{"gene":"INPP5D","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1997,"finding":"SHIP (INPP5D) is required for FcγRIIB-mediated inhibitory signaling in B cells but not for KIR-class inhibitory signaling (which requires SHP-1), defining two distinct inhibitory pathways; SHIP recruitment attenuates a pro-apoptotic signal initiated by FcγRIIB co-ligation with BCR.","method":"SHIP-deficient B cell lines generated by targeted deletion; functional inhibitory signaling assays; BCR-triggered apoptosis readouts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout cell lines with defined functional readouts, replicated across multiple inhibitory receptor systems in one rigorous study","pmids":["9244303"],"is_preprint":false},{"year":1998,"finding":"SHIP1 controls BCR signaling by reducing PIP3 levels, thereby regulating membrane recruitment of the tyrosine kinase Btk through PH domain–phosphoinositol lipid interactions; deletion of SHIP increases PIP3, increases Btk membrane association, and causes hyperresponsive BCR signaling and elevated calcium flux.","method":"FcγRIIB co-ligation assays; SHIP membrane expression constructs; PI3K inhibition; SHIP-deficient cells; Btk membrane-targeted chimera rescue experiments","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal genetic and pharmacological approaches in a single rigorous study with defined molecular mechanism","pmids":["9586640"],"is_preprint":false},{"year":1998,"finding":"SHIP-deficient DT40 B cells display enhanced and prolonged intracellular Ca2+ mobilization (sustained increase or long-lasting oscillations) in response to BCR ligation, while ERK activation is unaffected, demonstrating that SHIP specifically modulates Ca2+ mobilization during B cell activation.","method":"SHIP-deficient DT40 B cell line; BCR cross-linking; single-cell Ca2+ imaging; ERK phosphorylation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — isogenic knockout cell line with single-cell imaging and biochemical validation, clear molecular specificity shown","pmids":["9820480"],"is_preprint":false},{"year":1999,"finding":"Upon FLT3 receptor activation, SHC binds to SHIP1 via the SHC PTB domain; SHC overexpression increases SHIP1 tyrosine phosphorylation and limits FLT3-dependent cell growth in a PTB domain-dependent manner.","method":"FLT3-activatable Ba/F3 cells; SHC overexpression; co-precipitation; phosphorylation mapping; cell growth assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-precipitation and overexpression with domain mapping and functional readout, single lab","pmids":["10482988"],"is_preprint":false},{"year":2000,"finding":"SHIP1 forms a signaling complex with DOK1, PI3K, and CRKL in BCR/ABL-transformed cells; DOK1 binds SHIP1 directly through its PTB domain, and CRKL binds via the CRKL-SH2 domain. Tyr917 and Tyr1020 on SHIP1 mediate interactions with DOK1, and tyrosine mutations at these sites abrogate SHIP1-dependent suppression of cell migration.","method":"SHIP1 overexpression in BCR/ABL Ba/F3 cells; co-precipitation; domain mutants; migration assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-precipitation with domain mapping, mutagenesis, and functional migration readout, single lab","pmids":["11031258"],"is_preprint":false},{"year":2001,"finding":"The C-terminus (proline-rich region) of SHIP1 is essential for its ability to hydrolyze PIP3 and inhibit mast cell degranulation; C-terminally truncated SHIP1 constructs fail to revert the SHIP1-/- mast cell phenotype even when the 5'-phosphatase catalytic domain is intact. A phosphatase-dead mutant also cannot revert the phenotype, confirming catalytic activity is required.","method":"Retroviral reconstitution of SHIP-/- BMMCs with SHIP1 truncation and point mutants; PIP3 measurement; calcium entry assay; degranulation assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple deletion and point mutants reconstituted in knockout cells with direct biochemical (PIP3) and functional (degranulation) readouts","pmids":["11222379"],"is_preprint":false},{"year":2003,"finding":"A somatic mutation at codon 684 (Val→Glu) in the phosphatase active site of SHIP1 found in AML reduces catalytic activity in vitro, and expression of SHIP1-V684E in K562 cells confers growth advantage and resistance to apoptosis through deregulated PI(3,4,5)P3/Akt signaling.","method":"In vitro inositol 5'-phosphatase assay; transfection of mutant SHIP1-V684E; cell growth and apoptosis assays; Akt phosphorylation measurement","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro catalytic assay with disease-relevant mutant plus cellular functional readouts, single lab","pmids":["12529653"],"is_preprint":false},{"year":2003,"finding":"SHIP-1 becomes tyrosine-phosphorylated upon M-CSF stimulation in a Src family kinase-dependent manner and negatively regulates M-CSF-induced Akt activation. SHIP-1 binds Lyn via its SH2 domain (independent of Lyn kinase activity), and Lyn stabilizes SHIP-1 at the membrane to enhance its regulation of Akt.","method":"THP-1 cells; 3T3-Fms transfection; GST fusion protein pulldown; co-immunoprecipitation; SHIP-1 and Lyn knockout macrophages; Akt phosphorylation; NF-κB reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP, GST pulldown, domain mapping, knockout mouse cells, and NF-κB reporter all in one study","pmids":["12882960"],"is_preprint":false},{"year":2004,"finding":"SHIP1 and Lyn kinase negatively regulate integrin αIIbβ3 outside-in signaling in platelets by controlling PIP3 accumulation, cytosolic calcium response, and platelet spreading; SHIP1 phosphorylation is partially regulated by Lyn, and SHIP1-dependent PIP3 metabolism down-regulates the stability of integrin αIIbβ3-fibrinogen adhesive bonds.","method":"SHIP1 and Lyn knockout murine platelets; PIP3 measurement; calcium flux assay; platelet spreading; platelet adhesion under physiological blood flow","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse platelets with multiple orthogonal functional readouts (PIP3, Ca2+, spreading, adhesion) in single study","pmids":["15166241"],"is_preprint":false},{"year":2004,"finding":"SHIP1 and SHIP2 interact preferentially with the Tec kinase (vs. other Tec family members) through the Tec SH3 domain and inhibit Tec activity and membrane localization; inactivation of the Tec SH3 domain generates a hyperactive Tec, and constitutive targeting of Tec to the membrane relieves SHIP1-mediated inhibition.","method":"Co-immunoprecipitation; in vitro kinase inhibition assay; Tec SH3 domain mutagenesis; membrane-targeted Tec chimera rescue; Tec membrane localization imaging","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — four independent experimental approaches including in vitro activity assay, domain mutagenesis, and membrane targeting rescue in one study","pmids":["15492005"],"is_preprint":false},{"year":2006,"finding":"SHIP1 governs neutrophil polarization and chemotaxis by directing where PIP3 accumulates; genetic inactivation of SHIP1 leads to severe defects in neutrophil polarization and motility, with diffuse rather than leading-edge PIP3 distribution, while loss of PTEN has no impact on neutrophil chemotaxis.","method":"SHIP1 knockout mice; transgenic AktPH-GFP PIP3 bioprobe mice; time-lapse live imaging of chemotaxing neutrophils; comparison with PTEN-null neutrophils","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic knockout combined with live PIP3 imaging in primary cells, direct mechanistic comparison with PTEN","pmids":["17173042"],"is_preprint":false},{"year":2006,"finding":"SHIP1 negatively regulates osteoclast precursor proliferation through the Akt pathway by controlling D-type cyclin upregulation and p27 downregulation; SHIP1-null BMMs show increased Akt activation and retinoblastoma protein phosphorylation specifically in response to M-CSF, without altered cell survival.","method":"SHIP1-null mouse bone marrow macrophages; Akt phosphorylation; cyclin D and p27 western blotting; retinoblastoma phosphorylation; cell proliferation and survival assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse primary cells with multiple defined biochemical endpoints in one study","pmids":["17142780"],"is_preprint":false},{"year":2007,"finding":"Small-molecule activators of SHIP1 bind an allosteric activation domain