{"gene":"PTPN6","run_date":"2026-06-10T06:43:36","timeline":{"discoveries":[{"year":1993,"finding":"The motheaten (me) and viable motheaten (mev) mutations in mice are point mutations within the Hcph (PTPN6/SHP-1) gene that cause aberrant splicing, resulting in deficient SHP-1 protein expression and activity, and severe hematopoietic defects.","method":"Western blot, activity assays, cDNA molecular analysis, DNA sequencing of genomic clones","journal":"Cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple orthogonal methods (activity assay, Western blot, sequence analysis) in a landmark study; independently replicated across the field","pmids":["8324828"],"is_preprint":false},{"year":1996,"finding":"SHP-1 binds directly to the protein tyrosine kinase ZAP-70 upon T cell activation; this interaction increases SHP-1 phosphatase activity and decreases ZAP-70 kinase activity, establishing SHP-1 as a negative regulator that sets the threshold of TCR activation.","method":"Co-immunoprecipitation, kinase activity assays, dominant-negative SHP-1 expression in T cells","journal":"Science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — reciprocal binding shown, enzymatic activity measured, dominant-negative functional validation, widely replicated","pmids":["8638162"],"is_preprint":false},{"year":1997,"finding":"SHP-1 preferentially dephosphorylates Src at its carboxyl-terminal inhibitory phosphotyrosine site, activating Src kinase; Src associates with SHP-1 and phosphorylates SHP-1 via the NH2-terminal SH2 domain interaction, demonstrating a positive regulatory role of SHP-1 on Src activity.","method":"In vitro dephosphorylation assay, co-immunoprecipitation, kinase activity assays in SHP-1-deficient motheaten thymocytes, dominant-negative SHP-1 expression","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro phosphatase assay, genetic model (motheaten mice), dominant-negative validation, multiple orthogonal methods","pmids":["9261115"],"is_preprint":false},{"year":1997,"finding":"SHP-1 and SHIP define two distinct inhibitory signaling pathways downstream of inhibitory coreceptors: FcγRIIB-class inhibitory signaling requires SHIP and not SHP-1, whereas KIR-class inhibitory signaling requires SHP-1 and not SHIP. SHP-1-mediated inhibitory signaling blocks BCR-triggered apoptosis.","method":"Generation of SHP-1- or SHIP-deficient B cell lines, functional inhibitory signaling assays, apoptosis assays","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic deletion lines with clear phenotypic readouts, pathway dissection by selective deficiency, replicated concept","pmids":["9244303"],"is_preprint":false},{"year":1997,"finding":"SHP-1 is dispensable for FcγRIIB-mediated inhibition of B cell antigen receptor (sIgM) signaling; SHIP is recruited to tyrosyl-phosphorylated FcγRIIB and mediates inhibition in the absence of SHP-1.","method":"Immortalized SHP-1-deficient (me/me) B cell lines, calcium influx assays, co-immunoprecipitation of SHIP","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — negative finding established by genetic SHP-1 deficiency with functional assay; replicates and complements PMID 9244303","pmids":["9242674"],"is_preprint":false},{"year":1998,"finding":"SHP-1 is responsible for JAK2 dephosphorylation and termination of angiotensin II-induced JAK/STAT cascade in vascular smooth muscle cells, while SHP-2 has an opposing role in initiating JAK2 phosphorylation; SHP-1 forms complexes with JAK2.","method":"Electroporation with neutralizing antibodies, time-course co-immunoprecipitation, JAK2 kinase activity assays","journal":"The American journal of physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — single lab, antibody neutralization and co-IP, functional readout but limited orthogonal validation","pmids":["9814969"],"is_preprint":false},{"year":1998,"finding":"SHP-1 phosphatase activity is reversibly inactivated by oxidation (H2O2); activity can be restored by dithiothreitol, glutathione, or N-acetylcysteine, establishing redox regulation as a mechanism controlling SHP-1 activity.","method":"In vitro H2O2 inactivation assay, reactivation with reducing agents, H2O2-stimulated SHP-1-transfected HeLa cells","journal":"Biochemistry and molecular biology international","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro enzymatic assay with clear mechanistic result, single lab, limited orthogonal validation","pmids":["9739453"],"is_preprint":false},{"year":1999,"finding":"SHP-1 co-immunoprecipitates with the p85 regulatory subunit of PI3K in T cells; this association increases upon TCR ligation and requires Lck-phosphorylated Tyr564 on SHP-1. Wild-type SHP-1 (but not catalytically inactive mutant) dephosphorylates p85 and reduces PI3K activity and downstream Akt phosphorylation.","method":"Co-immunoprecipitation, co-expression with constitutively active Lck in COS7 cells, PI3K enzyme activity assay, phospho-Akt Western blot","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — multiple orthogonal methods (co-IP, enzymatic assay, catalytically inactive mutant), single lab","pmids":["10488096"],"is_preprint":false},{"year":1999,"finding":"SHP-1 is constitutively associated with JAK2 in pituitary AtT-20 cells; LIF induces recruitment of phosphorylated STAT3 to this SHP-1/JAK2 complex. SHP-1 dephosphorylates JAK2 and STAT3 to attenuate LIF-induced POMC promoter activity, as shown by wild-type vs. dominant-negative SHP-1 overexpression.","method":"Co-immunoprecipitation, dominant-negative and wild-type SHP-1 overexpression, POMC luciferase reporter, phospho-JAK2/STAT3 Western blot","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP showing constitutive complex, dominant-negative and wild-type rescue, functional promoter assay; single lab but multiple orthogonal methods","pmids":["10545526"],"is_preprint":false},{"year":1999,"finding":"Membrane-associated SHP-1 is required for receptor-mediated intracellular acidification and apoptosis in breast cancer cells (initiated by somatostatin receptor activation and Fas ligation); catalytically inactive SHP-1 (C455S) acts as dominant negative, blocking recruitment of wild-type SHP-1 to the membrane and preventing apoptosis.","method":"Ectopic SHP-1 expression, catalytically inactive mutant (C455S), SST agonist and Fas ligation assays, pH measurement, apoptosis assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — catalytic mutant and WT rescue with functional apoptosis readout, single lab","pmids":["10506221"],"is_preprint":false},{"year":1999,"finding":"SHP-1 dephosphorylates and associates with p62(DOK) in macrophages; p62(DOK) is constitutively associated with SHP-1 and is constitutively hyperphosphorylated in SHP-1-deficient (motheaten) macrophages, correlating with growth factor-independent survival.","method":"Co-immunoprecipitation, Far Western analysis, comparison of wild-type vs. me/me motheaten macrophages, SHP-1 C453S catalytically inactive mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP, genetic model, catalytic mutant, Far Western; single lab with multiple orthogonal methods","pmids":["10585470"],"is_preprint":false},{"year":2000,"finding":"Crystal structure of the SHP-1 catalytic domain complexed with SIRPα-derived peptide substrates reveals that the variable β5-loop-β6 motif confers substrate specificity at P-4 and further N-terminal subpockets, and identifies a novel residue shift at P-2.","method":"X-ray crystallography of catalytic domain–peptide substrate complexes","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with bound peptide substrates providing atomic-level mechanistic detail","pmids":["10660565"],"is_preprint":false},{"year":2000,"finding":"SHP-1 binds to and dephosphorylates p120 catenin (3A isoform) in EGF-stimulated cells; binding is mediated primarily by the N-terminal SH2 domain of SHP-1; tetracycline-mediated decrease of SHP-1 expression elevates p120 catenin phosphorylation.","method":"GST-SHP-1 pulldown, co-immunoprecipitation, mass spectrometry identification of p120ctn, tetracycline-regulated SHP-1 expression","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown, co-IP, and regulated expression system; single lab","pmids":["10835420"],"is_preprint":false},{"year":2000,"finding":"SHP-1 deficiency in macrophages leads to enhanced αmβ2 integrin-mediated adhesion/spreading and a 10–15-fold increase in D-3 phospholipid products of PI3-kinase, with 2–5-fold increased membrane-associated PI3-kinase activity; PI3-kinase inhibitors cause detachment, placing SHP-1 upstream of PI3-kinase in integrin adhesion regulation.","method":"Comparison of mev/mev vs. wild-type macrophages, PI3-kinase activity and lipid product assays, PI3-kinase inhibitors (wortmannin, LY294002)","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic model combined with pharmacological epistasis and biochemical measurement; single lab with multiple orthogonal methods","pmids":["9740804"],"is_preprint":false},{"year":2001,"finding":"SHP-1 is constitutively associated with and activated by the ITIM-containing receptor LAIR-1 at the plasma membrane in resting human T cells (both Jurkat and primary), as identified by yeast tri-hybrid screen and confirmed by co-immunoprecipitation of membrane-enriched fractions.","method":"Yeast tri-hybrid screen, co-immunoprecipitation from membrane-enriched fractions, SHP-1 activity assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — orthogonal identification method (tri-hybrid) confirmed by co-IP and activity assay; shown in both cell line and primary T cells","pmids":["11160222"],"is_preprint":false},{"year":2001,"finding":"Targeting activated SHP-1 to lipid rafts in T cells inhibits TCR-mediated signaling by causing rapid dephosphorylation of LAT (linker for activation of T cells), while leaving Lck kinase activity and TCR-ζ/ZAP-70 phosphorylation intact; endogenous SHP-1 is recruited to rafts and associates with LAT upon TCR engagement.","method":"Chimeric raft-targeting SHP-1 construct expressed in Jurkat cells, CD69 expression, signaling pathway analysis, co-immunoprecipitation of endogenous SHP-1 with LAT","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — engineered localization approach with specific substrate identification (LAT), functional and biochemical readouts; single lab","pmids":["11420038"],"is_preprint":false},{"year":2002,"finding":"Crystal structure of C-terminally truncated human SHP-1 at 2.8 Å resolution reveals an auto-inhibited conformation in which the N-SH2 domain blocks the catalytic domain active site, demonstrating that SHP-1 phosphatase activity is primarily regulated by intramolecular N-SH2 domain occlusion.","method":"X-ray crystallography","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure providing direct structural evidence for autoinhibitory mechanism","pmids":["12482860"],"is_preprint":false},{"year":2002,"finding":"Death receptors (TNF/NGF family) contain a conserved phosphotyrosine motif in their death domain that recruits SHP-1 (and SHP-2/SHIP) in a caspase-independent, cell-dependent manner; in neutrophils, SHP-1 recruited via this motif inactivates the anti-apoptotic kinase Lyn, preventing cytokine-induced survival signaling.","method":"Co-immunoprecipitation, phosphotyrosine motif mapping, Lyn kinase activity assay in neutrophils","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP with motif mapping, kinase activity assay with functional consequence; single lab","pmids":["11786908"],"is_preprint":false},{"year":2002,"finding":"SHP-1 associates with CBL in macrophages upon FcγR engagement; wild-type but not catalytically inactive SHP-1 overexpression dephosphorylates CBL, disrupts the CBL-CRKL interaction, suppresses RAC activation, and completely abrogates phagocytosis of IgG-sensitized targets.","method":"Heterologous expression of wild-type vs. catalytically inactive SHP-1, co-immunoprecipitation, RAC activation assay, phagocytosis assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — catalytic mutant compared to WT with co-IP substrate identification and functional phagocytosis readout; single lab","pmids":["12176909"],"is_preprint":false},{"year":2003,"finding":"SHP-1 forms complexes with TrkA at Y490 and dephosphorylates TrkA at Y674/675; SHP-1 expression in sympathetic neurons induces apoptosis and TrkA dephosphorylation, while dominant-inhibitory SHP-1 promotes NGF-independent survival; SHP-1-deficient mice have increased sympathetic neuron numbers during developmental cell death.","method":"Co-immunoprecipitation with phosphosite mapping, dominant-inhibitory SHP-1 expression, neuron survival assays, SHP-1-deficient motheaten mice","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP with phosphosite mapping, dominant-inhibitory and genetic model, in vitro and in vivo readouts; single lab with multiple orthogonal methods","pmids":["14662744"],"is_preprint":false},{"year":2003,"finding":"SHP-1 transfection inhibits growth of lymphoma/leukemia and breast cancer cell lines, and SHP-1 down-regulates activated JAK kinase levels partly by accelerating TYK2 and JAK1 degradation via the proteasome-mediated pathway (blocked by MG132).","method":"SHP-1 transfection, cell growth assays, Western blot for JAK1/TYK2, proteasome inhibitor MG132","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — functional transfection with proteasome inhibitor epistasis; single lab, limited mechanistic depth","pmids":["14624462"],"is_preprint":false},{"year":2004,"finding":"SHP-1 dephosphorylates α-actinin in vitro and in vivo; it was purified from platelet lysates and identified by mass spectrometry as a 68 kDa phosphatase of α-actinin; co-transfection of SHP-1 with FAK and α-actinin abolishes α-actinin phosphorylation without substantially affecting FAK phosphorylation.","method":"Sequential chromatography purification, electrospray tandem mass spectrometry identification, in vitro dephosphorylation assay, co-transfection in COS-7 cells, catalytic mutant (C453S)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — biochemical purification + MS identification + in vitro reconstitution + cellular validation with catalytic mutant; single lab","pmids":["15070900"],"is_preprint":false},{"year":2006,"finding":"SHP-1 deficiency (viable motheaten mice) results in markedly enhanced insulin receptor signaling via IRS-PI3K-Akt in liver and muscle; SHP-1 directly modulates hepatic insulin clearance by regulating CEACAM1 tyrosine phosphorylation. Adenoviral dominant-negative or shRNA-mediated SHP-1 silencing in liver recapitulates improved insulin sensitivity.","method":"Viable motheaten mice, adenoviral expression of catalytically inert SHP-1, shRNA knockdown, insulin signaling Western blots (IRS-PI3K-Akt), [125I]-insulin clearance assay, CEACAM1 phosphorylation in vitro","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model confirmed by two independent in vivo interventions (dominant-negative adenovirus and shRNA), in vitro substrate evidence; multiple orthogonal methods","pmids":["16617349"],"is_preprint":false},{"year":2006,"finding":"Leishmania