not identified","Whether the dual mechanism operates in other myeloid cells untested"]},{"year":2020,"claim":"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","pmids":["32960817"],"confidence":"High","gaps":["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"]},{"year":2022,"claim":"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","pmids":["36273174"],"confidence":"Medium","gaps":["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"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Low","gaps":["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":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[2,3,4,5,9,12,20,21,28,30]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[12,14,25]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9,10,12,15,18,23,30,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,11,13,14,22,30,35]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[16,23]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[13,40]}],"complexes":[],"partners":["SLP76","LAT","VAV1","JAK2","STAT3","TRPV1","ACTN1","THEMIS"],"other_free_text":[]},"mechanistic_narrative":"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]."},"prefetch_data":{"uniprot":{"accession":"P29350","full_name":"Tyrosine-protein phosphatase non-receptor type 6","aliases":["Hematopoietic cell protein-tyrosine phosphatase","Protein-tyrosine phosphatase 1C","PTP-1C","Protein-tyrosine phosphatase SHP-1","SH-PTP1"],"length_aa":595,"mass_kda":67.6,"function":"Tyrosine phosphatase enzyme that plays important roles in controlling immune signaling pathways and fundamental physiological processes such as hematopoiesis (PubMed:14739280, PubMed:29925997). Dephosphorylates and negatively regulate several receptor tyrosine kinases (RTKs) such as EGFR, PDGFR and FGFR, thereby modulating their signaling activities (PubMed:21258366, PubMed:9733788). When recruited to immunoreceptor tyrosine-based inhibitory motif (ITIM)-containing receptors such as immunoglobulin-like transcript 2/LILRB1, programmed cell death protein 1/PDCD1, CD3D, CD22, CLEC12A and other receptors involved in immune regulation, initiates their dephosphorylation and subsequently inhibits downstream signaling events (PubMed:11907092, PubMed:14739280, PubMed:37932456, PubMed:38166031). Modulates the signaling of several cytokine receptors including IL-4 receptor (PubMed:9065461). Additionally, targets multiple cytoplasmic signaling molecules including STING1, LCK or STAT1 among others involved in diverse cellular processes including modulation of T-cell activation or cGAS-STING signaling (PubMed:34811497, PubMed:38532423). Within the nucleus, negatively regulates the activity of some transcription factors such as NFAT5 via direct dephosphorylation. Also acts as a key transcriptional regulator of hepatic gluconeogenesis by controlling recruitment of RNA polymerase II to the PCK1 promoter together with STAT5A (PubMed:37595871)","subcellular_location":"Cytoplasm; Nucleus","url":"https://www.uniprot.org/uniprotkb/P29350/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/PTPN6","classification":"Not Classified","n_dependent_lines":1,"n_total_lines":1208,"dependency_fraction":0.0008278145695364238},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/PTPN6","total_profiled":1310},"omim":[{"mim_id":"617573","title":"C-TYPE LECTIN DOMAIN FAMILY 12, MEMBER B; CLEC12B","url":"https://www.omim.org/entry/617573"},{"mim_id":"616804","title":"V-SET AND TRANSMEMBRANE DOMAINS-CONTAINING PROTEIN 1; VSTM1","url":"https://www.omim.org/entry/616804"},{"mim_id":"616671","title":"KERATIN 76, TYPE II; KRT76","url":"https://www.omim.org/entry/616671"},{"mim_id":"615772","title":"WAP FOUR-DISULFIDE CORE DOMAIN 21, PSEUDOGENE; WFDC21P","url":"https://www.omim.org/entry/615772"},{"mim_id":"613562","title":"Fc RECEPTOR-LIKE PROTEIN 6; FCRL6","url":"https://www.omim.org/entry/613562"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Nucleoplasm","reliability":"Supported"},{"location":"Nucleoli","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"bone marrow","ntpm":124.6},{"tissue":"lymphoid tissue","ntpm":143.6}],"url":"https://www.proteinatlas.org/search/PTPN6"},"hgnc":{"alias_symbol":["HCP","HCPH","PTP-1C","SHP-1","SHP1"],"prev_symbol":[]},"alphafold":{"accession":"P29350","domains":[{"cath_id":"3.30.505.10","chopping":"10-98","consensus_level":"high","plddt":87.9062,"start":10,"end":98},{"cath_id":"3.30.505.10","chopping":"116-215","consensus_level":"high","plddt":92.3018,"start":116,"end":215},{"cath_id":"3.90.190.10","chopping":"251-525","consensus_level":"high","plddt":95.9328,"start":251,"end":525}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P29350","model_url":"https://alphafold.ebi.ac.uk/files/AF-P29350-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P29350-F1-predicted_aligned_error_v6.png","plddt_mean":86.44},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=PTPN6","jax_strain_url":"https://www.jax.org/strain/search?query=PTPN6"},"sequence":{"accession":"P29350","fasta_url":"https://rest.uniprot.org/uniprotkb/P29350.