within SHIP1 (not the catalytic site), activate recombinant SHIP1 in vitro, stimulate SHIP1 activity in intact macrophage and mast cells, and inhibit the PI3K pathway in hematopoietic cells in vivo.","method":"In vitro enzyme assay with recombinant SHIP1; intact cell PI3K pathway readouts; allosteric domain mapping; in vivo mouse models of endotoxemia and anaphylaxis","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro recombinant enzyme assay plus intact cell and in vivo validation with domain mapping","pmids":["17502453"],"is_preprint":false},{"year":2007,"finding":"SHIP-1 is recruited to forming phagosomes and sequestered at the leading edge, dissociating from phagocytic cups earlier than PI3K, restricting its inhibitory activity to early stages of phagocytosis; PTEN-YFP does not localize to phagosomes, indicating spatially distinct roles for the two phosphatases.","method":"YFP chimeras of SHIP-1, PTEN, p85; PH domain chimeras for PIP3/PI(3,4)P2 mapping; live-cell quantitative fluorescence imaging of phagosome formation","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct live imaging of multiple fluorescent probes with quantitative spatial-temporal analysis in one study","pmids":["17442886"],"is_preprint":false},{"year":2008,"finding":"SHIP-1 promotes an early phagosomal oxidative burst through localized conversion of PI(3,4,5)P3 to PI(3,4)P2; SHIP-1-deficient macrophages have elevated PI(3,4,5)P3/PI(3,4)P2 ratios on phagosomal membranes, decreased early NADPH oxidase activity, persistent PI(3)P elevation, and early Rab5a phagosomal localization, indicating altered phagosome maturation.","method":"SHIP-1-deficient mouse macrophages; phospholipid dynamics imaging on individual phagosomes; reactive oxygen intermediate assay in phagosomes; membrane trafficking markers","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse cells with direct phagosome-level phospholipid and ROS measurements using multiple complementary approaches","pmids":["18490750"],"is_preprint":false},{"year":2008,"finding":"SHIP1 is recruited to FcεRI signaling complexes through binding to two tyrosines on the LAT adaptor protein; this recruitment is dampened by NTAL, which reduces LAT-mediated SHIP1 recruitment leading to increased Akt phosphorylation and enhanced mast cell survival.","method":"NTAL-deficient mast cells; co-immunoprecipitation; Akt phosphorylation; mast cell survival assays; LAT tyrosine mapping","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with defined binding sites and functional survival readout, single lab","pmids":["18322174"],"is_preprint":false},{"year":2009,"finding":"SHIP1 is a direct target of miR-155; miR-155 represses SHIP1 through direct 3'UTR interactions conserved through evolution. Repression of SHIP1 by miR-155 results in increased Akt activation following LPS stimulation, and specific knockdown of SHIP1 in hematopoietic cells reproduces the myeloproliferative disorder seen in miR-155-expressing mice.","method":"Gain- and loss-of-function miR-155 in hematopoietic cells in vitro and in vivo; 3'UTR reporter assays; retroviral miR-155-formatted siRNA against SHIP1; Akt phosphorylation; LPS-treated WT vs. miR-155-/- macrophages","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct 3'UTR interaction validated plus in vivo phenocopy with SHIP1-specific knockdown, multiple orthogonal methods","pmids":["19359473"],"is_preprint":false},{"year":2009,"finding":"Lyn and SHIP-1 associate with PKC-δ specifically upon GPVI (but not PAR) agonist stimulation of platelets; Lyn-mediated phosphorylation of SHIP-1 (Y1020) and PKC-δ (Y311) and their association negatively regulate GPVI-mediated dense granule secretion; in Lyn-null platelets, GPVI-mediated SHIP-1 phosphorylation is inhibited.","method":"Human platelet stimulation; co-immunoprecipitation; Lyn-null and SHIP-1-null mouse platelets; phosphorylation site mapping; dense granule secretion assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP with knockout validation and defined phosphorylation sites in multiple experimental systems","pmids":["19587372"],"is_preprint":false},{"year":2010,"finding":"SHIP1 inhibits TREM2/DAP12-dependent PI3K activation by binding to DAP12 in an SH2 domain-dependent manner and blocking PI3K recruitment to DAP12; DAP10 is required for DAP12-dependent PI3K recruitment, while SHIP1 directly prevents this interaction.","method":"TREM2 ligation assays; co-immunoprecipitation; SH2 domain-dependent binding assays; PI3K, ERK, Vav3 activation readouts; Ca2+ mobilization; actin reorganization; apoptosis assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP with domain mapping and multiple downstream signaling readouts demonstrating mechanistic blockade of PI3K recruitment","pmids":["20484116"],"is_preprint":false},{"year":2010,"finding":"PKA phosphorylates SHIP1 at Ser440 within the catalytic region, and this phosphorylation increases SHIP1 enzymatic activity; the S440A mutant abolishes PKA-mediated SHIP1 activation and the resulting inhibition of Akt downstream of BCR engagement.","method":"Mass spectrometry identification of PKA phosphorylation sites; SHIP1 truncation and point mutants; in vitro kinase assay; mammalian cell Akt phosphorylation; SHIP1-null DT40 cells reconstituted with SHIP1 mutants; flow cytometry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — MS identification plus mutagenesis with in vitro and in-cell functional validation","pmids":["20810657"],"is_preprint":false},{"year":2010,"finding":"LPS stimulation of macrophages upregulates SHIP via MyD88-dependent TGFβ autocrine signaling; elevated SHIP then inhibits both MyD88-dependent and independent signaling to mediate endotoxin tolerance and cross-tolerance, and restrains LPS-induced IFN-β production. SHIP-/- mice overproduce IFN-β in response to LPS.","method":"SHIP-/- macrophages and mice; isoform-specific PI3K inhibitors; MyD88 pathway analysis; TGFβ neutralization; IFN-β measurement in vivo","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mice plus multiple pharmacological and genetic interventions establishing pathway position","pmids":["19139077"],"is_preprint":false},{"year":2011,"finding":"SHIP1 is a nucleo-cytoplasmic shuttling protein actively imported into and exported from the nucleus via two canonical NLS sequences (K327KSK and K547KLR); nuclear SHIP1 is enzymatically active with similar specific activity to cytoplasmic SHIP1, and mutational inactivation of either NLS reduces nuclear import and decreases cell proliferation.","method":"Confocal microscopy of SHIP1-GFP; nuclear fractionation; enzyme activity assay on nuclear fractions; NLS point mutagenesis; nuclear import/export inhibitor studies; cell proliferation assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct subcellular fractionation with enzymatic activity measurement, NLS mutagenesis, and functional proliferation readout","pmids":["21864674"],"is_preprint":false},{"year":2012,"finding":"The ITT-like motif of TIGIT is phosphorylated at Tyr225 upon TIGIT/PVR engagement and recruits cytosolic adaptor Grb2, which then recruits SHIP1 to prematurely terminate PI3K and MAPK signaling, suppressing granule polarization and NK cell cytotoxicity; SHIP1 silencing dramatically abolishes TIGIT/PVR-mediated killing inhibition.","method":"NK cell TIGIT/PVR engagement; phosphorylation mapping; co-immunoprecipitation; SHIP1 siRNA knockdown; granule polarization imaging; cytotoxicity assay; Tyr225/Asn227 mutant rescue","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 / Strong — co-IP, phosphorylation site mapping, siRNA knockdown, and point-mutant rescue all establishing the TIGIT→Grb2→SHIP1 signaling axis","pmids":["23154388"],"is_preprint":false},{"year":2012,"finding":"SHIP1 regulates PIP3 production specifically in response to cell adhesion (not in suspension) and prevents formation of top-down PIP3 polarity; SHIP1-/- neutrophils lose polarity upon adhesion, are extremely adherent, and show elevated Akt activation; chemotaxis can be restored by reducing adhesion.","method":"SHIP1-/- neutrophils; cell adhesion vs. suspension PIP3 measurement; Akt activation assay; cell polarity imaging; adhesion and chemotaxis assays","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — knockout mouse cells with direct