donovani-activated SHP-1 inhibits IFN-γ-dependent nitric oxide production in macrophages by inactivating JAK2 and ERK1/2 and preventing nuclear translocation of NF-κB and AP-1; SHP-1-deficient macrophages fail to suppress nitric oxide in response to Leishmania.","method":"SHP-1-/- macrophage cell line (motheaten-derived), JAK2/ERK1/2 phosphorylation assay, nuclear translocation assays for NF-κB/AP-1, nitric oxide production assay","journal":"Infection and immunity","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic null cell line with multiple signaling readouts; single lab with orthogonal methods","pmids":["17057094"],"is_preprint":false},{"year":2007,"finding":"FCRL5 inhibits BCR signaling by dual ITIM-dependent recruitment of SHP-1, which dephosphorylates the ITAM-based tyrosines in BCR Igα/Igβ heterodimers; ITIM tyrosine mutations abolish this effect.","method":"FCRL5-FcγRIIB chimeric construct expression in B cell line, ITIM mutational analysis, calcium mobilization assay, SHP-1 co-immunoprecipitation","journal":"Proceedings of the National Academy of Sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — mutational dissection of ITIMs, SHP-1 recruitment shown by co-IP, functional calcium assay; single lab","pmids":["17522256"],"is_preprint":false},{"year":2007,"finding":"PU.1, an Ets family transcription factor, directly binds the hematopoietic cell-specific P2 promoter of the SHP-1 gene and activates its transcription; siRNA-mediated depletion of PU.1 profoundly suppresses SHP-1 gene transcription.","method":"Luciferase reporter assays, EMSA (in vitro binding), ChIP (in vivo binding), PU.1 siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Moderate — in vitro and in vivo DNA binding confirmed, functional reporter and knockdown; single lab with multiple orthogonal methods","pmids":["17218319"],"is_preprint":false},{"year":2008,"finding":"Leishmania activates SHP-1 to directly inactivate IRAK-1 kinase activity by binding via an evolutionarily conserved ITIM-like motif (KTIM) in the kinase domain of IRAK-1; SHP-1 also interacts with ERK1/2 and IKKα/β via similar KTIM motifs.","method":"Co-immunoprecipitation of SHP-1 with IRAK-1, IRAK-1 kinase activity assay, KTIM motif mutational analysis, Leishmania infection model","journal":"PLoS neglected tropical diseases","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP with kinase activity assay, motif mutation, functional pathogen model; single lab","pmids":["19104650"],"is_preprint":false},{"year":2010,"finding":"SHP-1 phosphorylation at Tyr536 and Tyr564 by Lyn kinase is required for maximal SHP-1 phosphatase activity; Tyr564 phosphorylation by Lyn is indispensable for suppression of Stat5 activity and prevention of CMML-like myeloproliferative disease; Tyr536 is required for efficient SHP-1 interaction with Stat5. PLC-β3 acts upstream of this Lyn/SHP-1 regulatory axis.","method":"Lyn/PLC-β3 double-knockout mice, phosphorylation-defective SHP-1 mutants (Y536F, Y564F), SHP-1 activity assay, co-immunoprecipitation, Stat5 activity assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model, phosphosite mutants, enzymatic assay, binding assay; multiple orthogonal methods in one rigorous study","pmids":["20858858"],"is_preprint":false},{"year":2011,"finding":"Combinatorial peptide library screening established that SHP-1 has narrow substrate specificity with strong preference for acidic and aromatic hydrophobic residues on both sides of pY, requiring acidic residues at pY-1 and pY+1 and no basic residues; this intrinsic specificity correlates well with known in vivo substrates.","method":"On-bead combinatorial peptide library screening, solution-phase kinetic analysis of individually synthesized phosphotyrosyl peptides","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — rigorous in vitro biochemical reconstitution with quantitative kinetics; single lab but comprehensive peptide library approach","pmids":["21291263"],"is_preprint":false},{"year":2011,"finding":"Crystal structure of full-length SHP-1 at 3.1 Å reveals an open conformation in which the N-SH2 domain is shifted away from the active site, exposing the catalytic pocket; the C-SH2 domain is twisted ~110° relative to the autoinhibited structure; new interdomain interactions stabilize the open conformation.","method":"X-ray crystallography of full-length SHP-1","journal":"Journal of cellular biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — crystal structure providing direct visualization of open/active conformation; single lab but rigorous structural method","pmids":["21465528"],"is_preprint":false},{"year":2012,"finding":"SHP-1 is recruited to phagosomes early after phagocytosis and remains present for up to 4 h; loss of SHP-1 impairs phagosome acidification and prevents processing of procathepsin D (51 kDa) to cathepsin D (46 kDa) and reduces LAMP-1 recruitment, demonstrating a role for SHP-1 in phagolysosome biogenesis.","method":"Confocal immunofluorescence microscopy, Western blot on purified phagosome extracts, LysoTracker pH indicator, SHP-1-deficient motheaten macrophages","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — direct phagosome localization, genetic null model, biochemical phagosome fractionation, functional acidification assay; single lab with multiple orthogonal methods","pmids":["22826316"],"is_preprint":false},{"year":2012,"finding":"FcγRIII on neutrophils recruits SHP-1 upon IVIG engagement to mediate inhibition of neutrophil adhesion and activation; this inhibitory signaling is abrogated in SHP-1-mutant mice, demonstrating an unexpected inhibitory role for the classic activating receptor FcγRIII via SHP-1.","method":"Intravital microscopy, FcγRIII/FcγRIIB-deficient mice, SHP-1-mutant mice, co-immunoprecipitation","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — multiple genetic models, direct in vivo imaging, co-IP; single lab","pmids":["22415018"],"is_preprint":false},{"year":2013,"finding":"SHP-1 decreases STAT3 phosphorylation in CD4+ T cells in response to IL-6 and IL-21; genetic deletion, transgenic dominant-negative, or pharmacologic inhibition of SHP-1 strongly promotes Th17 development, identifying SHP-1 as a negative regulator of STAT3-driven Th17 differentiation.","method":"T cell-specific SHP-1 knockout, inducible dominant-negative SHP-1 transgenic mice, pharmacologic SHP-1 inhibition, Th17 skewing assays, STAT3 phosphorylation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — three complementary genetic/pharmacologic approaches with consistent STAT3 mechanistic readout; single lab but highly rigorous","pmids":["22438258"],"is_preprint":false},{"year":2014,"finding":"Regorafenib activates SHP-1 by directly disrupting the autoinhibitory association between the N-SH2 and catalytic PTP domain of SHP-1; deletion of N-SH2 (dN1) or D61A point mutation blocks regorafenib-induced SHP-1 activation and STAT3(Tyr705) dephosphorylation.","method":"SHP-1 activity assay, N-SH2 deletion and D61A point mutation constructs, Western blot for p-STAT3, xenograft tumor model","journal":"Oncotarget","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — enzymatic activity assay combined with domain deletion and point mutagenesis; in vivo confirmation; single lab","pmids":["25071018"],"is_preprint":false},{"year":2015,"finding":"SHP-1 is recruited to and dephosphorylates Cbl-b upon TCR stimulation; loss of SHP-1 in T cells leads to increased Cbl-b tyrosine phosphorylation, ubiquitination, and degradation. CD28 costimulation abrogates SHP-1/Cbl-b interaction, linking this mechanism to T cell activation control.","method":"Co-immunoprecipitation of SHP-1 with Cbl-b, phosphorylation and ubiquitination Western blots, T cell-specific Shp1-/- mice, Cbl-b overexpression rescue","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP, genetic null model, rescue by Cbl-b overexpression, multiple orthogonal methods; single lab","pmids":["26416283"],"is_preprint":false},{"year":2015,"finding":"SHP-1 co-localizes with and binds to TRPV1 in DRG nociceptive neurons and dephosphorylates TRPV1, reducing channel activity; pharmacological inhibition of SHP-1 sensitizes TRPV1 and induces thermal hyperalgesia in vivo.","method":"Co-immunoprecipitation of SHP-1 with TRPV1, whole-cell patch clamp of DRG neurons, intrathecal SHP-1 inhibitor injection, SHP-1 overexpression in DRG neurons","journal":"Pain","confidence":"High","confidence_rationale":"Tier 2 / Moderate — co-IP substrate identification, direct electrophysiology, pharmacological and genetic in vivo validation; single lab","pmids":["25790452"],"is_preprint":false},{"year":2015,"finding":"SHP-1 phosphatase activity (requiring N-SH2 domain and catalytic activity via D61A-constitutively-open mutant) directly dephosphorylates STAT3 at Tyr705 to suppress TGF-β1-induced epithelial-mesenchymal transition in hepatocellular carcinoma cells.","method":"SHP-1 overexpression/knockdown, constitutively open (D61A) and catalytic dead (C453S) SHP-1 mutants, TGF-β1 stimulation, p-STAT3 Western blot, migration/invasion assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — domain and catalytic mutants with functional EMT readout and STAT3 mechanistic link; single lab with multiple constructs","pmids":["25619838"],"is_preprint":false},{"year":2016,"finding":"Protein kinase D (PKD) phosphorylates SHP-1 directly; substitution of wild-type SHP-1 with phosphorylation-defective mutant SHP-1 S557A impairs CD4+ thymocyte generation, placing the PKD–SHP-1 axis as a positive regulator of TCR signaling during positive selection.","method":"PKD2/PKD3 double-deficient mice, phosphoproteomic substrate identification of SHP-1, SHP-1 S557A knock-in, T cell development analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — phosphoproteomic identification confirmed by genetic phospho-mutant knock-in with clear developmental phenotype; single lab but rigorous multi-method approach","pmids":["27670070"],"is_preprint":false},{"year":2018,"finding":"SHP-1 interacts with the ITIM on TGF-β receptor 1 and is required for TGF-β signaling activation in hematopoietic stem cells (HSCs); Shp-1 knockout HSCs fail to respond to TGF-β-enforced quiescence, demonstrating SHP-1 as a positive mediator of TGF-β–driven HSC quiescence.","method":"Shp-1 knockout mice, co-immunoprecipitation of SHP-1 with TGFβR1, in vitro and in vivo HSC quiescence/TGF-β response assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic null model, co-IP with receptor, in vitro and in vivo functional readouts; single lab","pmids":["29669741"],"is_preprint":false},{"year":2018,"finding":"SHP-1 inhibits JAK/STAT, NF-κB, and AKT (but not MAPK) signaling in hepatocytes and HCC cells; hepatocyte-specific Ptpn6 knockout enhances DEN-induced hepatocarcinogenesis and liver cancer metastasis in mice.","method":"Conditional Ptpn6 knockout in hepatocytes, adenoviral SHP-1 delivery, signaling pathway Western blots, DEN-induced tumor model, orthotopic HCC model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional knockout and adenoviral rescue in two in vivo models with pathway-specific mechanistic readouts; single lab with multiple orthogonal approaches","pmids":["29776962"],"is_preprint":false},{"year":2019,"finding":"Ptpn6 in neutrophils negatively regulates p38 MAPK-dependent production of TNF and IL-1α/β, and maintains Ripk1 function to prevent caspase-8- and Ripk3/Mlkl-dependent cell death and IL-1α/β release; combined deletion of caspase-8 and Ripk3 or Mlkl strongly protects Ptpn6-deficient neutrophils from inflammatory disease.","method":"Conditional Ptpn6 deletion in neutrophils, genetic deletion of Ripk1, Ripk3, Mlkl, caspase-8 in Ptpn6ΔPMN background, p38 MAPK activity assay, IL-1 and TNF measurement","journal":"Nature immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic epistasis crosses with defined pathway readouts; rigorous multi-deletion study","pmids":["31819256"],"is_preprint":false},{"year":2020,"finding":"PD-L1 activates SHP-1 in DRG TRPV1+ nociceptive neurons; SHP-1 inhibits TRPV1 currents and bone cancer pain. Conditional deletion of SHP-1 in NaV1.8+ neurons aggravates bone cancer pain and abolishes PD-L1-mediated inhibition of TRPV1 currents.","method":"Conditional SHP-1 deletion in NaV1.8+ neurons, patch-clamp recording of TRPV1 currents, PD-L1 injection, bone cancer pain behavioral assay, PD-1/TRPV1/SHP-1 co-localization","journal":"JCI insight","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout with electrophysiology and behavioral readouts; single lab with multiple orthogonal methods","pmids":["32960817"],"is_preprint":false},{"year":2020,"finding":"DJ-1 facilitates the interaction between SHP-1 and TRAF6 in astrocytes during cerebral ischemia/reperfusion; SHP-1/TRAF6 interaction promotes dissociation of NLRX1 from TRAF6 and reduces inflammatory cytokine production; a SHP-1 inhibitor blocks this DJ-1-dependent anti-inflammatory effect.","method":"Co-immunoprecipitation of SHP-1 with TRAF6 and NLRX1, DJ-1 knockdown/overexpression, SHP-1 inhibitor, OGD/R and MCAO/R models","journal":"Journal of neuroinflammation","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP and pharmacological inhibition with functional readout; single lab, limited mechanistic depth for SHP-1 catalytic role","pmids":["32151250"],"is_preprint":false},{"year":2022,"finding":"SKAP2 forms a complex with Sirpα and SHP-1 and recruits the Sirpα/SHP-1 complex to TLR4 to attenuate NF-κB inflammatory signaling; SKAP2 also directly associates with MyD88/TIRAP/TRAM adaptors of TLR4.","method":"Co-immunoprecipitation of SKAP2-Sirpα-SHP-1 complex, SKAP2 knockout mice, NF-κB activity assays, LPS stimulation model","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP complex and genetic knockout with signaling readout; single lab, limited direct SHP-1 enzymatic evidence","pmids":["35034964"],"is_preprint":false},{"year":2022,"finding":"SHP-1 interacts with ER-resident STING and suppresses K63-linked ubiquitination and activation of STING; SHP-1 knockdown leads to STING overactivation, which inhibits AMPK and represses mitochondrial biogenesis in RPE cells.","method":"Immunoprecipitation to detect SHP-1-STING interaction and STING ubiquitination, STING-specific antagonist H151, SHP-1 lentiviral knockdown, AMPK/mitochondrial biogenesis assays","journal":"Molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — co-IP with ubiquitination assay and pharmacological epistasis; single lab, single study","pmids":["36273174"],"is_preprint":false},{"year":2023,"finding":"SHP-1 reduces SUMO2 post-translational modification of podocin; podocyte-specific SHP-1 deletion preserves slit diaphragm protein complexes and prevents diabetes-induced podocyte loss and diabetic kidney disease progression, revealing a role for SHP-1 in regulating cytoskeleton dynamics and slit diaphragm stability.","method":"Conditional podocyte-specific Ptpn6 knockout mice, mass spectrometry SUMOylation analysis, albumin/creatinine ratio, glomerular morphology, Western blots for slit diaphragm proteins","journal":"Kidney international","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional knockout with mass spectrometry substrate identification and in vivo functional phenotype; single lab with multiple orthogonal methods","pmids":["37507049"],"is_preprint":false},{"year":2024,"finding":"SHP-1 inhibition in leukemia stem cells upregulates PFKP via the AKT–β-catenin pathway, increasing glycolysis and oxidative phosphorylation; elevated PFKP also promotes MYC degradation, reducing immune evasion. This dual mechanism enhances chemosensitivity and immunosurveillance of LSCs.","method":"SHP-1 inhibition in LSCs, AKT-β-catenin pathway analysis, PFKP expression assays, MYC degradation assay, metabolic activity assays, in vivo AML models","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — pathway dissection with multiple mechanistic readouts and in vivo validation; single lab but comprehensive approach","pmids":["38321204"],"is_preprint":false}],"current_model":"PTPN6/SHP-1 is a cytoplasmic non-receptor protein tyrosine phosphatase held in an autoinhibited conformation by intramolecular N-SH2 domain occlusion of the active site (crystal structures); it is activated by engagement of its SH2 domains with phosphotyrosine-containing ITIM receptors (LAIR-1, KIRs, inhibitory death receptors) or by phosphorylation at Tyr536/Tyr564 by Lyn and by PKD at Ser557, and reversibly inactivated by oxidation; once active, SHP-1 dephosphorylates a broad set of substrates including ZAP-70, LAT, Src, JAK2, STAT3, TrkA, TRPV1, Cbl-b, p62(DOK), α-actinin, IRAK-1, CBL, p85-PI3K, CEACAM1, and podocin, thereby acting as a central negative regulator of immune receptor, cytokine, growth factor, and integrin signaling in hematopoietic and non-hematopoietic cells, with loss-of-function causing the motheaten inflammatory/autoimmune phenotype in mice."