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P29350/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P29350"}},"corpus_meta":[{"pmid":"9244303","id":"PMC_9244303","title":"Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling.","date":"1997","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/9244303","citation_count":380,"is_preprint":false},{"pmid":"12577055","id":"PMC_12577055","title":"TCR ligand discrimination is enforced by competing ERK positive and SHP-1 negative feedback pathways.","date":"2003","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/12577055","citation_count":360,"is_preprint":false},{"pmid":"10995583","id":"PMC_10995583","title":"Roles of the SHP-1 tyrosine phosphatase in the negative regulation of cell signalling.","date":"2000","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10995583","citation_count":263,"is_preprint":false},{"pmid":"12657462","id":"PMC_12657462","title":"The function of the protein tyrosine phosphatase SHP-1 in cancer.","date":"2003","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/12657462","citation_count":237,"is_preprint":false},{"pmid":"11786908","id":"PMC_11786908","title":"Death receptors bind SHP-1 and block cytokine-induced anti-apoptotic signaling in neutrophils.","date":"2002","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/11786908","citation_count":151,"is_preprint":false},{"pmid":"12482860","id":"PMC_12482860","title":"Crystal structure of human protein-tyrosine phosphatase SHP-1.","date":"2002","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/12482860","citation_count":145,"is_preprint":false},{"pmid":"23896411","id":"PMC_23896411","title":"Thrombospondin-1 modulates VEGF signaling via CD36 by recruiting SHP-1 to VEGFR2 complex in microvascular endothelial 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research","url":"https://pubmed.ncbi.nlm.nih.gov/10197642","citation_count":92,"is_preprint":false},{"pmid":"9765283","id":"PMC_9765283","title":"SLP-76 is a direct substrate of SHP-1 recruited to killer cell inhibitory receptors.","date":"1998","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9765283","citation_count":92,"is_preprint":false},{"pmid":"17057094","id":"PMC_17057094","title":"Role of host protein tyrosine phosphatase SHP-1 in Leishmania donovani-induced inhibition of nitric oxide production.","date":"2006","source":"Infection and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/17057094","citation_count":91,"is_preprint":false},{"pmid":"21465528","id":"PMC_21465528","title":"Crystal structure of human protein tyrosine phosphatase SHP-1 in the open conformation.","date":"2011","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21465528","citation_count":85,"is_preprint":false},{"pmid":"17250594","id":"PMC_17250594","title":"Anaplasma phagocytophilum AnkA is tyrosine-phosphorylated at EPIYA motifs and recruits SHP-1 during early infection.","date":"2007","source":"Cellular microbiology","url":"https://pubmed.ncbi.nlm.nih.gov/17250594","citation_count":83,"is_preprint":false},{"pmid":"10545526","id":"PMC_10545526","title":"Inhibitory roles for SHP-1 and SOCS-3 following pituitary proopiomelanocortin induction by leukemia inhibitory factor.","date":"1999","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/10545526","citation_count":80,"is_preprint":false},{"pmid":"11420038","id":"PMC_11420038","title":"Involvement of SHP-1 tyrosine phosphatase in TCR-mediated signaling pathways in lipid rafts.","date":"2001","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/11420038","citation_count":80,"is_preprint":false},{"pmid":"11745335","id":"PMC_11745335","title":"Role of host phosphotyrosine phosphatase SHP-1 in the development of murine leishmaniasis.","date":"2001","source":"European journal of immunology","url":"https://pubmed.ncbi.nlm.nih.gov/11745335","citation_count":80,"is_preprint":false},{"pmid":"14699166","id":"PMC_14699166","title":"Effective dephosphorylation of Src substrates by SHP-1.","date":"2003","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14699166","citation_count":78,"is_preprint":false},{"pmid":"19104650","id":"PMC_19104650","title":"Leishmania-induced IRAK-1 inactivation is mediated by SHP-1 interacting with an evolutionarily conserved KTIM motif.","date":"2008","source":"PLoS neglected tropical diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19104650","citation_count":76,"is_preprint":false},{"pmid":"14624462","id":"PMC_14624462","title":"SHP-1 suppresses cancer cell growth by promoting degradation of JAK kinases.","date":"2003","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/14624462","citation_count":75,"is_preprint":false},{"pmid":"16389548","id":"PMC_16389548","title":"SHP-1 promoter 2 methylation in normal epithelial tissues and demethylation in psoriasis.","date":"2005","source":"Journal of molecular medicine (Berlin, Germany)","url":"https://pubmed.ncbi.nlm.nih.gov/16389548","citation_count":73,"is_preprint":false},{"pmid":"29776962","id":"PMC_29776962","title":"SHP-1 Acts as a Tumor Suppressor in Hepatocarcinogenesis and HCC Progression.","date":"2018","source":"Cancer research","url":"https://pubmed.ncbi.nlm.nih.gov/29776962","citation_count":71,"is_preprint":false},{"pmid":"28250424","id":"PMC_28250424","title":"THEMIS enhances TCR signaling and enables positive selection by selective inhibition of the phosphatase SHP-1.","date":"2017","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/28250424","citation_count":70,"is_preprint":false},{"pmid":"10660565","id":"PMC_10660565","title":"Structural basis for substrate specificity of protein-tyrosine phosphatase SHP-1.