PIP3 measurement and multiple functional readouts revealing adhesion-specific mechanism","pmids":["22323291"],"is_preprint":false},{"year":2012,"finding":"CD2AP forms a complex with SHIP1 (identified by co-immunoprecipitation and mass spectrometry) in plasmacytoid dendritic cells; upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associates with and inhibits the E3 ubiquitin ligase Cbl, preventing ubiquitination and degradation of Syk and FcεR1γ, thereby positively regulating BDCA2/FcεR1γ ITAM signaling.","method":"Co-immunoprecipitation; mass spectrometry; SHIP1 and CD2AP knockdown; ubiquitination assay; Syk/FcεR1γ stability assay; membrane co-localization imaging; IFN production assay","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — MS-confirmed interaction, siRNA knockdown, ubiquitination assay, and membrane co-localization providing mechanistic evidence for Cbl inhibition","pmids":["22706086"],"is_preprint":false},{"year":2013,"finding":"AQX-1125, a small-molecule SHIP1 activator, increases the catalytic activity of recombinant human SHIP1 in vitro through a mechanism requiring the C2 region; deletion of the C2 region abolishes AQX-1125-mediated activation. The compound inhibits Akt phosphorylation in SHIP1-proficient but not SHIP1-deficient cells.","method":"In vitro recombinant human SHIP1 enzyme assay; C2-region deletion construct; SHIP1-proficient vs. deficient cell lines; Akt phosphorylation; cytokine production; mast cell activation; leukocyte chemotaxis","journal":"British journal of pharmacology","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzyme assay with domain deletion mutant plus isogenic cell line comparison","pmids":["23121445"],"is_preprint":false},{"year":2011,"finding":"The SH2 domain of SHIP1 can bind to the C-terminus of SHIP1 itself (inter- and intramolecularly), and this intramolecular interaction regulates the association between SHIP1 and Ig-α; the SH2 domain of SHIP1 interacts with Ig-α in an Ig-α-dependent manner in cells, but full-length SHIP1 does not interact with phosphorylated Ig-α ITAM, suggesting SH2 domain auto-inhibition.","method":"FRET in S2 cells; fluorescently labeled SH2 domain translocation assay; pulldown with phospho-ITAM peptides; mutant Ig-α BCR B cell lines; pervanadate stimulation; SHIP1 phosphorylation and Akt activation readouts","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — FRET and membrane translocation with biochemical pulldown, single lab, single study","pmids":["22182704"],"is_preprint":false},{"year":2015,"finding":"SHIP1 associates with the death receptor CD95/Fas and promotes T-cell survival at mucosal surfaces; treatment with a Caspase 8 inhibitor prevents SHIP1 inhibitor-mediated T-cell death and reduces mucosal inflammation in SHIP1-/- mice, placing SHIP1 in the extrinsic apoptosis pathway.","method":"Co-immunoprecipitation of SHIP1 with CD95/Fas; caspase 8 inhibitor treatment; SHIP1-/- and CD4CreSHIP1flox/flox mice; T-cell survival and mucosal inflammation assays","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP plus pharmacological rescue with defined genetic models, single lab","pmids":["24781051"],"is_preprint":false},{"year":2015,"finding":"PSTPIP2 binds SHIP1 through critical tyrosine residues at the C-terminus of PSTPIP2; SHIP1 inhibition in neutrophils enhances IL-1β processing, demonstrating that the PSTPIP2-SHIP1 interaction is functionally important for suppressing neutrophil IL-1β production.","method":"Co-immunoprecipitation; phospho-site mapping; SHIP1 inhibitor in neutrophils; IL-1β processing assay; stimulation with silica, Ab aggregates, and LPS","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with defined binding sites and pharmacological functional validation, single lab","pmids":["26304991"],"is_preprint":false},{"year":2009,"finding":"SHIP1 gene transfer (lentiviral INPP5D) into CD34+ AML cells reduces GM-CSF-dependent and autonomous cell proliferation; an enzymatically inactive SHIP1 mutant (D672A) has no effect, establishing that SHIP1's catalytic activity is required for its anti-proliferative function.","method":"Lentiviral INPP5D gene transfer into AML patient CD34+ cells; GM-CSF-dependent and autonomous proliferation assays; catalytically inactive SHIP1-D672A control","journal":"Gene therapy","confidence":"High","confidence_rationale":"Tier 1 / Strong — catalytic mutant control directly proves enzymatic activity requirement; replicated across 12 patient samples","pmids":["19148132"],"is_preprint":false},{"year":2020,"finding":"SHIP-1 regulates macrophage M2 polarization and phagocytosis during Pseudomonas aeruginosa infection through a PI3K/Akt-STAT5-Trib1 axis; SHIP-1 deficiency augments PI3K phosphorylation and nuclear STAT5 translocation, inducing Trib1 expression critical for M2 differentiation.","method":"SHIP-1-/- mice; siRNA silencing in macrophages; PI3K, Akt, STAT5, Trib1 expression and phosphorylation; macrophage polarization markers; bacterial burden; survival assays","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — knockout and siRNA with multiple pathway markers defining the PI3K-STAT5-Trib1 axis, single lab","pmids":["32256487"],"is_preprint":false},{"year":2022,"finding":"A novel SHIP1 agonist (K306), identified via AI, activates SHIP1 through a mechanism that does not require the C2 domain (unlike other known SHIP1 agonists), suppresses inflammatory cytokines and iNOS in macrophages and microglia in a SHIP1-dependent manner, and enhances phagolysosomal degradation of synaptosomes and dead neurons by microglia.","method":"In vitro SHIP1 enzyme assay; SHIP1-/- macrophages/microglia as controls; C2 domain deletion constructs; cytokine and iNOS measurement; phagolysosomal degradation assay; in vivo LPS endotoxemia model","journal":"iScience","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro enzyme assay with domain comparison, SHIP1-null cell controls, and in vivo validation","pmids":["35465359"],"is_preprint":false},{"year":2023,"finding":"Reduction in INPP5D (SHIP1) activity in iPSC-derived human microglia leads to formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18; this is associated with disrupted autophagy; evidence from human AD brain confirms that reduced SHIP1 function in microglia results in inflammasome activation.","method":"INPP5D-disrupted iPSC-derived human microglia; RNA and protein profiling; pharmacological SHIP1 inhibition; NLRP3 inflammasome assembly assay; CASP1 cleavage and IL-1β/IL-18 ELISA; multi-analytic analysis of human AD brain tissue","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (genetic disruption, pharmacological validation, iPSC human cells, and post-mortem human brain) converging on NLRP3/CASP1 mechanism","pmids":["38016942"],"is_preprint":false},{"year":2023,"finding":"INPP5D and TREM2/TYROBP exert opposing effects on PI(3,4,5)P3 signaling and phosphoproteins involved in actin assembly; Inpp5d haplodeficiency in a TREM2 loss-of-function mouse model restores microglial association with Aβ plaques and partially restores plaque compaction, placing INPP5D downstream of TREM2/TYROBP in regulating the microglial barrier against Aβ toxicity.","method":"Tyrobp-deficient TREM2 loss-of-function mice crossed with Inpp5d haplodeficient mice; microglial clustering; plaque compaction; astrogliosis; phosphorylated tau+ dystrophic neurites; mechanistic PI(3,4,5)P3 signaling and phosphoproteomic analyses","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in mouse model with phosphoproteomic mechanistic analysis, single lab","pmids":["37035000"],"is_preprint":false},{"year":2024,"finding":"SHIP1 limits complement-mediated synaptic pruning in the developing hippocampus; conditional loss of microglial SHIP1 in early postnatal brain increases complement deposition and synapse loss, causes abnormal synaptic pruning, and leads to cognitive defects in adulthood; iPSC-derived microglia lacking SHIP1 also show increased engulfment of synaptic structures.","method":"Conditional microglial SHIP1 knockout mice (early vs. late postnatal deletion); proteomics; complement marker staining; synaptic pruning assays; cognitive behavioral tests; iPSC-derived microglia engulfment assay","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional in vivo genetic model at