},"narrative":{"mechanistic_narrative":"PTPN6/SHP-1 is a cytoplasmic non-receptor protein tyrosine phosphatase that functions as a central negative regulator of immune receptor, cytokine, growth factor, and integrin signaling, with loss of expression causing the severe hematopoietic and autoimmune phenotype of motheaten mice [PMID:8324828, PMID:8638162]. Its activity is governed by an autoinhibitory mechanism in which the N-SH2 domain occludes the catalytic active site (crystal structure), and engagement of the SH2 domains shifts the enzyme to an open, active conformation that exposes the catalytic pocket [PMID:12482860, PMID:21465528]. Activation is achieved physiologically through recruitment to phosphotyrosine-bearing ITIM receptors such as LAIR-1, FCRL5, and FcγRIII, and through phosphorylation: Lyn phosphorylates Tyr536/Tyr564 to enable maximal activity and Stat5 interaction, while PKD phosphorylates Ser557 to promote TCR signaling during positive selection; its activity is additionally subject to reversible redox inactivation by H2O2 [PMID:11160222, PMID:17522256, PMID:22415018, PMID:20858858, PMID:27670070, PMID:9739453]. SHP-1 has narrow substrate specificity favoring acidic and aromatic residues flanking the phosphotyrosine [PMID:21291263, PMID:10660565]. Once active it dephosphorylates a broad set of substrates to dampen signaling, including ZAP-70 and LAT in TCR signaling, JAK2 and STAT3 in cytokine pathways, p85-PI3K, Cbl-b, CBL, p62(DOK), TrkA, TRPV1, α-actinin, and CEACAM1, thereby setting activation thresholds and controlling apoptosis, phagocytosis, integrin adhesion, and insulin sensitivity [PMID:8638162, PMID:11420038, PMID:9814969, PMID:10545526, PMID:10488096, PMID:26416283, PMID:12176909, PMID:14662744, PMID:25790452, PMID:15070900, PMID:16617349]. In neutrophils SHP-1 also restrains p38 MAPK-driven cytokine production and maintains Ripk1 function to prevent inflammatory cell death [PMID:31819256]. Through suppression of JAK/STAT, NF-κB, and AKT signaling, SHP-1 acts as a tumor suppressor in hepatocellular carcinoma and modulates leukemia stem cell metabolism and immune evasion [PMID:29776962, PMID:38321204].","teleology":[{"year":1993,"claim":"Established the causal link between PTPN6/SHP-1 loss and disease by showing that motheaten mutations disrupt the gene and abolish phosphatase expression, defining SHP-1 as essential for normal hematopoiesis.","evidence":"DNA sequencing, Western blot, and activity assays on motheaten (me/mev) mouse genomic clones","pmids":["8324828"],"confidence":"High","gaps":["Did not define molecular substrates","Did not establish the biochemical mechanism of regulation"]},{"year":1996,"claim":"Defined SHP-1 as a negative regulator of antigen receptor signaling by demonstrating it binds and dephosphorylates ZAP-70 to raise the TCR activation threshold.","evidence":"Co-IP, kinase activity assays, and dominant-negative SHP-1 expression in T cells","pmids":["8638162"],"confidence":"High","gaps":["Did not address upstream receptors recruiting SHP-1","Mechanism of activation unresolved"]},{"year":1997,"claim":"Showed SHP-1 acts within distinct inhibitory coreceptor pathways and can also positively regulate Src, revealing context-dependent positive and negative roles.","evidence":"SHP-1/SHIP-deficient B cell lines and apoptosis assays; in vitro Src dephosphorylation in motheaten thymocytes","pmids":["9244303","9242674","9261115"],"confidence":"High","gaps":["Did not reconcile how the same enzyme can be inhibitory or activating in different contexts","Substrate selection determinants unknown"]},{"year":1998,"claim":"Identified cytokine-pathway substrates and a redox switch, showing SHP-1 terminates JAK2/STAT signaling and is reversibly inactivated by oxidation.","evidence":"Neutralizing antibody electroporation and JAK2 co-IP/activity assays; in vitro H2O2 inactivation and reducing-agent reactivation","pmids":["9814969","9739453"],"confidence":"Medium","gaps":["JAK2 finding from single lab with limited orthogonal validation","Physiological relevance of redox regulation in vivo not established"]},{"year":1999,"claim":"Expanded the substrate repertoire to PI3K signaling, apoptosis, and growth control by identifying p85-PI3K, p62(DOK), and JAK2/STAT3 as targets and demonstrating membrane recruitment is required for apoptosis.","evidence":"Co-IP, catalytically inactive mutants, PI3K activity and apoptosis assays; motheaten macrophages; POMC reporter in AtT-20 cells","pmids":["10488096","10545526","10506221","10585470","9740804"],"confidence":"High","gaps":["Direct versus indirect dephosphorylation not always distinguished","Spatial regulation of recruitment incompletely defined"]},{"year":2000,"claim":"Provided the first atomic-level view of substrate recognition and added p120 catenin as a substrate, defining the structural basis of specificity.","evidence":"X-ray crystallography of the catalytic domain with SIRPα peptides; GST pulldown, co-IP and MS for p120 catenin","pmids":["10660565","10835420"],"confidence":"High","gaps":["Full-length autoinhibition mechanism not yet visualized","p120 catenin functional consequence single-lab"]},{"year":2001,"claim":"Linked receptor recruitment to substrate dephosphorylation by showing ITIM receptor LAIR-1 binds and activates SHP-1, and raft-targeted SHP-1 selectively dephosphorylates LAT.","evidence":"Yeast tri-hybrid, membrane co-IP and activity assays; chimeric raft-targeting SHP-1 in Jurkat cells","pmids":["11160222","11420038"],"confidence":"High","gaps":["How substrate selectivity (LAT vs ZAP-70) is achieved spatially not fully resolved"]},{"year":2002,"claim":"Defined the master regulatory mechanism: the N-SH2 domain autoinhibits the active site, and death-receptor phosphotyrosine motifs recruit SHP-1 to control survival.","evidence":"X-ray crystallography of truncated SHP-1; phosphomotif mapping, co-IP and Lyn kinase assay in neutrophils","pmids":["12482860","11786908"],"confidence":"High","gaps":["The active open conformation was not yet structurally captured","Conformational transition kinetics unknown"]},{"year":2003,"claim":"Extended SHP-1 function into neuronal apoptosis and tumor suppression, identifying TrkA as a substrate and proteasomal JAK degradation as a downstream consequence.","evidence":"Co-IP with phosphosite mapping and motheaten mice for TrkA; SHP-1 transfection with MG132 for JAK degradation","pmids":["14662744","14624462"],"confidence":"High","gaps":["JAK degradation study lower mechanistic depth (Medium)","Direct versus indirect routes to JAK turnover unclear"]},{"year":2004,"claim":"Demonstrated a cytoskeletal substrate by purifying SHP-1 as the α-actinin phosphatase, broadening its role into structural protein regulation.","evidence":"Chromatographic purification, MS identification, in vitro dephosphorylation, COS-7 co-transfection with catalytic mutant","pmids":["15070900"],"confidence":"High","gaps":["Physiological setting of α-actinin dephosphorylation not defined in vivo"]},{"year":2006,"claim":"Established SHP-1 as a metabolic and inflammatory regulator, controlling insulin receptor/CEACAM1 signaling and macrophage antimicrobial responses.","evidence":"Viable motheaten mice with dominant-negative adenovirus and shRNA; insulin clearance and signaling assays; motheaten macrophage NO suppression by Leishmania","pmids":["16617349","17057094"],"confidence":"High","gaps":["Tissue-specific contributions to insulin sensitivity not fully dissected","Pathogen-driven SHP-1 activation mechanism incompletely defined"]},{"year":2007,"claim":"Connected SHP-1 to transcriptional control of its own expression and to additional ITIM receptors, mapping how SHP-1 abundance and recruitment are governed.","evidence":"Reporter, EMSA, ChIP and siRNA for PU.1; FCRL5-ITIM mutational analysis and calcium assays","pmids":["17218319","17522256"],"confidence":"High","gaps":["Other transcriptional regulators of PTPN6 not addressed"]},{"year":2010,"claim":"Resolved an activation mechanism by showing Lyn-mediated Tyr536/Tyr564 phosphorylation is required for maximal activity and Stat5 suppression, preventing myeloproliferative disease.","evidence":"Lyn/PLC-β3 knockout mice, Y536F/Y564F mutants, activity and Stat5 assays","pmids":["20858858"],"confidence":"High","gaps":["Interplay between tyrosine phosphorylation and SH2-mediated activation not fully integrated"]},{"year":2011,"claim":"Quantified intrinsic substrate specificity and captured the open active conformation, completing the structural model of conformational activation.","evidence":"Combinatorial peptide library kinetics; X-ray crystallography of full-length open SHP-1","pmids":["21291263","21465528"],"confidence":"High","gaps":["How specific receptors trigger the autoinhibited-to-open transition in cells not directly shown"]},{"year":2012,"claim":"Demonstrated direct roles in phagosome maturation and revealed inhibitory signaling through the classic activating receptor FcγRIII.","evidence":"Confocal microscopy and phagosome fractionation in motheaten macrophages; intravital microscopy and FcγRIII/FcγRIIB-deficient mice","pmids":["22826316","22415018"],"confidence":"High","gaps":["Substrates mediating phagolysosome biogenesis not identified","Mechanism of FcγRIII-SHP-1 coupling incompletely defined"]},{"year":2013,"claim":"Defined SHP-1 as a negative regulator of STAT3-driven Th17 differentiation, linking it to adaptive immune polarization.","evidence":"T cell-specific knockout, dominant-negative transgenic, pharmacologic inhibition, Th17 and STAT3 assays","pmids":["22438258"],"confidence":"High","gaps":["Direct STAT3 dephosphorylation versus upstream effects in this context not fully separated"]},{"year":2015,"claim":"Added Cbl-b, TRPV1, and STAT3 as substrates across immune, sensory, and cancer contexts, and showed the open/catalytic mutant directly dephosphorylates STAT3.","evidence":"Co-IP and Shp1-/- mice for Cbl-b; patch clamp and in vivo inhibition for TRPV1; D61A/C453S mutants in HCC EMT assays","pmids":["26416283","25790452","25619838"],"confidence":"High","gaps":["In vivo substrate selectivity determinants across tissues not resolved"]},{"year":2016,"claim":"Identified a positive regulatory phosphorylation by PKD at Ser557 required for TCR-driven thymocyte development, broadening SHP-1 regulation beyond tyrosine phosphorylation.","evidence":"PKD2/PKD3 double-deficient mice, phosphoproteomics, S557A knock-in, T cell development analysis","pmids":["27670070"],"confidence":"High","gaps":["How Ser557 phosphorylation alters conformation or activity mechanistically not defined"]},{"year":2018,"claim":"Revealed positive (signal-promoting) roles for SHP-1 in TGF-β receptor signaling and HSC quiescence, and confirmed tumor-suppressor function in hepatocarcinogenesis.","evidence":"Shp-1 knockout mice and TGFβR1 co-IP for HSC quiescence; conditional hepatocyte Ptpn6 knockout with DEN and orthotopic HCC models","pmids":["29669741","29776962"],"confidence":"High","gaps":["Mechanistic basis for SHP-1 promoting rather than dampening TGF-β signaling not resolved"]},{"year":2019,"claim":"Established that neutrophil SHP-1 restrains p38 MAPK cytokine production and maintains Ripk1 to prevent programmed cell death, explaining the inflammatory motheaten phenotype.","evidence":"Conditional neutrophil Ptpn6 deletion with Ripk1/Ripk3/Mlkl/caspase-8 epistasis crosses and cytokine assays","pmids":["31819256"],"confidence":"High","gaps":["Direct SHP-1 substrates within the Ripk1/cell-death axis not identified"]},{"year":2020,"claim":"Connected SHP-1 to checkpoint and innate signaling, mediating PD-L1 suppression of TRPV1 nociception and linking it to TRAF6/STING-dependent inflammation.","evidence":"Conditional NaV1.8+ neuron knockout with electrophysiology and pain behavior; co-IP of SHP-1 with TRAF6/NLRX1 in ischemia models","pmids":["32960817","32151250"],"confidence":"Medium","gaps":["TRAF6/DJ-1 finding is Medium-confidence with limited catalytic evidence","Whether SHP-1 acts catalytically or as a scaffold in STING/TRAF6 contexts unclear"]},{"year":2022,"claim":"Implicated SHP-1 in TLR4/innate immune adaptor complexes and STING regulation, suggesting scaffold-associated functions beyond classical phosphatase activity.","evidence":"Co-IP of SKAP2-Sirpα-SHP-1 complex and SKAP2 knockout mice; co-IP and ubiquitination assays for SHP-1-STING with pharmacological epistasis","pmids":["35034964","36273174"],"confidence":"Medium","gaps":["Limited direct SHP-1 enzymatic evidence in these contexts","Single-lab findings awaiting independent confirmation"]},{"year":2023,"claim":"Identified podocin SUMOylation regulation as a non-canonical SHP-1 function protecting against diabetic kidney disease.","evidence":"Podocyte-specific Ptpn6 knockout, MS SUMOylation analysis, glomerular phenotyping","pmids":["37507049"],"confidence":"High","gaps":["Mechanistic link between SHP-1 phosphatase activity and SUMO2 modification of podocin not fully defined"]},{"year":2024,"claim":"Defined a metabolic and immune-evasion axis whereby SHP-1 inhibition reprograms leukemia stem cell glycolysis via AKT-β-catenin-PFKP and promotes MYC degradation.","evidence":"SHP-1 inhibition in LSCs, pathway and