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10660565","citation_count":68,"is_preprint":false},{"pmid":"9740804","id":"PMC_9740804","title":"The protein tyrosine phosphatase SHP-1 regulates integrin-mediated adhesion of macrophages.","date":"1998","source":"Current biology : CB","url":"https://pubmed.ncbi.nlm.nih.gov/9740804","citation_count":67,"is_preprint":false},{"pmid":"15721837","id":"PMC_15721837","title":"Leishmania donovani engages in regulatory interference by targeting macrophage protein tyrosine phosphatase SHP-1.","date":"2005","source":"Clinical immunology 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\"confidence_rationale\": \"Tier 1 — crystal structure with functional model proposed, replicated by open-conformation structure\",\n      \"pmids\": [\"12482860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure complementing autoinhibited structure, provides mechanistic model\",\n      \"pmids\": [\"21465528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography and site-directed mutagenesis with kinetic measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — crystal structure plus mutagenesis and kinetic validation\",\n      \"pmids\": [\"9774441\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography (substrate-bound structures)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — peptide-bound crystal structures defining substrate specificity determinants\",\n      \"pmids\": [\"10660565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Expressed protein ligation (semisynthetic phosphoproteins), size exclusion chromatography, phosphotyrosine peptide stimulation, site-directed mutagenesis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with phosphonate analogues, multiple orthogonal methods in one study\",\n      \"pmids\": [\"12468540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinase assay with recombinant proteins, mutagenesis of SHP-1 phosphorylation sites, GST-pulldown of Src-generated phosphoproteins, molecular modeling\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis and multiple orthogonal approaches\",\n      \"pmids\": [\"14699166\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, in vitro phosphatase assay, PKC inhibitor studies in human platelets\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus in vitro activity assay; multiple orthogonal methods\",\n      \"pmids\": [\"15269224\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"14C-PA binding chromatographic assay, ELISA plate binding, silica bead (TRANSIL) assay, fluorescently labeled PA liposome spectroscopy, in vitro phosphatase activity assays\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct binding demonstrated by multiple orthogonal biochemical methods with activity validation\",\n      \"pmids\": [\"10508402\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"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.\",\n      \"method\": \"SHP-1-deficient B cell lines (genetic deletion), inhibitory receptor co-engagement functional assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean genetic KO with defined cellular and molecular phenotype, highly cited foundational study\",\n      \"pmids\": [\"9244303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Direct binding assays, in vitro dephosphorylation assays, functional inhibition assays in T cells and NK cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct substrate identified by binding and in vitro dephosphorylation assays with functional validation\",\n      \"pmids\": [\"9765283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"ERK inhibition, TCR stimulation assays, phosphorylation analysis of Lck and SHP-1 recruitment in T cells\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary approaches in primary T cells defining feedback pathway; highly cited\",\n      \"pmids\": [\"12577055\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, overexpression of WT and dominant-negative SHP-1, promoter activity assays\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP plus dominant-negative and WT overexpression with functional read-out\",\n      \"pmids\": [\"10545526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Chimeric raft-targeting SHP-1 construct in Jurkat transfectants, immunoprecipitation, kinase assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — targeted localization experiment with defined substrate (LAT) and specific cellular phenotype\",\n      \"pmids\": [\"11420038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Motheaten viable mouse model, adenoviral shRNA and dominant-negative expression, in vitro hepatocyte assays with [125I]-insulin clearance\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple complementary in vivo and in vitro approaches, genetic and acute knockdown models\",\n      \"pmids\": [\"16617349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, SHP-1 phosphatase activity assays on immunoprecipitated complexes, siRNA knockdown, cd36-/- mouse endothelial cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, enzymatic activity assay in complex, genetic and siRNA validation\",\n      \"pmids\": [\"23896411\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"Direct binding assays (CABIT–SHP-1 phosphatase domain), oxidation state analysis of catalytic cysteine, genetic epistasis (Themis-/- × SHP-1-/- double mutant)\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding + catalytic mechanism + genetic epistasis; multiple orthogonal approaches\",\n      \"pmids\": [\"28250424\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, SHP-1 activity assays, mutational analysis of death-domain phosphotyrosine motif\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — molecular binding characterized plus functional consequence in primary cells\",\n      \"pmids\": [\"11786908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro PTPase assay with H2O2 and reducing agents, cellular SHP-1 activity measurement after H2O2 stimulation\",\n      \"journal\": \"Biochemistry and molecular biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — in vitro and cellular assay, single lab, single paper\",\n      \"pmids\": [\"9739453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Synthetic phosphopeptides, ITAM tyrosine mutant stable transfectants, Co-immunoprecipitation, NF-κB reporter assay, SHP-1 activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — phosphopeptide binding specificity, IP, functional reporter, mutant transfectants — multiple orthogonal methods\",\n      \"pmids\": [\"12832410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Phospho-ITIM peptide-coated agarose beads at varying density, in vivo co-immunoprecipitation in B cells and mast cells, pervanadate treatment\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic dissection with quantitative bead assay and cellular validation\",\n      \"pmids\": [\"11099496\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"Sequential column chromatography purification from platelets, electrospray MS identification, in vitro dephosphorylation by recombinant SHP-1, triple transfection COS-7 assays, platelet adhesion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — substrate identified by biochemical purification, MS, in vitro assay, and cellular validation\",\n      \"pmids\": [\"15070900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA library screen, SHP-1 overexpression, in vivo and in vitro dephosphorylation at Y143, Co-immunoprecipitation, nuclear localization assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro and in vivo dephosphorylation at specific site, Co-IP, overexpression/knockdown with mechanistic detail\",\n      \"pmids\": [\"20351292\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation (SHP-1 with TGFβR1 ITIM), Shp-1 conditional knockout mice, HSC quiescence assays, in vitro and in vivo TGF-β signaling\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus conditional KO with defined cellular phenotype and in vitro/in vivo validation\",\n      \"pmids\": [\"29669741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional Ptpn6 deletion in neutrophils, genetic epistasis with Ripk1-, caspase-8-, Ripk3-, Mlkl-deficient mice, p38 MAPK inhibition, cytokine assays, cell death assays\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple genetic epistasis experiments defining dual pathway role, rigorous controls\",\n      \"pmids\": [\"31819256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, SHP-1 activity assay, Lyn kinase assay, SHP-1 knockdown and inhibitor (PTP-I-I) treatment\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal Co-IP, kinase assay establishing Lyn as SHP-1 recruiter, pharmacological and genetic validation\",\n      \"pmids\": [\"21701493\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"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.\",\n      \"method\": \"Antibody array, Co-immunoprecipitation, siRNA knockdown, integrin α2β1-/- mouse-derived endothelial cells, chimeric integrin constructs\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and siRNA evidence, Co-IP, engineered receptor chimera — multiple orthogonal approaches\",\n      \"pmids\": [\"19789387\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"SHP-1 transfection into lymphoma/breast cancer cell lines, MG132 proteasome inhibitor treatment, western blotting of JAK kinase levels\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function/gain-of-function with pharmacological rescue, single lab\",\n      \"pmids\": [\"14624462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Motheaten viable macrophages, adhesion/spreading assays, PI 3-kinase activity assay, PI 3-kinase inhibitor treatment\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with biochemical pathway placement and pharmacological epistasis\",\n      \"pmids\": [\"9740804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP demonstrating direct interaction, pharmacological and viral overexpression in vivo, electrophysiology\",\n      \"pmids\": [\"25790452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Conditional SHP-1 knockout (NaV1.8-Cre), electrophysiology (TRPV1 current recording), co-localization of PD-1/TRPV1/SHP-1, SHP-1 phosphorylation assays\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional KO with electrophysiological and in vivo pain phenotype, mechanistic pathway established\",\n      \"pmids\": [\"32960817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — three complementary approaches (genetic, transgenic DN, pharmacological) defining STAT3 as target\",\n      \"pmids\": [\"22438258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of β-actin and SHP-1, ARF perturbation, primary human NK cell cytotoxicity assays, conformational analysis\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus functional cytotoxicity assay, single lab, novel mechanism\",\n      \"pmids\": [\"29449322\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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).