defined developmental windows with proteomics, human iPSC validation, and behavioral readouts","pmids":["39657671"],"is_preprint":false},{"year":2010,"finding":"Ikaros binds to the promoter of the INPP5D gene (demonstrated by ChIP) and transcriptionally regulates SHIP expression; loss of Ikaros upregulates SHIP while loss of Helios downregulates SHIP, and these expression changes underlie opposite BCR signaling phenotypes (calcium mobilization strength).","method":"Ikaros-deficient and Helios-deficient DT40 B cell lines; chromatin immunoprecipitation (ChIP) of Ikaros at INPP5D promoter; BCR cross-linking calcium assay; SHIP mRNA/protein measurement","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct ChIP establishes transcription factor binding with functional consequence, single lab","pmids":["20602434"],"is_preprint":false}],"current_model":"INPP5D/SHIP1 is a hematopoietic-enriched (and microglial) inositol 5'-phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2 at the plasma membrane (and in the nucleus) to oppose PI3K signaling; it is recruited to inhibitory receptors (FcγRIIB, TIGIT, DAP12) and activation scaffolds (LAT, Ig-α, integrin αIIbβ3) via its SH2 domain and C-terminal proline-rich region, dampening Akt/Btk/Tec kinase membrane localization and calcium flux; its catalytic activity is allosterically enhanced by compounds binding the C2 domain and by PKA-mediated phosphorylation at Ser440; it acts as a spatial regulator of PIP3 polarity in neutrophil chemotaxis and phagosome maturation, a suppressor of NLRP3 inflammasome activation in microglia, a brake on complement-mediated synaptic pruning in developing brain, and a downstream effector of TREM2/TYROBP signaling."},"narrative":{"mechanistic_narrative":"INPP5D (SHIP1) is a hematopoietic and microglial inositol 5'-phosphatase that hydrolyzes PI(3,4,5)P3 to oppose PI3K/Akt signaling and thereby acts as a brake on immune cell activation [PMID:9586640, PMID:11222379, PMID:19148132]. Its catalytic activity is genetically required: phosphatase-dead and active-site mutants fail to revert knockout phenotypes or to suppress proliferation, and the C-terminal proline-rich region is also essential for substrate hydrolysis [PMID:11222379, PMID:19148132]. SHIP1 is recruited to inhibitory and activation receptors through its SH2 domain — including FcγRIIB co-ligated with the BCR, DAP12/TREM2, TIGIT (via Grb2), and the LAT adaptor — where it lowers membrane PIP3 and dampens membrane recruitment of PH-domain kinases such as Btk and Tec, calcium flux, and granule/degranulation responses [PMID:9244303, PMID:9586640, PMID:15492005, PMID:18322174, PMID:20484116, PMID:23154388]. Beyond simple suppression, it functions as a spatial regulator of PIP3 polarity, directing leading-edge PIP3 accumulation during neutrophil adhesion and chemotaxis and restricting its activity to early phagosome formation to control the oxidative burst and phagosome maturation [PMID:17173042, PMID:17442886, PMID:18490750, PMID:22323291]. SHIP1 activity is tuned by Lyn/Src-family-dependent tyrosine phosphorylation, by PKA phosphorylation at Ser440, and by small-molecule allosteric activators acting through the C2 region, while its expression is set by Ikaros at the INPP5D promoter and repressed post-transcriptionally by miR-155 [PMID:12882960, PMID:19359473, PMID:20810657, PMID:23121445, PMID:20602434]. In the brain it operates downstream of TREM2/TYROBP signaling, where loss of SHIP1 function in microglia triggers NLRP3 inflammasome assembly, CASP1 cleavage and IL-1β/IL-18 release, drives excess complement-mediated synaptic pruning during development, and shapes the microglial barrier against amyloid-β [PMID:38016942, PMID:37035000, PMID:39657671].","teleology":[{"year":1997,"claim":"Established SHIP1 as the defining effector of one of two distinct inhibitory receptor pathways, separating FcγRIIB-driven inhibition from KIR/SHP-1 inhibition.","evidence":"SHIP-deficient B cell lines with BCR-triggered apoptosis and inhibitory signaling readouts","pmids":["9244303"],"confidence":"High","gaps":["Did not define the lipid substrate or molecular mechanism of inhibition","Recruitment determinants to FcγRIIB not mapped"]},{"year":1998,"claim":"Defined the molecular mechanism: SHIP1 lowers PIP3 to limit PH-domain kinase membrane recruitment (Btk) and specifically restrains calcium mobilization without affecting ERK.","evidence":"FcγRIIB co-ligation, SHIP-deficient and DT40 B cells, Btk membrane-targeted chimera rescue, single-cell Ca2+ imaging","pmids":["9586640","9820480"],"confidence":"High","gaps":["Did not address spatial control of PIP3","Other PH-domain effectors not enumerated"]},{"year":2001,"claim":"Showed that catalytic activity and the C-terminal proline-rich region are both required for SHIP1 function, defining a substrate-hydrolysis-dependent inhibitory output.","evidence":"Retroviral reconstitution of SHIP-/- mast cells with truncation and phosphatase-dead mutants; PIP3, calcium, degranulation readouts","pmids":["11222379"],"confidence":"High","gaps":["Why the C-terminus is needed for catalysis in cells was not resolved","Structural basis not determined"]},{"year":2003,"claim":"Connected SHIP1 to receptor tyrosine kinase signaling and disease, showing Lyn-dependent phosphorylation/membrane stabilization and that an AML active-site mutation impairs catalysis and deregulates Akt.","evidence":"GST pulldown, reciprocal co-IP, knockout macrophages, in vitro 5'-phosphatase assay with V684E mutant, Akt and growth readouts","pmids":["12882960","12529653"],"confidence":"High","gaps":["Frequency and pathogenic role of V684E in AML not established","Direct structural effect of the mutation not modeled"]},{"year":2004,"claim":"Generalized SHIP1's inhibitory mechanism across cell types, showing it restrains Tec-family kinase activity/membrane localization and integrin αIIbβ3 outside-in signaling in platelets.","evidence":"Co-IP, in vitro kinase inhibition, Tec SH3 mutagenesis and membrane-targeting rescue; Lyn/SHIP1 knockout platelets with PIP3, Ca2+, spreading and adhesion assays","pmids":["15492005","15166241"],"confidence":"High","gaps":["Relative contribution of catalytic vs. scaffolding functions to platelet adhesion not separated"]},{"year":2006,"claim":"Revealed SHIP1 as a spatial regulator of PIP3 rather than a bulk suppressor, directing leading-edge polarity in neutrophil chemotaxis distinct from PTEN.","evidence":"SHIP1 knockout mice with AktPH-GFP PIP3 bioprobe live imaging; comparison with PTEN-null neutrophils; osteoclast precursor proliferation assays","pmids":["17173042","17142780"],"confidence":"High","gaps":["Mechanism targeting SHIP1 to the leading edge not defined","Link between spatial PIP3 control and cytoskeletal machinery incomplete"]},{"year":2007,"claim":"Demonstrated pharmacologically tractable allosteric activation and refined the spatiotemporal model, showing SHIP1 acts at early phagocytic cups distinct from PTEN.","evidence":"In vitro recombinant enzyme assay with allosteric domain mapping plus in vivo endotoxemia/anaphylaxis; live-cell imaging of SHIP1/PTEN/PH-domain probes at phagosomes","pmids":["17502453","17442886"],"confidence":"High","gaps":["Identity of the endogenous allosteric ligand not determined","Recruitment timing determinants at phagosomes not fully mapped"]},{"year":2008,"claim":"Linked SHIP1's local PI(3,4,5)P3-to-PI(3,4)P2 conversion to functional phagosome outcomes (oxidative burst, maturation) and identified LAT-mediated recruitment at FcεRI tuned by NTAL.","evidence":"SHIP-1-deficient macrophages with phagosome-level phospholipid/ROS imaging; NTAL-deficient mast cells with co-IP and LAT tyrosine mapping","pmids":["18490750","18322174"],"confidence":"High","gaps":["LAT recruitment (Medium) lacks reciprocal in vivo validation","Coupling of PI(3,4)P2 to NADPH oxidase effectors not resolved"]},{"year":2009,"claim":"Established transcriptional/post-transcriptional control and proved catalytic activity is required for tumor-suppressive function in primary AML cells.","evidence":"miR-155 gain/loss with 3'UTR reporters and in vivo phenocopy; lentiviral INPP5D vs. catalytically dead D672A in AML CD34+ cells","pmids":["19359473","19148132"],"confidence":"High","gaps":["Full set of upstream regulators