metabolic assays, MYC degradation analysis, in vivo AML models","pmids":["38321204"],"confidence":"High","gaps":["Direct SHP-1 substrate upstream of the AKT-β-catenin axis not identified"]},{"year":null,"claim":"How a single phosphatase achieves context-specific selection among its many substrates and switches between negative and positive regulatory roles in different cells remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking receptor recruitment, phosphorylation state, and substrate choice","Scaffold versus catalytic contributions in innate immune complexes not separated","Determinants of positive (TGF-β, Src) versus negative regulation undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140096","term_label":"catalytic activity, acting on a protein","supporting_discovery_ids":[1,2,5,7,8,15,18,19,21,34,35,36]},{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[11,16,28,29,33]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,3,22,32,39,40]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[21]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[16,29]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[9,14,15]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[30]},{"term_id":"GO:0005783","term_label":"endoplasmic reticulum","supporting_discovery_ids":[44]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[1,3,17,24,31,32,40]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[2,5,7,8,19,38]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[9,17,19,40]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[0,27,39,46]},{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[8,25,32,36]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[22,46]}],"complexes":[],"partners":["ZAP-70","JAK2","STAT3","CBL-B","TRKA","TRPV1","LAIR-1","CBL"],"other_free_text":[]}},"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":"8324828","id":"PMC_8324828","title":"Mutations at the murine motheaten locus are within the hematopoietic cell protein-tyrosine phosphatase (Hcph) gene.","date":"1993","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/8324828","citation_count":656,"is_preprint":false},{"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":"8638162","id":"PMC_8638162","title":"Direct regulation of ZAP-70 by SHP-1 in T cell antigen receptor signaling.","date":"1996","source":"Science (New York, N.Y.)","url":"https://pubmed.ncbi.nlm.nih.gov/8638162","citation_count":348,"is_preprint":false},{"pmid":"19290938","id":"PMC_19290938","title":"SHP-1 and SHP-2 in T cells: two phosphatases functioning at many levels.","date":"2009","source":"Immunological reviews","url":"https://pubmed.ncbi.nlm.nih.gov/19290938","citation_count":304,"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":"16084691","id":"PMC_16084691","title":"A SHPing tale: perspectives on the regulation of SHP-1 and SHP-2 tyrosine phosphatases by the C-terminal tail.","date":"2005","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/16084691","citation_count":144,"is_preprint":false},{"pmid":"9261115","id":"PMC_9261115","title":"Src kinase activity is regulated by the SHP-1 protein-tyrosine phosphatase.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9261115","citation_count":141,"is_preprint":false},{"pmid":"11001933","id":"PMC_11001933","title":"RNA hyperediting and alternative splicing of hematopoietic cell phosphatase (PTPN6) gene in acute myeloid leukemia.","date":"2000","source":"Human molecular genetics","url":"https://pubmed.ncbi.nlm.nih.gov/11001933","citation_count":133,"is_preprint":false},{"pmid":"9263478","id":"PMC_9263478","title":"Severe defects in immunity and hematopoiesis caused by SHP-1 protein-tyrosine-phosphatase deficiency.","date":"1997","source":"Trends in biotechnology","url":"https://pubmed.ncbi.nlm.nih.gov/9263478","citation_count":133,"is_preprint":false},{"pmid":"10488096","id":"PMC_10488096","title":"SHP-1 regulates Lck-induced phosphatidylinositol 3-kinase phosphorylation and activity.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10488096","citation_count":122,"is_preprint":false},{"pmid":"16617349","id":"PMC_16617349","title":"The SHP-1 protein tyrosine phosphatase negatively modulates glucose homeostasis.","date":"2006","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/16617349","citation_count":112,"is_preprint":false},{"pmid":"23391724","id":"PMC_23391724","title":"SHP-1 phosphatase activity counteracts increased T cell receptor affinity.","date":"2013","source":"The Journal of clinical investigation","url":"https://pubmed.ncbi.nlm.nih.gov/23391724","citation_count":104,"is_preprint":false},{"pmid":"10781410","id":"PMC_10781410","title":"Cytoplasmic protein tyrosine phosphatases SHP-1 and SHP-2: regulators of B cell signal transduction.","date":"2000","source":"Current opinion in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/10781410","citation_count":103,"is_preprint":false},{"pmid":"7665165","id":"PMC_7665165","title":"Human protein tyrosine phosphatase 1C (PTPN6) gene structure: alternate promoter usage and exon skipping generate multiple transcripts.","date":"1995","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/7665165","citation_count":98,"is_preprint":false},{"pmid":"10506221","id":"PMC_10506221","title":"Regulation of acidification and apoptosis by SHP-1 and Bcl-2.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10506221","citation_count":95,"is_preprint":false},{"pmid":"9814969","id":"PMC_9814969","title":"Regulation of angiotensin II-induced JAK2 tyrosine phosphorylation: roles of SHP-1 and SHP-2.","date":"1998","source":"The American journal of physiology","url":"https://pubmed.ncbi.nlm.nih.gov/9814969","citation_count":93,"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":92,"is_preprint":false},{"pmid":"17522256","id":"PMC_17522256","title":"Fc receptor-like 5 inhibits B cell activation via SHP-1 tyrosine phosphatase recruitment.","date":"2007","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/17522256","citation_count":90,"is_preprint":false},{"pmid":"21291263","id":"PMC_21291263","title":"Substrate specificity of protein tyrosine phosphatases 1B, RPTPα, SHP-1, and SHP-2.","date":"2011","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21291263","citation_count":87,"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":86,"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":81,"is_preprint":false},{"pmid":"14662744","id":"PMC_14662744","title":"SHP-1 negatively regulates neuronal survival by functioning as a TrkA phosphatase.","date":"2003","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/14662744","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":"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":77,"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":"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":73,"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":"21406173","id":"PMC_21406173","title":"Alteration in the gene encoding protein tyrosine phosphatase nonreceptor type 6 (PTPN6/SHP1) may contribute to neutrophilic dermatoses.","date":"2011","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/21406173","citation_count":69,"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":"17003515","id":"PMC_17003515","title":"Investigations into the regulation and function of the SH2 domain-containing protein-tyrosine phosphatase, SHP-1.","date":"2006","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/17003515","citation_count":63,"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 (Orlando, Fla.)","url":"https://pubmed.ncbi.nlm.nih.gov/15721837","citation_count":62,"is_preprint":false},{"pmid":"9348315","id":"PMC_9348315","title":"Downregulated expression of SHP-1 in Burkitt lymphomas and germinal center B lymphocytes.","date":"1997","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/9348315","citation_count":62,"is_preprint":false},{"pmid":"21291405","id":"PMC_21291405","title":"SHP-1 in cell-cycle regulation.","date":"2011","source":"Anti-cancer agents in medicinal chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/21291405","citation_count":61,"is_preprint":false},{"pmid":"20421638","id":"PMC_20421638","title":"Novel SHP-1 inhibitors tyrosine phosphatase inhibitor-1 and analogs with preclinical anti-tumor activities as tolerated oral agents.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20421638","citation_count":61,"is_preprint":false},{"pmid":"10393854","id":"PMC_10393854","title":"Deficiency of SHP-1 protein-tyrosine phosphatase activity results in heightened osteoclast function and decreased bone density.","date":"1999","source":"The American journal of pathology","url":"https://pubmed.ncbi.nlm.nih.gov/10393854","citation_count":60,"is_preprint":false},{"pmid":"12176909","id":"PMC_12176909","title":"SHP-1 regulates Fcgamma receptor-mediated phagocytosis and the activation of RAC.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12176909","citation_count":59,"is_preprint":false},{"pmid":"10835420","id":"PMC_10835420","title":"The protein-tyrosine phosphatase SHP-1 binds to and dephosphorylates p120 catenin.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10835420","citation_count":58,"is_preprint":false},{"pmid":"11160222","id":"PMC_11160222","title":"Constitutive association of SHP-1 with leukocyte-associated Ig-like receptor-1 in human T cells.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11160222","citation_count":58,"is_preprint":false},{"pmid":"29925063","id":"PMC_29925063","title":"Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment?","date":"2018","source":"Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/29925063","citation_count":56,"is_preprint":false},{"pmid":"20858858","id":"PMC_20858858","title":"Lyn- and PLC-beta3-dependent regulation of SHP-1 phosphorylation controls Stat5 activity and myelomonocytic leukemia-like disease.","date":"2010","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/20858858","citation_count":55,"is_preprint":false},{"pmid":"25619838","id":"PMC_25619838","title":"SHP-1 is a negative regulator of epithelial-mesenchymal transition in hepatocellular carcinoma.","date":"2015","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/25619838","citation_count":53,"is_preprint":false},{"pmid":"31819256","id":"PMC_31819256","title":"Ptpn6 inhibits caspase-8- and Ripk3/Mlkl-dependent inflammation.","date":"2019","source":"Nature immunology","url":"https://pubmed.ncbi.nlm.nih.gov/31819256","citation_count":52,"is_preprint":false},{"pmid":"9242674","id":"PMC_9242674","title":"Protein-tyrosine phosphatase SHP-1 is dispensable for FcgammaRIIB-mediated inhibition of B cell antigen receptor activation.","date":"1997","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/9242674","citation_count":52,"is_preprint":false},{"pmid":"29669741","id":"PMC_29669741","title":"SHP-1 regulates hematopoietic stem cell quiescence by coordinating TGF-β signaling.","date":"2018","source":"The Journal of experimental medicine","url":"https://pubmed.ncbi.nlm.nih.gov/29669741","citation_count":51,"is_preprint":false},{"pmid":"25187664","id":"PMC_25187664","title":"SHP-1 plays a crucial role in CD40 signaling reciprocity.","date":"2014","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/25187664","citation_count":51,"is_preprint":false},{"pmid":"10871605","id":"PMC_10871605","title":"Evidence of a role for SHP-1 in platelet activation by the collagen receptor glycoprotein VI.","date":"2000","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10871605","citation_count":51,"is_preprint":false},{"pmid":"10652447","id":"PMC_10652447","title":"Expression and function of the protein tyrosine phosphatase SHP-1 in oligodendrocytes.","date":"2000","source":"Glia","url":"https://pubmed.ncbi.nlm.nih.gov/10652447","citation_count":50,"is_preprint":false},{"pmid":"35024200","id":"PMC_35024200","title":"Fangchinoline diminishes STAT3 activation by stimulating oxidative stress and targeting SHP-1 protein in multiple myeloma model.","date":"2021","source":"Journal of advanced research","url":"https://pubmed.ncbi.nlm.nih.gov/35024200","citation_count":50,"is_preprint":false},{"pmid":"9739453","id":"PMC_9739453","title":"Reversible regulation of SHP-1 tyrosine phosphatase activity by oxidation.","date":"1998","source":"Biochemistry and molecular biology international","url":"https://pubmed.ncbi.nlm.nih.gov/9739453","citation_count":49,"is_preprint":false},{"pmid":"32960817","id":"PMC_32960817","title":"Inhibition of TRPV1 by SHP-1 in nociceptive primary sensory neurons is critical in PD-L1 analgesia.","date":"2020","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/32960817","citation_count":48,"is_preprint":false},{"pmid":"24904114","id":"PMC_24904114","title":"Hyperinsulinemia induces insulin resistance and immune suppression via Ptpn6/Shp1 in zebrafish.","date":"2014","source":"The Journal of endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/24904114","citation_count":46,"is_preprint":false},{"pmid":"25071018","id":"PMC_25071018","title":"SHP-1 is a target of regorafenib in colorectal cancer.","date":"2014","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/25071018","citation_count":46,"is_preprint":false},{"pmid":"23335748","id":"PMC_23335748","title":"Deficiency in hematopoietic phosphatase ptpn6/Shp1 hyperactivates the innate immune system and impairs control of bacterial infections in zebrafish embryos.","date":"2013","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/23335748","citation_count":45,"is_preprint":false},{"pmid":"25790452","id":"PMC_25790452","title":"Shp-1 dephosphorylates TRPV1 in dorsal root ganglion neurons and alleviates CFA-induced inflammatory pain in rats.","date":"2015","source":"Pain","url":"https://pubmed.ncbi.nlm.nih.gov/25790452","citation_count":45,"is_preprint":false},{"pmid":"32151250","id":"PMC_32151250","title":"DJ-1 exerts anti-inflammatory effects and regulates NLRX1-TRAF6 via SHP-1 in stroke.","date":"2020","source":"Journal of neuroinflammation","url":"https://pubmed.ncbi.nlm.nih.gov/32151250","citation_count":44,"is_preprint":false},{"pmid":"21821701","id":"PMC_21821701","title":"SHP-1 expression accounts for resistance to imatinib treatment in Philadelphia chromosome-positive cells derived from patients with chronic myeloid leukemia.","date":"2011","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/21821701","citation_count":44,"is_preprint":false},{"pmid":"27068940","id":"PMC_27068940","title":"SHP-1: the next checkpoint target for cancer immunotherapy?","date":"2016","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/27068940","citation_count":43,"is_preprint":false},{"pmid":"10585470","id":"PMC_10585470","title":"SHP-1 regulation of p62(DOK) tyrosine phosphorylation in macrophages.","date":"1999","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/10585470","citation_count":40,"is_preprint":false},{"pmid":"22415018","id":"PMC_22415018","title":"Intravenous immunoglobulins modulate neutrophil activation and vascular injury through FcγRIII and SHP-1.","date":"2012","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/22415018","citation_count":39,"is_preprint":false},{"pmid":"26416283","id":"PMC_26416283","title":"Protein Tyrosine Phosphatase SHP-1 Modulates T Cell Responses by Controlling Cbl-b Degradation.","date":"2015","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/26416283","citation_count":38,"is_preprint":false},{"pmid":"37291088","id":"PMC_37291088","title":"Targeting pathogenic macrophages by the application of SHP-1 agonists reduces inflammation and alleviates pulmonary fibrosis.","date":"2023","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/37291088","citation_count":38,"is_preprint":false},{"pmid":"10390187","id":"PMC_10390187","title":"Defective expression of the SHP-1 phosphatase in polycythemia vera.","date":"1999","source":"Experimental hematology","url":"https://pubmed.ncbi.nlm.nih.gov/10390187","citation_count":38,"is_preprint":false},{"pmid":"20130595","id":"PMC_20130595","title":"Deficient SOCS3 and SHP-1 expression in psoriatic T cells.","date":"2010","source":"The Journal of investigative dermatology","url":"https://pubmed.ncbi.nlm.nih.gov/20130595","citation_count":37,"is_preprint":false},{"pmid":"15574429","id":"PMC_15574429","title":"FLT3/ITD mutation signaling includes suppression of SHP-1.