\",\n      \"method\": \"Co-immunoprecipitation, IRAK-1 kinase activity assay, KTIM motif identification and mutagenesis, SHP-1-deficient macrophage cell line\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — binding motif identified, kinase activity assay, SHP-1-deficient validation — multiple approaches\",\n      \"pmids\": [\"19104650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Motheaten viable mouse macrophages, adhesion assays, PI 3-kinase activity and lipid product measurements, PI3K inhibitor treatment\",\n      \"journal\": \"Current biology : CB\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic model plus biochemical and pharmacological pathway analysis\",\n      \"pmids\": [\"9740804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Motheaten (SHP-1-deficient) astrocytes, EMSA (GAF activity), vanadate-treated cultures, MHC class I immunostaining\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic model with signaling and transcriptional readout in neural cells\",\n      \"pmids\": [\"8943425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"SHP-1-/- macrophage cell line from motheaten mice, phosphorylation assays (JAK2, ERK1/2), NF-κB/AP-1 nuclear translocation, nitric oxide measurements\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — SHP-1-deficient cell line with biochemical pathway analysis at multiple signaling nodes\",\n      \"pmids\": [\"17057094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"GST-SH2 domain pulldown, kinase assays, motheaten viable (mev/mev) platelet analysis, SHP-1 immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — GST pulldown plus genetic model, but substrate identity not fully defined\",\n      \"pmids\": [\"10871605\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"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-\",\n      \"journal\": \"Journal of the American College of Cardiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — RNAi knockdown with biochemical pathway validation in endothelial cells\",\n      \"pmids\": [\"15893190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"Repressible/inducible SHP-1 overexpression in RAW-TT10 macrophages, LPS stimulation, Vav1 phosphorylation analysis, TNF ELISA, iNOS western blot\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — overexpression with substrate-level readout, single lab\",\n      \"pmids\": [\"16487932\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of SHP-1 and STING, ubiquitination assay (K63-linkage), STING antagonist rescue, AMPK pathway analysis, SHP-1 knockdown via lentivirus\",\n      \"journal\": \"Molecular medicine (Cambridge, Mass.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — Co-IP plus ubiquitination assay and pharmacological rescue, single lab\",\n      \"pmids\": [\"36273174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"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.\",\n      \"method\": \"SHP-1 inhibition in LSCs, PFKP overexpression/knockdown, AKT-β-catenin pathway analysis, metabolic assays, MYC stability assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined mechanism through identified intermediate (PFKP), multiple orthogonal approaches, single lab\",\n      \"pmids\": [\"38321204\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, SHP-1 exogenous expression, proliferation assay, western blot of phosphotyrosyl proteins\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 — single Co-IP, correlative dephosphorylation, no direct substrate identification\",\n      \"pmids\": [\"11516103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation, GST-SH2 domain pulldown, synthetic peptide binding, hyperphosphorylated protein detection in motheaten cells\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — binding demonstrated but substrates not fully identified; single lab, single approach\",\n      \"pmids\": [\"9573011\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPN6 (SHP-1) is an SH2 domain-containing cytoplasmic protein tyrosine phosphatase that is maintained in an autoinhibited conformation through intramolecular occlusion of its catalytic domain by the N-SH2 domain; activation occurs by phosphotyrosine-mediated displacement of this N-SH2 block (or by C-terminal Tyr536 phosphorylation by Src, phosphatidic acid binding, or THEMIS-mediated catalytic cysteine oxidation), after which SHP-1 dephosphorylates substrates including SLP-76, LAT, TRPV1, alpha-actinin, TonEBP/OREBP, and JAK/STAT components to dampen immune receptor (TCR, BCR, KIR, FcγR, cytokine receptor), integrin, growth-factor-receptor, and ion-channel signaling; its activity is further regulated by PKCα-mediated Ser591 phosphorylation (inhibitory) and reversible oxidation of its catalytic cysteine.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"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].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"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.