of INPP5D expression not catalogued"]},{"year":2010,"claim":"Defined direct biochemical regulation (PKA-Ser440 activation), receptor-blockade mechanism at DAP12/TREM2, transcriptional control by Ikaros, and a role in endotoxin tolerance.","evidence":"MS phospho-site mapping and S440A mutant rescue; TREM2/DAP12 co-IP with SH2-dependent PI3K-blockade; Ikaros ChIP at INPP5D promoter; SHIP-/- mice in LPS tolerance","pmids":["20810657","20484116","20602434","19139077"],"confidence":"High","gaps":["Ikaros regulation (Medium) shown in DT40 only","Integration of multiple regulatory inputs on SHIP1 in vivo unresolved"]},{"year":2011,"claim":"Revealed SHIP1 has an enzymatically active nuclear pool and an autoinhibited SH2 domain, expanding its regulatory and localization repertoire.","evidence":"SHIP1-GFP confocal, nuclear fractionation with activity assay, NLS mutagenesis; FRET and phospho-ITAM pulldowns for SH2 auto-inhibition","pmids":["21864674","22182704"],"confidence":"High","gaps":["Nuclear substrates and functions of SHIP1 not identified","SH2 auto-inhibition (Medium) not validated structurally"]},{"year":2012,"claim":"Extended the adaptor-recruitment paradigm to NK cell TIGIT inhibition (via Grb2), adhesion-specific PIP3 polarity control, and a positive ITAM-stabilizing role via CD2AP/Cbl.","evidence":"TIGIT/PVR phospho-mapping, co-IP, siRNA and mutant rescue in NK cells; SHIP1-/- neutrophil adhesion/PIP3 assays; CD2AP co-IP/MS and ubiquitination assays in pDCs","pmids":["23154388","22323291","22706086"],"confidence":"High","gaps":["How SHIP1 switches between inhibitory and ITAM-stabilizing outputs not defined"]},{"year":2013,"claim":"Validated a clinical-candidate allosteric activator acting through the C2 region, confirming SHIP1 as a drug target with isogenic specificity.","evidence":"In vitro recombinant human SHIP1 assay with C2-deletion construct; SHIP1-proficient vs. deficient cells; Akt and functional readouts","pmids":["23121445"],"confidence":"High","gaps":["Precise C2 binding site and conformational change not structurally resolved"]},{"year":2015,"claim":"Implicated SHIP1 in extrinsic apoptosis (CD95/Fas) for T-cell survival and in neutrophil IL-1β suppression via PSTPIP2 binding.","evidence":"SHIP1/CD95 co-IP with caspase-8 inhibitor rescue in SHIP1-/- mice; PSTPIP2 co-IP/phospho-mapping with IL-1β processing assays","pmids":["24781051","26304991"],"confidence":"Medium","gaps":["Both interactions (Medium) from single labs without reciprocal in vivo validation","Mechanism linking SHIP1 to caspase-8 not defined"]},{"year":2020,"claim":"Placed SHIP1 within a defined macrophage polarization circuit, restraining M2 differentiation via a PI3K/Akt-STAT5-Trib1 axis during bacterial infection.","evidence":"SHIP-1-/- mice and siRNA with pathway phosphorylation, polarization markers, bacterial burden and survival","pmids":["32256487"],"confidence":"Medium","gaps":["Single-lab axis (Medium); direct vs. indirect control of STAT5/Trib1 not separated"]},{"year":2022,"claim":"Distinguished a C2-independent activation mechanism (K306 agonist) and demonstrated SHIP1 activation enhances microglial phagolysosomal degradation and suppresses inflammation.","evidence":"In vitro enzyme assay with C2-deletion comparison, SHIP1-null cell controls, microglial cytokine/iNOS and phagolysosomal assays, in vivo LPS model","pmids":["35465359"],"confidence":"High","gaps":["Binding site of the C2-independent activator not mapped"]},{"year":2023,"claim":"Established SHIP1 as a microglial node in neurodegeneration: loss of activity triggers NLRP3/CASP1 inflammasome activation, and it acts downstream of TREM2/TYROBP to shape the amyloid barrier.","evidence":"INPP5D-disrupted iPSC microglia with inflammasome/IL-1β/IL-18 assays and human AD brain analysis; Inpp5d-haploinsufficient × Tyrobp-deficient TREM2-LOF mice with plaque and phosphoproteomic analyses","pmids":["38016942","37035000"],"confidence":"High","gaps":["Epistasis study (Medium) from single lab","Mechanistic link between disrupted autophagy and NLRP3 assembly not fully resolved"]},{"year":2024,"claim":"Defined a developmental neuronal function: microglial SHIP1 limits complement-mediated synaptic pruning, with loss causing aberrant pruning and adult cognitive deficits.","evidence":"Conditional microglial SHIP1 knockout at defined postnatal windows with proteomics, complement staining, pruning and behavioral assays, plus iPSC-microglia engulfment","pmids":["39657671"],"confidence":"High","gaps":["Lipid-substrate vs. scaffolding contribution to pruning not separated","Link from PIP3 control to complement deposition not mechanistically defined"]},{"year":null,"claim":"The nuclear function and substrates of SHIP1, and how its scaffolding (inhibitory vs. ITAM-stabilizing) outputs are switched in different receptor contexts, remain unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No nuclear substrate identified","No structural model for SH2 auto-inhibition or allosteric activation","Determinants selecting inhibitory vs. positive scaffolding output undefined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,5,6,14,29]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,14,23]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[1,9,18]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[22,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[1,7,13,23]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[21]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[21]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[13,14]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,1,18,22,32]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,7,18,20]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[0,27]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[13,14,31]}],"complexes":[],"partners":["LYN","DAP12","TIGIT","LAT","GRB2","CD2AP","DOK1","PSTPIP2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q92835","full_name":"Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1","aliases":["Inositol polyphosphate-5-phosphatase D","Inositol polyphosphate-5-phosphatase of 145 kDa","SIP-145","Phosphatidylinositol 4,5-bisphosphate 5-phosphatase","SH2 domain-containing inositol 5'-phosphatase 1","SH2 domain-containing inositol phosphatase 1","SHIP-1","p150Ship","hp51CN"],"length_aa":1189,"mass_kda":133.3,"function":"Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways (PubMed:10764818, PubMed:8723348, PubMed:8769125). 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Key regulator of neutrophil migration, by governing the formation of the leading edge and polarization required for chemotaxis. Modulates FCGR3/CD16-mediated cytotoxicity in NK cells. Mediates the activin/TGF-beta-induced apoptosis through its Smad-dependent expression","subcellular_location":"Cytoplasm; Cell membrane; Membrane raft; Cytoplasm, cytoskeleton; Membrane","url":"https://www.uniprot.org/uniprotkb/Q92835/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INPP5D","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":74,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/INPP5D","total_profiled":1310},"omim":[{"mim_id":"613562","title":"Fc RECEPTOR-LIKE PROTEIN 6; FCRL6","url":"https://www.omim.org/entry/613562"},{"mim_id":"612374","title":"STIMULATOR OF INTERFERON RESPONSE cGAMP INTERACTOR 1; STING1","url":"https://www.omim.org/entry/612374"},{"mim_id":"612088","title":"C-TYPE LECTIN DOMAIN FAMILY 12, MEMBER A; CLEC12A","url":"https://www.omim.org/entry/612088"},{"mim_id":"611435","title":"DOCKING PROTEIN 3; DOK3","url":"https://www.omim.org/entry/611435"},{"mim_id":"609807","title":"CD300 ANTIGEN-LIKE FAMILY, MEMBER F; CD300LF","url":"https://www.omim.org/entry/609807"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"intestine","ntpm":47.7},{"tissue":"lymphoid tissue","ntpm":95.6}],"url":"https://www.proteinatlas.org/search/INPP5D"},"hgnc":{"alias_symbol":["SHIP","hp51CN","SHIP1"],"prev_symbol":[]},"alphafold":{"accession":"Q92835","domains":[{"cath_id":"3.30.505.10","chopping":"13-101","consensus_level":"high","plddt":87.4736,"start":13,"end":101},{"cath_id":"2.30.29.30","chopping":"300-397","consensus_level":"high","plddt":84.3853,"start":300,"end":397},{"cath_id":"3.60.10.10","chopping":"404-712","consensus_level":"high","plddt":94.526,"start":404,"end":712},{"cath_id":"2.60.40.150","chopping":"731-866","consensus_level":"high","plddt":92.742,"start":731,"end":866}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92835","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q92835-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q92835-F1-predicted_aligned_error_v6.png","plddt_mean":71.