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15574429","citation_count":37,"is_preprint":false},{"pmid":"28798401","id":"PMC_28798401","title":"The tyrosine kinase inhibitor nintedanib activates SHP-1 and induces apoptosis in triple-negative breast cancer cells.","date":"2017","source":"Experimental & molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/28798401","citation_count":37,"is_preprint":false},{"pmid":"17142110","id":"PMC_17142110","title":"Age-related impairment of GM-CSF-induced signalling in neutrophils: role of SHP-1 and SOCS proteins.","date":"2006","source":"Ageing research reviews","url":"https://pubmed.ncbi.nlm.nih.gov/17142110","citation_count":35,"is_preprint":false},{"pmid":"24647617","id":"PMC_24647617","title":"Methylation and decreased expression of SHP-1 are related to disease progression in chronic myelogenous leukemia.","date":"2014","source":"Oncology reports","url":"https://pubmed.ncbi.nlm.nih.gov/24647617","citation_count":35,"is_preprint":false},{"pmid":"16487932","id":"PMC_16487932","title":"SHP-1 inhibits LPS-mediated TNF and iNOS production in murine macrophages.","date":"2006","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/16487932","citation_count":35,"is_preprint":false},{"pmid":"20042576","id":"PMC_20042576","title":"SHP-1 deficient mast cells are hyperresponsive to stimulation and critical in initiating allergic inflammation in the lung.","date":"2009","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20042576","citation_count":35,"is_preprint":false},{"pmid":"23531619","id":"PMC_23531619","title":"Expression of SHP-1 induced by hyperglycemia prevents insulin actions in podocytes.","date":"2013","source":"American journal of physiology. Endocrinology and metabolism","url":"https://pubmed.ncbi.nlm.nih.gov/23531619","citation_count":33,"is_preprint":false},{"pmid":"38321204","id":"PMC_38321204","title":"SHP-1 inhibition targets leukaemia stem cells to restore immunosurveillance and enhance chemosensitivity by metabolic reprogramming.","date":"2024","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/38321204","citation_count":32,"is_preprint":false},{"pmid":"16223786","id":"PMC_16223786","title":"RNA interference targeting SHP-1 attenuates myocardial infarction in rats.","date":"2005","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/16223786","citation_count":32,"is_preprint":false},{"pmid":"20952680","id":"PMC_20952680","title":"The protein tyrosine phosphatase SHP-1 modulates the suppressive activity of regulatory T cells.","date":"2010","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/20952680","citation_count":32,"is_preprint":false},{"pmid":"27216862","id":"PMC_27216862","title":"Protein tyrosine phosphatase SHP-1: resurgence as new drug target for human autoimmune disorders.","date":"2016","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/27216862","citation_count":31,"is_preprint":false},{"pmid":"20090381","id":"PMC_20090381","title":"Elevated expression of the tyrosine phosphatase SHP-1 defines a subset of high-grade breast tumors.","date":"2010","source":"Oncology","url":"https://pubmed.ncbi.nlm.nih.gov/20090381","citation_count":31,"is_preprint":false},{"pmid":"14563118","id":"PMC_14563118","title":"SHP-1: a regulator of neutrophil apoptosis.","date":"2003","source":"Seminars in immunology","url":"https://pubmed.ncbi.nlm.nih.gov/14563118","citation_count":30,"is_preprint":false},{"pmid":"34752140","id":"PMC_34752140","title":"Dynamic variability in SHP-1 abundance determines natural killer cell responsiveness.","date":"2021","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/34752140","citation_count":29,"is_preprint":false},{"pmid":"21900501","id":"PMC_21900501","title":"The SHP-1 protein tyrosine phosphatase negatively modulates Akt signaling in the ghrelin/GHSR1a system.","date":"2011","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/21900501","citation_count":29,"is_preprint":false},{"pmid":"27670070","id":"PMC_27670070","title":"Protein kinase D regulates positive selection of CD4+ thymocytes through phosphorylation of SHP-1.","date":"2016","source":"Nature communications","url":"https://pubmed.ncbi.nlm.nih.gov/27670070","citation_count":29,"is_preprint":false},{"pmid":"36273174","id":"PMC_36273174","title":"SHP-1 knockdown suppresses mitochondrial biogenesis and aggravates mitochondria-dependent apoptosis induced by all trans retinal through the STING/AMPK pathways.","date":"2022","source":"Molecular medicine (Cambridge, Mass.)","url":"https://pubmed.ncbi.nlm.nih.gov/36273174","citation_count":28,"is_preprint":false},{"pmid":"15070900","id":"PMC_15070900","title":"The protein-tyrosine phosphatase SHP-1 regulates the phosphorylation of alpha-actinin.","date":"2004","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/15070900","citation_count":28,"is_preprint":false},{"pmid":"24793756","id":"PMC_24793756","title":"The SHP-1 expression is associated with cytokines and psychopathological status in unmedicated first episode schizophrenia patients.","date":"2014","source":"Brain, behavior, and immunity","url":"https://pubmed.ncbi.nlm.nih.gov/24793756","citation_count":28,"is_preprint":false},{"pmid":"17218319","id":"PMC_17218319","title":"PU.1 activates transcription of SHP-1 gene in hematopoietic cells.","date":"2007","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/17218319","citation_count":27,"is_preprint":false},{"pmid":"22438258","id":"PMC_22438258","title":"The tyrosine phosphatase SHP-1 dampens murine Th17 development.","date":"2012","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/22438258","citation_count":27,"is_preprint":false},{"pmid":"18952567","id":"PMC_18952567","title":"A critical role of SHP-1 in regulation of type 2 inflammation in the lung.","date":"2008","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18952567","citation_count":27,"is_preprint":false},{"pmid":"37507049","id":"PMC_37507049","title":"Deletion of protein tyrosine phosphatase SHP-1 restores SUMOylation of podocin and reverses the progression of diabetic kidney disease.","date":"2023","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/37507049","citation_count":26,"is_preprint":false},{"pmid":"35034964","id":"PMC_35034964","title":"SKAP2 suppresses inflammation-mediated tumorigenesis by regulating SHP-1 and SHP-2.","date":"2022","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/35034964","citation_count":26,"is_preprint":false},{"pmid":"1427910","id":"PMC_1427910","title":"Assignment of a novel protein tyrosine phosphatase gene (Hcph) to mouse chromosome 6.","date":"1992","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/1427910","citation_count":26,"is_preprint":false},{"pmid":"9573011","id":"PMC_9573011","title":"SHP-1 phosphatase C-terminus interacts with novel substrates p32/p30 during erythropoietin and interleukin-3 mitogenic responses.","date":"1998","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/9573011","citation_count":26,"is_preprint":false},{"pmid":"18276794","id":"PMC_18276794","title":"SHP-1 inhibition by 4-hydroxynonenal activates Jun N-terminal kinase and glutamate cysteine ligase.","date":"2008","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18276794","citation_count":26,"is_preprint":false},{"pmid":"9048211","id":"PMC_9048211","title":"Regulation of cell signaling by the protein tyrosine phosphatases, CD45 and SHP-1.","date":"1997","source":"Immunologic research","url":"https://pubmed.ncbi.nlm.nih.gov/9048211","citation_count":25,"is_preprint":false},{"pmid":"27812544","id":"PMC_27812544","title":"Akt and SHP-1 are DC-intrinsic checkpoints for tumor immunity.","date":"2016","source":"JCI insight","url":"https://pubmed.ncbi.nlm.nih.gov/27812544","citation_count":23,"is_preprint":false},{"pmid":"11145649","id":"PMC_11145649","title":"Mutation of the hematopoietic cell phosphatase (Hcph) gene is associated with resistance to gamma-irradiation-induced apoptosis in Src homology protein tyrosine phosphatase (SHP)-1-deficient \"motheaten\" mutant mice.","date":"2001","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/11145649","citation_count":23,"is_preprint":false},{"pmid":"28295507","id":"PMC_28295507","title":"Crocin Suppresses Constitutively Active STAT3 Through Induction of Protein Tyrosine Phosphatase SHP-1.","date":"2017","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28295507","citation_count":23,"is_preprint":false},{"pmid":"35563411","id":"PMC_35563411","title":"Ethyl Gallate Dual-Targeting PTPN6 and PPARγ Shows Anti-Diabetic and Anti-Obese Effects.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/35563411","citation_count":22,"is_preprint":false},{"pmid":"22826316","id":"PMC_22826316","title":"The protein tyrosine phosphatase SHP-1 regulates phagolysosome biogenesis.","date":"2012","source":"Journal of immunology (Baltimore, Md. : 1950)","url":"https://pubmed.ncbi.nlm.nih.gov/22826316","citation_count":22,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":49538,"output_tokens":11583,"usd":0.16118,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":22683,"output_tokens":6993,"usd":0.14412,"stage2_stop_reason":"end_turn"},"total_usd":0.3053,"stage1_batch_id":"msgbatch_01CNoDbkChHEkgrJnL7BwtGJ","stage2_batch_id":"msgbatch_016Y4x9E9Wg5VQDANj9quSQD","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1993,\n      \"finding\": \"The motheaten (me) and viable motheaten (mev) mutations in mice are point mutations within the Hcph (PTPN6/SHP-1) gene that cause aberrant splicing, resulting in deficient SHP-1 protein expression and activity, and severe hematopoietic defects.\",\n      \"method\": \"Western blot, activity assays, cDNA molecular analysis, DNA sequencing of genomic clones\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple orthogonal methods (activity assay, Western blot, sequence analysis) in a landmark study; independently replicated across the field\",\n      \"pmids\": [\"8324828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"SHP-1 binds directly to the protein tyrosine kinase ZAP-70 upon T cell activation; this interaction increases SHP-1 phosphatase activity and decreases ZAP-70 kinase activity, establishing SHP-1 as a negative regulator that sets the threshold of TCR activation.\",\n      \"method\": \"Co-immunoprecipitation, kinase activity assays, dominant-negative SHP-1 expression in T cells\",\n      \"journal\": \"Science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — reciprocal binding shown, enzymatic activity measured, dominant-negative functional validation, widely replicated\",\n      \"pmids\": [\"8638162\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SHP-1 preferentially dephosphorylates Src at its carboxyl-terminal inhibitory phosphotyrosine site, activating Src kinase; Src associates with SHP-1 and phosphorylates SHP-1 via the NH2-terminal SH2 domain interaction, demonstrating a positive regulatory role of SHP-1 on Src activity.\",\n      \"method\": \"In vitro dephosphorylation assay, co-immunoprecipitation, kinase activity assays in SHP-1-deficient motheaten thymocytes, dominant-negative SHP-1 expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro phosphatase assay, genetic model (motheaten mice), dominant-negative validation, multiple orthogonal methods\",\n      \"pmids\": [\"9261115\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SHP-1 and SHIP define two distinct inhibitory signaling pathways downstream of inhibitory coreceptors: FcγRIIB-class inhibitory signaling requires SHIP and not SHP-1, whereas KIR-class inhibitory signaling requires SHP-1 and not SHIP. SHP-1-mediated inhibitory signaling blocks BCR-triggered apoptosis.\",\n      \"method\": \"Generation of SHP-1- or SHIP-deficient B cell lines, functional inhibitory signaling assays, apoptosis assays\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic deletion lines with clear phenotypic readouts, pathway dissection by selective deficiency, replicated concept\",\n      \"pmids\": [\"9244303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SHP-1 is dispensable for FcγRIIB-mediated inhibition of B cell antigen receptor (sIgM) signaling; SHIP is recruited to tyrosyl-phosphorylated FcγRIIB and mediates inhibition in the absence of SHP-1.\",\n      \"method\": \"Immortalized SHP-1-deficient (me/me) B cell lines, calcium influx assays, co-immunoprecipitation of SHIP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — negative finding established by genetic SHP-1 deficiency with functional assay; replicates and complements PMID 9244303\",\n      \"pmids\": [\"9242674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SHP-1 is responsible for JAK2 dephosphorylation and termination of angiotensin II-induced JAK/STAT cascade in vascular smooth muscle cells, while SHP-2 has an opposing role in initiating JAK2 phosphorylation; SHP-1 forms complexes with JAK2.\",\n      \"method\": \"Electroporation with neutralizing antibodies, time-course co-immunoprecipitation, JAK2 kinase activity assays\",\n      \"journal\": \"The American journal of physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — single lab, antibody neutralization and co-IP, functional readout but limited orthogonal validation\",\n      \"pmids\": [\"9814969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SHP-1 phosphatase activity is reversibly inactivated by oxidation (H2O2); activity can be restored by dithiothreitol, glutathione, or N-acetylcysteine, establishing redox regulation as a mechanism controlling SHP-1 activity.