\",\n      \"evidence\": \"SHP-1-deficient B cell lines with inhibitory receptor co-engagement functional assays\",\n      \"pmids\": [\"9244303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SHP-1 substrate(s) mediating KIR-dependent apoptosis block not identified\", \"Whether SHP-1 and SHIP cross-compensate in other cell types untested\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"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)\",\n      \"pmids\": [\"9774441\", \"9765283\", \"9740804\", \"9739453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How WPD loop dynamics differ from PTP1B in a physiological context unclear\", \"Redox regulation mechanism at the catalytic cysteine not structurally resolved\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"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.\",\n      \"evidence\": \"SIRPα phosphopeptide-bound crystal structures; phospho-ITIM agarose bead density assays with in vivo Co-IP validation\",\n      \"pmids\": [\"10660565\", \"11099496\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No full-length structure with phosphopeptide-engaged SH2 domains\", \"Quantitative affinity thresholds for in vivo recruitment not defined\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"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.\",\n      \"evidence\": \"2.8 Å crystal structure of autoinhibited SHP-1; expressed protein ligation with non-hydrolyzable phosphotyrosine mimetics at Tyr536/Tyr564\",\n      \"pmids\": [\"12482860\", \"12468540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Tyr536 phosphorylation fully displaces N-SH2 or adopts an intermediate state unknown\", \"Contribution of Tyr564/Grb2 binding to downstream signaling unclear\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"12577055\", \"12832410\", \"14699166\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP/PKC inhibitor studies in human platelets (Ser591); sequential chromatography, electrospray MS, in vitro dephosphorylation, and COS-7 triple transfection (alpha-actinin)\",\n      \"pmids\": [\"15269224\", \"15070900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether Ser591 phosphorylation alters SHP-1 conformation or protein interactions not structurally resolved\", \"Full platelet SHP-1 substrate repertoire not catalogued\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"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.\",\n      \"evidence\": \"Motheaten viable mouse model, adenoviral shRNA and dominant-negative SHP-1 in mouse liver, [125I]-insulin clearance assays\",\n      \"pmids\": [\"16617349\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"20351292\", \"16487932\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SHP-1 dephosphorylates TonEBP directly at the chromatin level unknown\", \"Vav1 dephosphorylation site by SHP-1 not mapped\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"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.\",\n      \"evidence\": \"X-ray crystallography of full-length SHP-1 in open conformation\",\n      \"pmids\": [\"21465528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Intermediate conformational states during activation not captured\", \"No structure of SHP-1 bound to a physiological phospho-ITIM peptide in the open state\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP and co-localization in DRG neurons, SHP-1 inhibitors and adenoviral overexpression in vivo, TRPV1 current measurements\",\n      \"pmids\": [\"25790452\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Specific TRPV1 phosphotyrosine site(s) dephosphorylated by SHP-1 not identified\", \"Whether SHP-1 regulates other TRP channels unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"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.\",\n      \"evidence\": \"Direct binding assays (CABIT–PTP domain), catalytic cysteine oxidation analysis, Themis−/− × SHP-1−/− double knockout genetic epistasis\",\n      \"pmids\": [\"28250424\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether THEMIS-mediated oxidation involves ROS generation or direct electron transfer unresolved\", \"Structural basis of CABIT–PTP domain interaction not determined\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"31819256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SHP-1 substrate in the RIPK1-protective pathway not identified\", \"Whether the dual mechanism operates in other myeloid cells untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"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.\",\n      \"evidence\": \"Conditional SHP-1 knockout (NaV1.8-Cre), TRPV1 electrophysiology, PD-1/SHP-1 co-localization, in vivo bone cancer pain model\",\n      \"pmids\": [\"32960817\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"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.\",\n      \"evidence\": \"Co-IP of SHP-1 and STING, K63-ubiquitination assay, STING antagonist rescue, lentiviral SHP-1 knockdown in RPE cells\",\n      \"pmids\": [\"36273174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [2, 3, 4, 5, 9, 12, 20, 21, 28, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [12, 14, 25]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9, 10, 12, 15, 18, 23, 30, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 11, 13, 14, 22, 30, 35]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [16, 23]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [13, 40]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"SLP76\",\n      \"LAT\",\n      \"VAV1\",\n      \"JAK2\",\n      \"STAT3\",\n      \"TRPV1\",\n      \"ACTN1\",\n      \"THEMIS\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}