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INPP5D","jax_strain_url":"https://www.jax.org/strain/search?query=INPP5D"},"sequence":{"accession":"Q92835","fasta_url":"https://rest.uniprot.org/uniprotkb/Q92835.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q92835/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q92835"}},"corpus_meta":[{"pmid":"19359473","id":"PMC_19359473","title":"Inositol phosphatase SHIP1 is a primary target of miR-155.","date":"2009","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19359473","citation_count":688,"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":"20484116","id":"PMC_20484116","title":"TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1.","date":"2010","source":"Science signaling","url":"https://pubmed.ncbi.nlm.nih.gov/20484116","citation_count":348,"is_preprint":false},{"pmid":"9586640","id":"PMC_9586640","title":"SHIP modulates immune receptor responses by regulating membrane association of Btk.","date":"1998","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/9586640","citation_count":286,"is_preprint":false},{"pmid":"23154388","id":"PMC_23154388","title":"Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells.","date":"2012","source":"Cell death and differentiation","url":"https://pubmed.ncbi.nlm.nih.gov/23154388","citation_count":263,"is_preprint":false},{"pmid":"17173042","id":"PMC_17173042","title":"Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1.","date":"2006","source":"Nature cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/17173042","citation_count":240,"is_preprint":false},{"pmid":"17901198","id":"PMC_17901198","title":"Functional selectivity through protean and biased agonism: who steers the ship?","date":"2007","source":"Molecular pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/17901198","citation_count":216,"is_preprint":false},{"pmid":"19890474","id":"PMC_19890474","title":"Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas.","date":"2009","source":"EMBO molecular medicine","url":"https://pubmed.ncbi.nlm.nih.gov/19890474","citation_count":177,"is_preprint":false},{"pmid":"20861880","id":"PMC_20861880","title":"The engine driving the ship: metabolic steering of cell proliferation and death.","date":"2010","source":"Nature reviews. 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functional inhibitory signaling assays; BCR-triggered apoptosis readouts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout cell lines with defined functional readouts, replicated across multiple inhibitory receptor systems in one rigorous study\",\n      \"pmids\": [\"9244303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SHIP1 controls BCR signaling by reducing PIP3 levels, thereby regulating membrane recruitment of the tyrosine kinase Btk through PH domain–phosphoinositol lipid interactions; deletion of SHIP increases PIP3, increases Btk membrane association, and causes hyperresponsive BCR signaling and elevated calcium flux.\",\n      \"method\": \"FcγRIIB co-ligation assays; SHIP membrane expression constructs; PI3K inhibition; SHIP-deficient cells; Btk membrane-targeted chimera rescue experiments\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal genetic and pharmacological approaches in a single rigorous study with defined molecular mechanism\",\n      \"pmids\": [\"9586640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SHIP-deficient DT40 B cells display enhanced and prolonged intracellular Ca2+ mobilization (sustained increase or long-lasting oscillations) in response to BCR ligation, while ERK activation is unaffected, demonstrating that SHIP specifically modulates Ca2+ mobilization during B cell activation.\",\n      \"method\": \"SHIP-deficient DT40 B cell line; BCR cross-linking; single-cell Ca2+ imaging; ERK phosphorylation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — isogenic knockout cell line with single-cell imaging and biochemical validation, clear molecular specificity shown\",\n      \"pmids\": [\"9820480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Upon FLT3 receptor activation, SHC binds to SHIP1 via the SHC PTB domain; SHC overexpression increases SHIP1 tyrosine phosphorylation and limits FLT3-dependent cell growth in a PTB domain-dependent manner.\",\n      \"method\": \"FLT3-activatable Ba/F3 cells; SHC overexpression; co-precipitation; phosphorylation mapping; cell growth assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-precipitation and overexpression with domain mapping and functional readout, single lab\",\n      \"pmids\": [\"10482988\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SHIP1 forms a signaling complex with DOK1, PI3K, and CRKL in BCR/ABL-transformed cells; DOK1 binds SHIP1 directly through its PTB domain, and CRKL binds via the CRKL-SH2 domain. Tyr917 and Tyr1020 on SHIP1 mediate interactions with DOK1, and tyrosine mutations at these sites abrogate SHIP1-dependent suppression of cell migration.\",\n      \"method\": \"SHIP1 overexpression in BCR/ABL Ba/F3 cells; co-precipitation; domain mutants; migration assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-precipitation with domain mapping, mutagenesis, and functional migration readout, single lab\",\n      \"pmids\": [\"11031258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The C-terminus (proline-rich region) of SHIP1 is essential for its ability to hydrolyze PIP3 and inhibit mast cell degranulation; C-terminally truncated SHIP1 constructs fail to revert the SHIP1-/- mast cell phenotype even when the 5'-phosphatase catalytic domain is intact. A phosphatase-dead mutant also cannot revert the phenotype, confirming catalytic activity is required.\",\n      \"method\": \"Retroviral reconstitution of SHIP-/- BMMCs with SHIP1 truncation and point mutants; PIP3 measurement; calcium entry assay; degranulation assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple deletion and point mutants reconstituted in knockout cells with direct biochemical (PIP3) and functional (degranulation) readouts\",\n      \"pmids\": [\"11222379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A somatic mutation at codon 684 (Val→Glu) in the phosphatase active site of SHIP1 found in AML reduces catalytic activity in vitro, and expression of SHIP1-V684E in K562 cells confers growth advantage and resistance to apoptosis through deregulated PI(3,4,5)P3/Akt signaling.\",\n      \"method\": \"In vitro inositol 5'-phosphatase assay; transfection of mutant SHIP1-V684E; cell growth and apoptosis assays; Akt phosphorylation measurement\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro catalytic assay with disease-relevant mutant plus cellular functional readouts, single lab\",\n      \"pmids\": [\"12529653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SHIP-1 becomes tyrosine-phosphorylated upon M-CSF stimulation in a Src family kinase-dependent manner and negatively regulates M-CSF-induced Akt activation. SHIP-1 binds Lyn via its SH2 domain (independent of Lyn kinase activity), and Lyn stabilizes SHIP-1 at the membrane to enhance its regulation of Akt.\",\n      \"method\": \"THP-1 cells; 3T3-Fms transfection; GST fusion protein pulldown; co-immunoprecipitation; SHIP-1 and Lyn knockout macrophages; Akt phosphorylation; NF-κB reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP, GST pulldown, domain mapping, knockout mouse cells, and NF-κB reporter all in one study\",\n      \"pmids\": [\"12882960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 and Lyn kinase negatively regulate integrin αIIbβ3 outside-in signaling in platelets by controlling PIP3 accumulation, cytosolic calcium response, and platelet spreading; SHIP1 phosphorylation is partially regulated by Lyn, and SHIP1-dependent PIP3 metabolism down-regulates the stability of integrin αIIbβ3-fibrinogen adhesive bonds.