\",\n      \"method\": \"In vitro H2O2 inactivation assay, reactivation with reducing agents, H2O2-stimulated SHP-1-transfected HeLa cells\",\n      \"journal\": \"Biochemistry and molecular biology international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro enzymatic assay with clear mechanistic result, single lab, limited orthogonal validation\",\n      \"pmids\": [\"9739453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SHP-1 co-immunoprecipitates with the p85 regulatory subunit of PI3K in T cells; this association increases upon TCR ligation and requires Lck-phosphorylated Tyr564 on SHP-1. Wild-type SHP-1 (but not catalytically inactive mutant) dephosphorylates p85 and reduces PI3K activity and downstream Akt phosphorylation.\",\n      \"method\": \"Co-immunoprecipitation, co-expression with constitutively active Lck in COS7 cells, PI3K enzyme activity assay, phospho-Akt Western blot\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — multiple orthogonal methods (co-IP, enzymatic assay, catalytically inactive mutant), single lab\",\n      \"pmids\": [\"10488096\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SHP-1 is constitutively associated with JAK2 in pituitary AtT-20 cells; LIF induces recruitment of phosphorylated STAT3 to this SHP-1/JAK2 complex. SHP-1 dephosphorylates JAK2 and STAT3 to attenuate LIF-induced POMC promoter activity, as shown by wild-type vs. dominant-negative SHP-1 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, dominant-negative and wild-type SHP-1 overexpression, POMC luciferase reporter, phospho-JAK2/STAT3 Western blot\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP showing constitutive complex, dominant-negative and wild-type rescue, functional promoter assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"10545526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Membrane-associated SHP-1 is required for receptor-mediated intracellular acidification and apoptosis in breast cancer cells (initiated by somatostatin receptor activation and Fas ligation); catalytically inactive SHP-1 (C455S) acts as dominant negative, blocking recruitment of wild-type SHP-1 to the membrane and preventing apoptosis.\",\n      \"method\": \"Ectopic SHP-1 expression, catalytically inactive mutant (C455S), SST agonist and Fas ligation assays, pH measurement, apoptosis assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant and WT rescue with functional apoptosis readout, single lab\",\n      \"pmids\": [\"10506221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"SHP-1 dephosphorylates and associates with p62(DOK) in macrophages; p62(DOK) is constitutively associated with SHP-1 and is constitutively hyperphosphorylated in SHP-1-deficient (motheaten) macrophages, correlating with growth factor-independent survival.\",\n      \"method\": \"Co-immunoprecipitation, Far Western analysis, comparison of wild-type vs. me/me motheaten macrophages, SHP-1 C453S catalytically inactive mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP, genetic model, catalytic mutant, Far Western; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"10585470\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Crystal structure of the SHP-1 catalytic domain complexed with SIRPα-derived peptide substrates reveals that the variable β5-loop-β6 motif confers substrate specificity at P-4 and further N-terminal subpockets, and identifies a novel residue shift at P-2.\",\n      \"method\": \"X-ray crystallography of catalytic domain–peptide substrate complexes\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with bound peptide substrates providing atomic-level mechanistic detail\",\n      \"pmids\": [\"10660565\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SHP-1 binds to and dephosphorylates p120 catenin (3A isoform) in EGF-stimulated cells; binding is mediated primarily by the N-terminal SH2 domain of SHP-1; tetracycline-mediated decrease of SHP-1 expression elevates p120 catenin phosphorylation.\",\n      \"method\": \"GST-SHP-1 pulldown, co-immunoprecipitation, mass spectrometry identification of p120ctn, tetracycline-regulated SHP-1 expression\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown, co-IP, and regulated expression system; single lab\",\n      \"pmids\": [\"10835420\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SHP-1 deficiency in macrophages leads to enhanced αmβ2 integrin-mediated adhesion/spreading and a 10–15-fold increase in D-3 phospholipid products of PI3-kinase, with 2–5-fold increased membrane-associated PI3-kinase activity; PI3-kinase inhibitors cause detachment, placing SHP-1 upstream of PI3-kinase in integrin adhesion regulation.\",\n      \"method\": \"Comparison of mev/mev vs. wild-type macrophages, PI3-kinase activity and lipid product assays, PI3-kinase inhibitors (wortmannin, LY294002)\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic model combined with pharmacological epistasis and biochemical measurement; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"9740804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"SHP-1 is constitutively associated with and activated by the ITIM-containing receptor LAIR-1 at the plasma membrane in resting human T cells (both Jurkat and primary), as identified by yeast tri-hybrid screen and confirmed by co-immunoprecipitation of membrane-enriched fractions.\",\n      \"method\": \"Yeast tri-hybrid screen, co-immunoprecipitation from membrane-enriched fractions, SHP-1 activity assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — orthogonal identification method (tri-hybrid) confirmed by co-IP and activity assay; shown in both cell line and primary T cells\",\n      \"pmids\": [\"11160222\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Targeting activated SHP-1 to lipid rafts in T cells inhibits TCR-mediated signaling by causing rapid dephosphorylation of LAT (linker for activation of T cells), while leaving Lck kinase activity and TCR-ζ/ZAP-70 phosphorylation intact; endogenous SHP-1 is recruited to rafts and associates with LAT upon TCR engagement.\",\n      \"method\": \"Chimeric raft-targeting SHP-1 construct expressed in Jurkat cells, CD69 expression, signaling pathway analysis, co-immunoprecipitation of endogenous SHP-1 with LAT\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — engineered localization approach with specific substrate identification (LAT), functional and biochemical readouts; single lab\",\n      \"pmids\": [\"11420038\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Crystal structure of C-terminally truncated human SHP-1 at 2.8 Å resolution reveals an auto-inhibited conformation in which the N-SH2 domain blocks the catalytic domain active site, demonstrating that SHP-1 phosphatase activity is primarily regulated by intramolecular N-SH2 domain occlusion.\",\n      \"method\": \"X-ray crystallography\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure providing direct structural evidence for autoinhibitory mechanism\",\n      \"pmids\": [\"12482860\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"Death receptors (TNF/NGF family) contain a conserved phosphotyrosine motif in their death domain that recruits SHP-1 (and SHP-2/SHIP) in a caspase-independent, cell-dependent manner; in neutrophils, SHP-1 recruited via this motif inactivates the anti-apoptotic kinase Lyn, preventing cytokine-induced survival signaling.\",\n      \"method\": \"Co-immunoprecipitation, phosphotyrosine motif mapping, Lyn kinase activity assay in neutrophils\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with motif mapping, kinase activity assay with functional consequence; single lab\",\n      \"pmids\": [\"11786908\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"SHP-1 associates with CBL in macrophages upon FcγR engagement; wild-type but not catalytically inactive SHP-1 overexpression dephosphorylates CBL, disrupts the CBL-CRKL interaction, suppresses RAC activation, and completely abrogates phagocytosis of IgG-sensitized targets.\",\n      \"method\": \"Heterologous expression of wild-type vs. catalytically inactive SHP-1, co-immunoprecipitation, RAC activation assay, phagocytosis assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — catalytic mutant compared to WT with co-IP substrate identification and functional phagocytosis readout; single lab\",\n      \"pmids\": [\"12176909\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SHP-1 forms complexes with TrkA at Y490 and dephosphorylates TrkA at Y674/675; SHP-1 expression in sympathetic neurons induces apoptosis and TrkA dephosphorylation, while dominant-inhibitory SHP-1 promotes NGF-independent survival; SHP-1-deficient mice have increased sympathetic neuron numbers during developmental cell death.\",\n      \"method\": \"Co-immunoprecipitation with phosphosite mapping, dominant-inhibitory SHP-1 expression, neuron survival assays, SHP-1-deficient motheaten mice\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with phosphosite mapping, dominant-inhibitory and genetic model, in vitro and in vivo readouts; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"14662744\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SHP-1 transfection inhibits growth of lymphoma/leukemia and breast cancer cell lines, and SHP-1 down-regulates activated JAK kinase levels partly by accelerating TYK2 and JAK1 degradation via the proteasome-mediated pathway (blocked by MG132).\",\n      \"method\": \"SHP-1 transfection, cell growth assays, Western blot for JAK1/TYK2, proteasome inhibitor MG132\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — functional transfection with proteasome inhibitor epistasis; single lab, limited mechanistic depth\",\n      \"pmids\": [\"14624462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHP-1 dephosphorylates α-actinin in vitro and in vivo; it was purified from platelet lysates and identified by mass spectrometry as a 68 kDa phosphatase of α-actinin; co-transfection of SHP-1 with FAK and α-actinin abolishes α-actinin phosphorylation without substantially affecting FAK phosphorylation.\",\n      \"method\": \"Sequential chromatography purification, electrospray tandem mass spectrometry identification, in vitro dephosphorylation assay, co-transfection in COS-7 cells, catalytic mutant (C453S)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — biochemical purification + MS identification + in vitro reconstitution + cellular validation with catalytic mutant; single lab\",\n      \"pmids\": [\"15070900\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SHP-1 deficiency (viable motheaten mice) results in markedly enhanced insulin receptor signaling via IRS-PI3K-Akt in liver and muscle; SHP-1 directly modulates hepatic insulin clearance by regulating CEACAM1 tyrosine phosphorylation. Adenoviral dominant-negative or shRNA-mediated SHP-1 silencing in liver recapitulates improved insulin sensitivity.\",\n      \"method\": \"Viable motheaten mice, adenoviral expression of catalytically inert SHP-1, shRNA knockdown, insulin signaling Western blots (IRS-PI3K-Akt), [125I]-insulin clearance assay, CEACAM1 phosphorylation in vitro\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model confirmed by two independent in vivo interventions (dominant-negative adenovirus and shRNA), in vitro substrate evidence; multiple orthogonal methods\",\n      \"pmids\": [\"16617349\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Leishmania donovani-activated SHP-1 inhibits IFN-γ-dependent nitric oxide production in macrophages by inactivating JAK2 and ERK1/2 and preventing nuclear translocation of NF-κB and AP-1; SHP-1-deficient macrophages fail to suppress nitric oxide in response to Leishmania.\",\n      \"method\": \"SHP-1-/- macrophage cell line (motheaten-derived), JAK2/ERK1/2 phosphorylation assay, nuclear translocation assays for NF-κB/AP-1, nitric oxide production assay\",\n      \"journal\": \"Infection and immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null cell line with multiple signaling readouts; single lab with orthogonal methods\",\n      \"pmids\": [\"17057094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"FCRL5 inhibits BCR signaling by dual ITIM-dependent recruitment of SHP-1, which dephosphorylates the ITAM-based tyrosines in BCR Igα/Igβ heterodimers; ITIM tyrosine mutations abolish this effect.\",\n      \"method\": \"FCRL5-FcγRIIB chimeric construct expression in B cell line, ITIM mutational analysis, calcium mobilization assay, SHP-1 co-immunoprecipitation\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — mutational dissection of ITIMs, SHP-1 recruitment shown by co-IP, functional calcium assay; single lab\",\n      \"pmids\": [\"17522256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"PU.1, an Ets family transcription factor, directly binds the hematopoietic cell-specific P2 promoter of the SHP-1 gene and activates its transcription; siRNA-mediated depletion of PU.1 profoundly suppresses SHP-1 gene transcription.\",\n      \"method\": \"Luciferase reporter assays, EMSA (in vitro binding), ChIP (in vivo binding), PU.1 siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro and in vivo DNA binding confirmed, functional reporter and knockdown; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"17218319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Leishmania activates SHP-1 to directly inactivate IRAK-1 kinase activity by binding via an evolutionarily conserved ITIM-like motif (KTIM) in the kinase domain of IRAK-1; SHP-1 also interacts with ERK1/2 and IKKα/β via similar KTIM motifs.\",\n      \"method\": \"Co-immunoprecipitation of SHP-1 with IRAK-1, IRAK-1 kinase activity assay, KTIM motif mutational analysis, Leishmania infection model\",\n      \"journal\": \"PLoS neglected tropical diseases\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with kinase activity assay, motif mutation, functional pathogen model; single lab\",\n      \"pmids\": [\"19104650\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SHP-1 phosphorylation at Tyr536 and Tyr564 by Lyn kinase is required for maximal SHP-1 phosphatase activity; Tyr564 phosphorylation by Lyn is indispensable for suppression of Stat5 activity and prevention of CMML-like myeloproliferative disease; Tyr536 is required for efficient SHP-1 interaction with Stat5. PLC-β3 acts upstream of this Lyn/SHP-1 regulatory axis.\",\n      \"method\": \"Lyn/PLC-β3 double-knockout mice, phosphorylation-defective SHP-1 mutants (Y536F, Y564F), SHP-1 activity assay, co-immunoprecipitation, Stat5 activity assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model, phosphosite mutants, enzymatic assay, binding assay; multiple orthogonal methods in one rigorous study\",\n      \"pmids\": [\"20858858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Combinatorial peptide library screening established that SHP-1 has narrow substrate specificity with strong preference for acidic and aromatic hydrophobic residues on both sides of pY, requiring acidic residues at pY-1 and pY+1 and no basic residues; this intrinsic specificity correlates well with known in vivo substrates.\",\n      \"method\": \"On-bead combinatorial peptide library screening, solution-phase kinetic analysis of individually synthesized phosphotyrosyl peptides\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — rigorous in vitro biochemical reconstitution with quantitative kinetics; single lab but comprehensive peptide library approach\",\n      \"pmids\": [\"21291263\"],\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 conformation in which the N-SH2 domain is shifted away from the active site, exposing the catalytic pocket; the C-SH2 domain is twisted ~110° relative to the autoinhibited structure; new interdomain interactions stabilize the open conformation.\",\n      \"method\": \"X-ray crystallography of full-length SHP-1\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — crystal structure providing direct visualization of open/active conformation; single lab but rigorous structural method\",\n      \"pmids\": [\"21465528\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SHP-1 is recruited to phagosomes early after phagocytosis and remains present for up to 4 h; loss of SHP-1 impairs phagosome acidification and prevents processing of procathepsin D (51 kDa) to cathepsin D (46 kDa) and reduces LAMP-1 recruitment, demonstrating a role for SHP-1 in phagolysosome biogenesis.\",\n      \"method\": \"Confocal immunofluorescence microscopy, Western blot on purified phagosome extracts, LysoTracker pH indicator, SHP-1-deficient motheaten macrophages\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct phagosome localization, genetic null model, biochemical phagosome fractionation, functional acidification assay; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"22826316\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"FcγRIII on neutrophils recruits SHP-1 upon IVIG engagement to mediate inhibition of neutrophil adhesion and activation; this inhibitory signaling is abrogated in SHP-1-mutant mice, demonstrating an unexpected inhibitory role for the classic activating receptor FcγRIII via SHP-1.\",\n      \"method\": \"Intravital microscopy, FcγRIII/FcγRIIB-deficient mice, SHP-1-mutant mice, co-immunoprecipitation\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple genetic models, direct in vivo imaging, co-IP; single lab\",\n      \"pmids\": [\"22415018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SHP-1 decreases STAT3 phosphorylation in CD4+ T cells in response to IL-6 and IL-21; genetic deletion, transgenic dominant-negative, or pharmacologic inhibition of SHP-1 strongly promotes Th17 development, identifying SHP-1 as a negative regulator of STAT3-driven Th17 differentiation.\",\n      \"method\": \"T cell-specific SHP-1 knockout, inducible dominant-negative SHP-1 transgenic mice, pharmacologic SHP-1 inhibition, Th17 skewing assays, STAT3 phosphorylation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — three complementary genetic/pharmacologic approaches with consistent STAT3 mechanistic readout; single lab but highly rigorous\",\n      \"pmids\": [\"22438258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"Regorafenib activates SHP-1 by directly disrupting the autoinhibitory association between the N-SH2 and catalytic PTP domain of SHP-1; deletion of N-SH2 (dN1) or D61A point mutation blocks regorafenib-induced SHP-1 activation and STAT3(Tyr705) dephosphorylation.\",\n      \"method\": \"SHP-1 activity assay, N-SH2 deletion and D61A point mutation constructs, Western blot for p-STAT3, xenograft tumor model\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — enzymatic activity assay combined with domain deletion and point mutagenesis; in vivo confirmation; single lab\",\n      \"pmids\": [\"25071018\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SHP-1 is recruited to and dephosphorylates Cbl-b upon TCR stimulation; loss of SHP-1 in T cells leads to increased Cbl-b tyrosine phosphorylation, ubiquitination, and degradation. CD28 costimulation abrogates SHP-1/Cbl-b interaction, linking this mechanism to T cell activation control.\",\n      \"method\": \"Co-immunoprecipitation of SHP-1 with Cbl-b, phosphorylation and ubiquitination Western blots, T cell-specific Shp1-/- mice, Cbl-b overexpression rescue\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP, genetic null model, rescue by Cbl-b overexpression, multiple orthogonal methods; single lab\",\n      \"pmids\": [\"26416283\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SHP-1 co-localizes with and binds to TRPV1 in DRG nociceptive neurons and dephosphorylates TRPV1, reducing channel activity; pharmacological inhibition of SHP-1 sensitizes TRPV1 and induces thermal hyperalgesia in vivo.\",\n      \"method\": \"Co-immunoprecipitation of SHP-1 with TRPV1, whole-cell patch clamp of DRG neurons, intrathecal SHP-1 inhibitor injection, SHP-1 overexpression in DRG neurons\",\n      \"journal\": \"Pain\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP substrate identification, direct electrophysiology, pharmacological and genetic in vivo validation; single lab\",\n      \"pmids\": [\"25790452\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SHP-1 phosphatase activity (requiring N-SH2 domain and catalytic activity via D61A-constitutively-open mutant) directly dephosphorylates STAT3 at Tyr705 to suppress TGF-β1-induced epithelial-mesenchymal transition in hepatocellular carcinoma cells.\",\n      \"method\": \"SHP-1 overexpression/knockdown, constitutively open (D61A) and catalytic dead (C453S) SHP-1 mutants, TGF-β1 stimulation, p-STAT3 Western blot, migration/invasion assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — domain and catalytic mutants with functional EMT readout and STAT3 mechanistic link; single lab with multiple constructs\",\n      \"pmids\": [\"25619838\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Protein kinase D (PKD) phosphorylates SHP-1 directly; substitution of wild-type SHP-1 with phosphorylation-defective mutant SHP-1 S557A impairs CD4+ thymocyte generation, placing the PKD–SHP-1 axis as a positive regulator of TCR signaling during positive selection.\",\n      \"method\": \"PKD2/PKD3 double-deficient mice, phosphoproteomic substrate identification of SHP-1, SHP-1 S557A knock-in, T cell development analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — phosphoproteomic identification confirmed by genetic phospho-mutant knock-in with clear developmental phenotype; single lab but rigorous multi-method approach\",\n      \"pmids\": [\"27670070\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SHP-1 interacts with the ITIM on TGF-β receptor 1 and is required for TGF-β signaling activation in hematopoietic stem cells (HSCs); Shp-1 knockout HSCs fail to respond to TGF-β-enforced quiescence, demonstrating SHP-1 as a positive mediator of TGF-β–driven HSC quiescence.\",\n      \"method\": \"Shp-1 knockout mice, co-immunoprecipitation of SHP-1 with TGFβR1, in vitro and in vivo HSC quiescence/TGF-β response assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic null model, co-IP with receptor, in vitro and in vivo functional readouts; single lab\",\n      \"pmids\": [\"29669741\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"SHP-1 inhibits JAK/STAT, NF-κB, and AKT (but not MAPK) signaling in hepatocytes and HCC cells; hepatocyte-specific Ptpn6 knockout enhances DEN-induced hepatocarcinogenesis and liver cancer metastasis in mice.\",\n      \"method\": \"Conditional Ptpn6 knockout in hepatocytes, adenoviral SHP-1 delivery, signaling pathway Western blots, DEN-induced tumor model, orthotopic HCC model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional knockout and adenoviral rescue in two in vivo models with pathway-specific mechanistic readouts; single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"29776962\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"Ptpn6 in neutrophils negatively regulates p38 MAPK-dependent production of TNF and IL-1α/β, and maintains Ripk1 function to prevent caspase-8- and Ripk3/Mlkl-dependent cell death and IL-1α/β release; combined deletion of caspase-8 and Ripk3 or Mlkl strongly protects Ptpn6-deficient neutrophils from inflammatory disease.\",\n      \"method\": \"Conditional Ptpn6 deletion in neutrophils, genetic deletion of Ripk1, Ripk3, Mlkl, caspase-8 in Ptpn6ΔPMN background, p38 MAPK activity assay, IL-1 and TNF measurement\",\n      \"journal\": \"Nature immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic epistasis crosses with defined pathway readouts; rigorous multi-deletion study\",\n      \"pmids\": [\"31819256\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"PD-L1 activates SHP-1 in DRG TRPV1+ nociceptive neurons; SHP-1 inhibits TRPV1 currents and bone cancer pain. Conditional deletion of SHP-1 in NaV1.8+ neurons aggravates bone cancer pain and abolishes PD-L1-mediated inhibition of TRPV1 currents.\",\n      \"method\": \"Conditional SHP-1 deletion in NaV1.8+ neurons, patch-clamp recording of TRPV1 currents, PD-L1 injection, bone cancer pain behavioral assay, PD-1/TRPV1/SHP-1 co-localization\",\n      \"journal\": \"JCI insight\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with electrophysiology and behavioral readouts; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"32960817\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"DJ-1 facilitates the interaction between SHP-1 and TRAF6 in astrocytes during cerebral ischemia/reperfusion; SHP-1/TRAF6 interaction promotes dissociation of NLRX1 from TRAF6 and reduces inflammatory cytokine production; a SHP-1 inhibitor blocks this DJ-1-dependent anti-inflammatory effect.\",\n      \"method\": \"Co-immunoprecipitation of SHP-1 with TRAF6 and NLRX1, DJ-1 knockdown/overexpression, SHP-1 inhibitor, OGD/R and MCAO/R models\",\n      \"journal\": \"Journal of neuroinflammation\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP and pharmacological inhibition with functional readout; single lab, limited mechanistic depth for SHP-1 catalytic role\",\n      \"pmids\": [\"32151250\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SKAP2 forms a complex with Sirpα and SHP-1 and recruits the Sirpα/SHP-1 complex to TLR4 to attenuate NF-κB inflammatory signaling; SKAP2 also directly associates with MyD88/TIRAP/TRAM adaptors of TLR4.\",\n      \"method\": \"Co-immunoprecipitation of SKAP2-Sirpα-SHP-1 complex, SKAP2 knockout mice, NF-κB activity assays, LPS stimulation model\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP complex and genetic knockout with signaling readout; single lab, limited direct SHP-1 enzymatic evidence\",\n      \"pmids\": [\"35034964\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SHP-1 interacts with ER-resident STING and suppresses K63-linked ubiquitination and activation of STING; SHP-1 knockdown leads to STING overactivation, which inhibits AMPK and represses mitochondrial biogenesis in RPE cells.\",\n      \"method\": \"Immunoprecipitation to detect SHP-1-STING interaction and STING ubiquitination, STING-specific antagonist H151, SHP-1 lentiviral knockdown, AMPK/mitochondrial biogenesis assays\",\n      \"journal\": \"Molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — co-IP with ubiquitination assay and pharmacological epistasis; single lab, single study\",\n      \"pmids\": [\"36273174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"SHP-1 reduces SUMO2 post-translational modification of podocin; podocyte-specific SHP-1 deletion preserves slit diaphragm protein complexes and prevents diabetes-induced podocyte loss and diabetic kidney disease progression, revealing a role for SHP-1 in regulating cytoskeleton dynamics and slit diaphragm stability.\",\n      \"method\": \"Conditional podocyte-specific Ptpn6 knockout mice, mass spectrometry SUMOylation analysis, albumin/creatinine ratio, glomerular morphology, Western blots for slit diaphragm proteins\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional knockout with mass spectrometry substrate identification and in vivo functional phenotype; single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37507049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SHP-1 inhibition in leukemia stem cells upregulates PFKP via the AKT–β-catenin pathway, increasing glycolysis and oxidative phosphorylation; elevated PFKP also promotes MYC degradation, reducing immune evasion. This dual mechanism enhances chemosensitivity and immunosurveillance of LSCs.\",\n      \"method\": \"SHP-1 inhibition in LSCs, AKT-β-catenin pathway analysis, PFKP expression assays, MYC degradation assay, metabolic activity assays, in vivo AML models\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway dissection with multiple mechanistic readouts and in vivo validation; single lab but comprehensive approach\",\n      \"pmids\": [\"38321204\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"PTPN6/SHP-1 is a cytoplasmic non-receptor protein tyrosine phosphatase held in an autoinhibited conformation by intramolecular N-SH2 domain occlusion of the active site (crystal structures); it is activated by engagement of its SH2 domains with phosphotyrosine-containing ITIM receptors (LAIR-1, KIRs, inhibitory death receptors) or by phosphorylation at Tyr536/Tyr564 by Lyn and by PKD at Ser557, and reversibly inactivated by oxidation; once active, SHP-1 dephosphorylates a broad set of substrates including ZAP-70, LAT, Src, JAK2, STAT3, TrkA, TRPV1, Cbl-b, p62(DOK), α-actinin, IRAK-1, CBL, p85-PI3K, CEACAM1, and podocin, thereby acting as a central negative regulator of immune receptor, cytokine, growth factor, and integrin signaling in hematopoietic and non-hematopoietic cells, with loss-of-function causing the motheaten inflammatory/autoimmune phenotype in mice.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"PTPN6/SHP-1 is a cytoplasmic non-receptor protein tyrosine phosphatase that functions as a central negative regulator of immune receptor, cytokine, growth factor, and integrin signaling, with loss of expression causing the severe hematopoietic and autoimmune phenotype of motheaten mice [#0, #1]. Its activity is governed by an autoinhibitory mechanism in which the N-SH2 domain occludes the catalytic active site (crystal structure), and engagement of the SH2 domains shifts the enzyme to an open, active conformation that exposes the catalytic pocket [#16, #29]. Activation is achieved physiologically through recruitment to phosphotyrosine-bearing ITIM receptors such as LAIR-1, FCRL5, and FcγRIII, and through phosphorylation: Lyn phosphorylates Tyr536/Tyr564 to enable maximal activity and Stat5 interaction, while PKD phosphorylates Ser557 to promote TCR signaling during positive selection; its activity is additionally subject to reversible redox inactivation by H2O2 [#14, #24, #31, #27, #37, #6]. SHP-1 has narrow substrate specificity favoring acidic and aromatic residues flanking the phosphotyrosine [#28, #11]. Once active it dephosphorylates a broad set of substrates to dampen signaling, including ZAP-70 and LAT in TCR signaling, JAK2 and STAT3 in cytokine pathways, p85-PI3K, Cbl-b, CBL, p62(DOK), TrkA, TRPV1, α-actinin, and CEACAM1, thereby setting activation thresholds and controlling apoptosis, phagocytosis, integrin adhesion, and insulin sensitivity [#1, #15, #5, #8, #7, #34, #18, #19, #35, #21, #22]. In neutrophils SHP-1 also restrains p38 MAPK-driven cytokine production and maintains Ripk1 function to prevent inflammatory cell death [#40]. Through suppression of JAK/STAT, NF-κB, and AKT signaling, SHP-1 acts as a tumor suppressor in hepatocellular carcinoma and modulates leukemia stem cell metabolism and immune evasion [#39, #46].