\",\n      \"method\": \"SHIP1 and Lyn knockout murine platelets; PIP3 measurement; calcium flux assay; platelet spreading; platelet adhesion under physiological blood flow\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse platelets with multiple orthogonal functional readouts (PIP3, Ca2+, spreading, adhesion) in single study\",\n      \"pmids\": [\"15166241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 and SHIP2 interact preferentially with the Tec kinase (vs. other Tec family members) through the Tec SH3 domain and inhibit Tec activity and membrane localization; inactivation of the Tec SH3 domain generates a hyperactive Tec, and constitutive targeting of Tec to the membrane relieves SHIP1-mediated inhibition.\",\n      \"method\": \"Co-immunoprecipitation; in vitro kinase inhibition assay; Tec SH3 domain mutagenesis; membrane-targeted Tec chimera rescue; Tec membrane localization imaging\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — four independent experimental approaches including in vitro activity assay, domain mutagenesis, and membrane targeting rescue in one study\",\n      \"pmids\": [\"15492005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SHIP1 governs neutrophil polarization and chemotaxis by directing where PIP3 accumulates; genetic inactivation of SHIP1 leads to severe defects in neutrophil polarization and motility, with diffuse rather than leading-edge PIP3 distribution, while loss of PTEN has no impact on neutrophil chemotaxis.\",\n      \"method\": \"SHIP1 knockout mice; transgenic AktPH-GFP PIP3 bioprobe mice; time-lapse live imaging of chemotaxing neutrophils; comparison with PTEN-null neutrophils\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic knockout combined with live PIP3 imaging in primary cells, direct mechanistic comparison with PTEN\",\n      \"pmids\": [\"17173042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SHIP1 negatively regulates osteoclast precursor proliferation through the Akt pathway by controlling D-type cyclin upregulation and p27 downregulation; SHIP1-null BMMs show increased Akt activation and retinoblastoma protein phosphorylation specifically in response to M-CSF, without altered cell survival.\",\n      \"method\": \"SHIP1-null mouse bone marrow macrophages; Akt phosphorylation; cyclin D and p27 western blotting; retinoblastoma phosphorylation; cell proliferation and survival assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse primary cells with multiple defined biochemical endpoints in one study\",\n      \"pmids\": [\"17142780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Small-molecule activators of SHIP1 bind an allosteric activation domain within SHIP1 (not the catalytic site), activate recombinant SHIP1 in vitro, stimulate SHIP1 activity in intact macrophage and mast cells, and inhibit the PI3K pathway in hematopoietic cells in vivo.\",\n      \"method\": \"In vitro enzyme assay with recombinant SHIP1; intact cell PI3K pathway readouts; allosteric domain mapping; in vivo mouse models of endotoxemia and anaphylaxis\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro recombinant enzyme assay plus intact cell and in vivo validation with domain mapping\",\n      \"pmids\": [\"17502453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SHIP-1 is recruited to forming phagosomes and sequestered at the leading edge, dissociating from phagocytic cups earlier than PI3K, restricting its inhibitory activity to early stages of phagocytosis; PTEN-YFP does not localize to phagosomes, indicating spatially distinct roles for the two phosphatases.\",\n      \"method\": \"YFP chimeras of SHIP-1, PTEN, p85; PH domain chimeras for PIP3/PI(3,4)P2 mapping; live-cell quantitative fluorescence imaging of phagosome formation\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct live imaging of multiple fluorescent probes with quantitative spatial-temporal analysis in one study\",\n      \"pmids\": [\"17442886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SHIP-1 promotes an early phagosomal oxidative burst through localized conversion of PI(3,4,5)P3 to PI(3,4)P2; SHIP-1-deficient macrophages have elevated PI(3,4,5)P3/PI(3,4)P2 ratios on phagosomal membranes, decreased early NADPH oxidase activity, persistent PI(3)P elevation, and early Rab5a phagosomal localization, indicating altered phagosome maturation.\",\n      \"method\": \"SHIP-1-deficient mouse macrophages; phospholipid dynamics imaging on individual phagosomes; reactive oxygen intermediate assay in phagosomes; membrane trafficking markers\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse cells with direct phagosome-level phospholipid and ROS measurements using multiple complementary approaches\",\n      \"pmids\": [\"18490750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SHIP1 is recruited to FcεRI signaling complexes through binding to two tyrosines on the LAT adaptor protein; this recruitment is dampened by NTAL, which reduces LAT-mediated SHIP1 recruitment leading to increased Akt phosphorylation and enhanced mast cell survival.\",\n      \"method\": \"NTAL-deficient mast cells; co-immunoprecipitation; Akt phosphorylation; mast cell survival assays; LAT tyrosine mapping\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with defined binding sites and functional survival readout, single lab\",\n      \"pmids\": [\"18322174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SHIP1 is a direct target of miR-155; miR-155 represses SHIP1 through direct 3'UTR interactions conserved through evolution. Repression of SHIP1 by miR-155 results in increased Akt activation following LPS stimulation, and specific knockdown of SHIP1 in hematopoietic cells reproduces the myeloproliferative disorder seen in miR-155-expressing mice.\",\n      \"method\": \"Gain- and loss-of-function miR-155 in hematopoietic cells in vitro and in vivo; 3'UTR reporter assays; retroviral miR-155-formatted siRNA against SHIP1; Akt phosphorylation; LPS-treated WT vs. miR-155-/- macrophages\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct 3'UTR interaction validated plus in vivo phenocopy with SHIP1-specific knockdown, multiple orthogonal methods\",\n      \"pmids\": [\"19359473\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Lyn and SHIP-1 associate with PKC-δ specifically upon GPVI (but not PAR) agonist stimulation of platelets; Lyn-mediated phosphorylation of SHIP-1 (Y1020) and PKC-δ (Y311) and their association negatively regulate GPVI-mediated dense granule secretion; in Lyn-null platelets, GPVI-mediated SHIP-1 phosphorylation is inhibited.\",\n      \"method\": \"Human platelet stimulation; co-immunoprecipitation; Lyn-null and SHIP-1-null mouse platelets; phosphorylation site mapping; dense granule secretion assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal co-IP with knockout validation and defined phosphorylation sites in multiple experimental systems\",\n      \"pmids\": [\"19587372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SHIP1 inhibits TREM2/DAP12-dependent PI3K activation by binding to DAP12 in an SH2 domain-dependent manner and blocking PI3K recruitment to DAP12; DAP10 is required for DAP12-dependent PI3K recruitment, while SHIP1 directly prevents this interaction.\",\n      \"method\": \"TREM2 ligation assays; co-immunoprecipitation; SH2 domain-dependent binding assays; PI3K, ERK, Vav3 activation readouts; Ca2+ mobilization; actin reorganization; apoptosis assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP with domain mapping and multiple downstream signaling readouts demonstrating mechanistic blockade of PI3K recruitment\",\n      \"pmids\": [\"20484116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PKA phosphorylates SHIP1 at Ser440 within the catalytic region, and this phosphorylation increases SHIP1 enzymatic activity; the S440A mutant abolishes PKA-mediated SHIP1 activation and the resulting inhibition of Akt downstream of BCR engagement.\",\n      \"method\": \"Mass spectrometry identification of PKA phosphorylation sites; SHIP1 truncation and point mutants; in vitro kinase assay; mammalian cell Akt phosphorylation; SHIP1-null DT40 cells reconstituted with SHIP1 mutants; flow cytometry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — MS identification plus mutagenesis with in vitro and in-cell functional validation\",\n      \"pmids\": [\"20810657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"LPS stimulation of macrophages upregulates SHIP via MyD88-dependent TGFβ autocrine signaling; elevated SHIP then inhibits both MyD88-dependent and independent signaling to mediate endotoxin tolerance and cross-tolerance, and restrains LPS-induced IFN-β production. SHIP-/- mice overproduce IFN-β in response to LPS.