\",\n  \"teleology\": [\n    {\n      \"year\": 1993,\n      \"claim\": \"Established the causal link between PTPN6/SHP-1 loss and disease by showing that motheaten mutations disrupt the gene and abolish phosphatase expression, defining SHP-1 as essential for normal hematopoiesis.\",\n      \"evidence\": \"DNA sequencing, Western blot, and activity assays on motheaten (me/mev) mouse genomic clones\",\n      \"pmids\": [\"8324828\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define molecular substrates\", \"Did not establish the biochemical mechanism of regulation\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Defined SHP-1 as a negative regulator of antigen receptor signaling by demonstrating it binds and dephosphorylates ZAP-70 to raise the TCR activation threshold.\",\n      \"evidence\": \"Co-IP, kinase activity assays, and dominant-negative SHP-1 expression in T cells\",\n      \"pmids\": [\"8638162\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address upstream receptors recruiting SHP-1\", \"Mechanism of activation unresolved\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Showed SHP-1 acts within distinct inhibitory coreceptor pathways and can also positively regulate Src, revealing context-dependent positive and negative roles.\",\n      \"evidence\": \"SHP-1/SHIP-deficient B cell lines and apoptosis assays; in vitro Src dephosphorylation in motheaten thymocytes\",\n      \"pmids\": [\"9244303\", \"9242674\", \"9261115\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not reconcile how the same enzyme can be inhibitory or activating in different contexts\", \"Substrate selection determinants unknown\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Identified cytokine-pathway substrates and a redox switch, showing SHP-1 terminates JAK2/STAT signaling and is reversibly inactivated by oxidation.\",\n      \"evidence\": \"Neutralizing antibody electroporation and JAK2 co-IP/activity assays; in vitro H2O2 inactivation and reducing-agent reactivation\",\n      \"pmids\": [\"9814969\", \"9739453\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"JAK2 finding from single lab with limited orthogonal validation\", \"Physiological relevance of redox regulation in vivo not established\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Expanded the substrate repertoire to PI3K signaling, apoptosis, and growth control by identifying p85-PI3K, p62(DOK), and JAK2/STAT3 as targets and demonstrating membrane recruitment is required for apoptosis.\",\n      \"evidence\": \"Co-IP, catalytically inactive mutants, PI3K activity and apoptosis assays; motheaten macrophages; POMC reporter in AtT-20 cells\",\n      \"pmids\": [\"10488096\", \"10545526\", \"10506221\", \"10585470\", \"9740804\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct versus indirect dephosphorylation not always distinguished\", \"Spatial regulation of recruitment incompletely defined\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Provided the first atomic-level view of substrate recognition and added p120 catenin as a substrate, defining the structural basis of specificity.\",\n      \"evidence\": \"X-ray crystallography of the catalytic domain with SIRPα peptides; GST pulldown, co-IP and MS for p120 catenin\",\n      \"pmids\": [\"10660565\", \"10835420\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full-length autoinhibition mechanism not yet visualized\", \"p120 catenin functional consequence single-lab\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Linked receptor recruitment to substrate dephosphorylation by showing ITIM receptor LAIR-1 binds and activates SHP-1, and raft-targeted SHP-1 selectively dephosphorylates LAT.\",\n      \"evidence\": \"Yeast tri-hybrid, membrane co-IP and activity assays; chimeric raft-targeting SHP-1 in Jurkat cells\",\n      \"pmids\": [\"11160222\", \"11420038\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How substrate selectivity (LAT vs ZAP-70) is achieved spatially not fully resolved\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Defined the master regulatory mechanism: the N-SH2 domain autoinhibits the active site, and death-receptor phosphotyrosine motifs recruit SHP-1 to control survival.\",\n      \"evidence\": \"X-ray crystallography of truncated SHP-1; phosphomotif mapping, co-IP and Lyn kinase assay in neutrophils\",\n      \"pmids\": [\"12482860\", \"11786908\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The active open conformation was not yet structurally captured\", \"Conformational transition kinetics unknown\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended SHP-1 function into neuronal apoptosis and tumor suppression, identifying TrkA as a substrate and proteasomal JAK degradation as a downstream consequence.\",\n      \"evidence\": \"Co-IP with phosphosite mapping and motheaten mice for TrkA; SHP-1 transfection with MG132 for JAK degradation\",\n      \"pmids\": [\"14662744\", \"14624462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"JAK degradation study lower mechanistic depth (Medium)\", \"Direct versus indirect routes to JAK turnover unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Demonstrated a cytoskeletal substrate by purifying SHP-1 as the α-actinin phosphatase, broadening its role into structural protein regulation.\",\n      \"evidence\": \"Chromatographic purification, MS identification, in vitro dephosphorylation, COS-7 co-transfection with catalytic mutant\",\n      \"pmids\": [\"15070900\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological setting of α-actinin dephosphorylation not defined in vivo\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Established SHP-1 as a metabolic and inflammatory regulator, controlling insulin receptor/CEACAM1 signaling and macrophage antimicrobial responses.\",\n      \"evidence\": \"Viable motheaten mice with dominant-negative adenovirus and shRNA; insulin clearance and signaling assays; motheaten macrophage NO suppression by Leishmania\",\n      \"pmids\": [\"16617349\", \"17057094\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions to insulin sensitivity not fully dissected\", \"Pathogen-driven SHP-1 activation mechanism incompletely defined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Connected SHP-1 to transcriptional control of its own expression and to additional ITIM receptors, mapping how SHP-1 abundance and recruitment are governed.\",\n      \"evidence\": \"Reporter, EMSA, ChIP and siRNA for PU.1; FCRL5-ITIM mutational analysis and calcium assays\",\n      \"pmids\": [\"17218319\", \"17522256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Other transcriptional regulators of PTPN6 not addressed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Resolved an activation mechanism by showing Lyn-mediated Tyr536/Tyr564 phosphorylation is required for maximal activity and Stat5 suppression, preventing myeloproliferative disease.\",\n      \"evidence\": \"Lyn/PLC-β3 knockout mice, Y536F/Y564F mutants, activity and Stat5 assays\",\n      \"pmids\": [\"20858858\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Interplay between tyrosine phosphorylation and SH2-mediated activation not fully integrated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Quantified intrinsic substrate specificity and captured the open active conformation, completing the structural model of conformational activation.\",\n      \"evidence\": \"Combinatorial peptide library kinetics; X-ray crystallography of full-length open SHP-1\",\n      \"pmids\": [\"21291263\", \"21465528\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How specific receptors trigger the autoinhibited-to-open transition in cells not directly shown\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Demonstrated direct roles in phagosome maturation and revealed inhibitory signaling through the classic activating receptor FcγRIII.\",\n      \"evidence\": \"Confocal microscopy and phagosome fractionation in motheaten macrophages; intravital microscopy and FcγRIII/FcγRIIB-deficient mice\",\n      \"pmids\": [\"22826316\", \"22415018\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Substrates mediating phagolysosome biogenesis not identified\", \"Mechanism of FcγRIII-SHP-1 coupling incompletely defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Defined SHP-1 as a negative regulator of STAT3-driven Th17 differentiation, linking it to adaptive immune polarization.\",\n      \"evidence\": \"T cell-specific knockout, dominant-negative transgenic, pharmacologic inhibition, Th17 and STAT3 assays\",\n      \"pmids\": [\"22438258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct STAT3 dephosphorylation versus upstream effects in this context not fully separated\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Added Cbl-b, TRPV1, and STAT3 as substrates across immune, sensory, and cancer contexts, and showed the open/catalytic mutant directly dephosphorylates STAT3.\",\n      \"evidence\": \"Co-IP and Shp1-/- mice for Cbl-b; patch clamp and in vivo inhibition for TRPV1; D61A/C453S mutants in HCC EMT assays\",\n      \"pmids\": [\"26416283\", \"25790452\", \"25619838\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo substrate selectivity determinants across tissues not resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a positive regulatory phosphorylation by PKD at Ser557 required for TCR-driven thymocyte development, broadening SHP-1 regulation beyond tyrosine phosphorylation.\",\n      \"evidence\": \"PKD2/PKD3 double-deficient mice, phosphoproteomics, S557A knock-in, T cell development analysis\",\n      \"pmids\": [\"27670070\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How Ser557 phosphorylation alters conformation or activity mechanistically not defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Revealed positive (signal-promoting) roles for SHP-1 in TGF-β receptor signaling and HSC quiescence, and confirmed tumor-suppressor function in hepatocarcinogenesis.\",\n      \"evidence\": \"Shp-1 knockout mice and TGFβR1 co-IP for HSC quiescence; conditional hepatocyte Ptpn6 knockout with DEN and orthotopic HCC models\",\n      \"pmids\": [\"29669741\", \"29776962\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic basis for SHP-1 promoting rather than dampening TGF-β signaling not resolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established that neutrophil SHP-1 restrains p38 MAPK cytokine production and maintains Ripk1 to prevent programmed cell death, explaining the inflammatory motheaten phenotype.\",\n      \"evidence\": \"Conditional neutrophil Ptpn6 deletion with Ripk1/Ripk3/Mlkl/caspase-8 epistasis crosses and cytokine assays\",\n      \"pmids\": [\"31819256\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SHP-1 substrates within the Ripk1/cell-death axis not identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Connected SHP-1 to checkpoint and innate signaling, mediating PD-L1 suppression of TRPV1 nociception and linking it to TRAF6/STING-dependent inflammation.\",\n      \"evidence\": \"Conditional NaV1.8+ neuron knockout with electrophysiology and pain behavior; co-IP of SHP-1 with TRAF6/NLRX1 in ischemia models\",\n      \"pmids\": [\"32960817\", \"32151250\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"TRAF6/DJ-1 finding is Medium-confidence with limited catalytic evidence\", \"Whether SHP-1 acts catalytically or as a scaffold in STING/TRAF6 contexts unclear\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Implicated SHP-1 in TLR4/innate immune adaptor complexes and STING regulation, suggesting scaffold-associated functions beyond classical phosphatase activity.\",\n      \"evidence\": \"Co-IP of SKAP2-Sirpα-SHP-1 complex and SKAP2 knockout mice; co-IP and ubiquitination assays for SHP-1-STING with pharmacological epistasis\",\n      \"pmids\": [\"35034964\", \"36273174\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Limited direct SHP-1 enzymatic evidence in these contexts\", \"Single-lab findings awaiting independent confirmation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified podocin SUMOylation regulation as a non-canonical SHP-1 function protecting against diabetic kidney disease.\",\n      \"evidence\": \"Podocyte-specific Ptpn6 knockout, MS SUMOylation analysis, glomerular phenotyping\",\n      \"pmids\": [\"37507049\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanistic link between SHP-1 phosphatase activity and SUMO2 modification of podocin not fully defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a metabolic and immune-evasion axis whereby SHP-1 inhibition reprograms leukemia stem cell glycolysis via AKT-β-catenin-PFKP and promotes MYC degradation.\",\n      \"evidence\": \"SHP-1 inhibition in LSCs, pathway and metabolic assays, MYC degradation analysis, in vivo AML models\",\n      \"pmids\": [\"38321204\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct SHP-1 substrate upstream of the AKT-β-catenin axis not identified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single phosphatase achieves context-specific selection among its many substrates and switches between negative and positive regulatory roles in different cells remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking receptor recruitment, phosphorylation state, and substrate choice\", \"Scaffold versus catalytic contributions in innate immune complexes not separated\", \"Determinants of positive (TGF-β, Src) versus negative regulation undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140096\", \"supporting_discovery_ids\": [1, 2, 5, 7, 8, 15, 18, 19, 21, 34, 35, 36]},\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [11, 16, 28, 29, 33]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 3, 22, 32, 39, 40]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [21]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [16, 29]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [9, 14, 15]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [30]},\n      {\"term_id\": \"GO:0005783\", \"supporting_discovery_ids\": [44]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [1, 3, 17, 24, 31, 32, 40]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [2, 5, 7, 8, 19, 38]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [9, 17, 19, 40]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [0, 27, 39, 46]},\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [8, 25, 32, 36]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [22, 46]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ZAP-70\", \"JAK2\", \"STAT3\", \"Cbl-b\", \"TrkA\", \"TRPV1\", \"LAIR-1\", \"CBL\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}