\",\n      \"method\": \"SHIP-/- macrophages and mice; isoform-specific PI3K inhibitors; MyD88 pathway analysis; TGFβ neutralization; IFN-β measurement in vivo\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mice plus multiple pharmacological and genetic interventions establishing pathway position\",\n      \"pmids\": [\"19139077\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SHIP1 is a nucleo-cytoplasmic shuttling protein actively imported into and exported from the nucleus via two canonical NLS sequences (K327KSK and K547KLR); nuclear SHIP1 is enzymatically active with similar specific activity to cytoplasmic SHIP1, and mutational inactivation of either NLS reduces nuclear import and decreases cell proliferation.\",\n      \"method\": \"Confocal microscopy of SHIP1-GFP; nuclear fractionation; enzyme activity assay on nuclear fractions; NLS point mutagenesis; nuclear import/export inhibitor studies; cell proliferation assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct subcellular fractionation with enzymatic activity measurement, NLS mutagenesis, and functional proliferation readout\",\n      \"pmids\": [\"21864674\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"The ITT-like motif of TIGIT is phosphorylated at Tyr225 upon TIGIT/PVR engagement and recruits cytosolic adaptor Grb2, which then recruits SHIP1 to prematurely terminate PI3K and MAPK signaling, suppressing granule polarization and NK cell cytotoxicity; SHIP1 silencing dramatically abolishes TIGIT/PVR-mediated killing inhibition.\",\n      \"method\": \"NK cell TIGIT/PVR engagement; phosphorylation mapping; co-immunoprecipitation; SHIP1 siRNA knockdown; granule polarization imaging; cytotoxicity assay; Tyr225/Asn227 mutant rescue\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — co-IP, phosphorylation site mapping, siRNA knockdown, and point-mutant rescue all establishing the TIGIT→Grb2→SHIP1 signaling axis\",\n      \"pmids\": [\"23154388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"SHIP1 regulates PIP3 production specifically in response to cell adhesion (not in suspension) and prevents formation of top-down PIP3 polarity; SHIP1-/- neutrophils lose polarity upon adhesion, are extremely adherent, and show elevated Akt activation; chemotaxis can be restored by reducing adhesion.\",\n      \"method\": \"SHIP1-/- neutrophils; cell adhesion vs. suspension PIP3 measurement; Akt activation assay; cell polarity imaging; adhesion and chemotaxis assays\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — knockout mouse cells with direct PIP3 measurement and multiple functional readouts revealing adhesion-specific mechanism\",\n      \"pmids\": [\"22323291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD2AP forms a complex with SHIP1 (identified by co-immunoprecipitation and mass spectrometry) in plasmacytoid dendritic cells; upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associates with and inhibits the E3 ubiquitin ligase Cbl, preventing ubiquitination and degradation of Syk and FcεR1γ, thereby positively regulating BDCA2/FcεR1γ ITAM signaling.\",\n      \"method\": \"Co-immunoprecipitation; mass spectrometry; SHIP1 and CD2AP knockdown; ubiquitination assay; Syk/FcεR1γ stability assay; membrane co-localization imaging; IFN production assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — MS-confirmed interaction, siRNA knockdown, ubiquitination assay, and membrane co-localization providing mechanistic evidence for Cbl inhibition\",\n      \"pmids\": [\"22706086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"AQX-1125, a small-molecule SHIP1 activator, increases the catalytic activity of recombinant human SHIP1 in vitro through a mechanism requiring the C2 region; deletion of the C2 region abolishes AQX-1125-mediated activation. The compound inhibits Akt phosphorylation in SHIP1-proficient but not SHIP1-deficient cells.\",\n      \"method\": \"In vitro recombinant human SHIP1 enzyme assay; C2-region deletion construct; SHIP1-proficient vs. deficient cell lines; Akt phosphorylation; cytokine production; mast cell activation; leukocyte chemotaxis\",\n      \"journal\": \"British journal of pharmacology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzyme assay with domain deletion mutant plus isogenic cell line comparison\",\n      \"pmids\": [\"23121445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The SH2 domain of SHIP1 can bind to the C-terminus of SHIP1 itself (inter- and intramolecularly), and this intramolecular interaction regulates the association between SHIP1 and Ig-α; the SH2 domain of SHIP1 interacts with Ig-α in an Ig-α-dependent manner in cells, but full-length SHIP1 does not interact with phosphorylated Ig-α ITAM, suggesting SH2 domain auto-inhibition.\",\n      \"method\": \"FRET in S2 cells; fluorescently labeled SH2 domain translocation assay; pulldown with phospho-ITAM peptides; mutant Ig-α BCR B cell lines; pervanadate stimulation; SHIP1 phosphorylation and Akt activation readouts\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — FRET and membrane translocation with biochemical pulldown, single lab, single study\",\n      \"pmids\": [\"22182704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SHIP1 associates with the death receptor CD95/Fas and promotes T-cell survival at mucosal surfaces; treatment with a Caspase 8 inhibitor prevents SHIP1 inhibitor-mediated T-cell death and reduces mucosal inflammation in SHIP1-/- mice, placing SHIP1 in the extrinsic apoptosis pathway.\",\n      \"method\": \"Co-immunoprecipitation of SHIP1 with CD95/Fas; caspase 8 inhibitor treatment; SHIP1-/- and CD4CreSHIP1flox/flox mice; T-cell survival and mucosal inflammation assays\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP plus pharmacological rescue with defined genetic models, single lab\",\n      \"pmids\": [\"24781051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSTPIP2 binds SHIP1 through critical tyrosine residues at the C-terminus of PSTPIP2; SHIP1 inhibition in neutrophils enhances IL-1β processing, demonstrating that the PSTPIP2-SHIP1 interaction is functionally important for suppressing neutrophil IL-1β production.\",\n      \"method\": \"Co-immunoprecipitation; phospho-site mapping; SHIP1 inhibitor in neutrophils; IL-1β processing assay; stimulation with silica, Ab aggregates, and LPS\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with defined binding sites and pharmacological functional validation, single lab\",\n      \"pmids\": [\"26304991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SHIP1 gene transfer (lentiviral INPP5D) into CD34+ AML cells reduces GM-CSF-dependent and autonomous cell proliferation; an enzymatically inactive SHIP1 mutant (D672A) has no effect, establishing that SHIP1's catalytic activity is required for its anti-proliferative function.\",\n      \"method\": \"Lentiviral INPP5D gene transfer into AML patient CD34+ cells; GM-CSF-dependent and autonomous proliferation assays; catalytically inactive SHIP1-D672A control\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — catalytic mutant control directly proves enzymatic activity requirement; replicated across 12 patient samples\",\n      \"pmids\": [\"19148132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"SHIP-1 regulates macrophage M2 polarization and phagocytosis during Pseudomonas aeruginosa infection through a PI3K/Akt-STAT5-Trib1 axis; SHIP-1 deficiency augments PI3K phosphorylation and nuclear STAT5 translocation, inducing Trib1 expression critical for M2 differentiation.\",\n      \"method\": \"SHIP-1-/- mice; siRNA silencing in macrophages; PI3K, Akt, STAT5, Trib1 expression and phosphorylation; macrophage polarization markers; bacterial burden; survival assays\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — knockout and siRNA with multiple pathway markers defining the PI3K-STAT5-Trib1 axis, single lab\",\n      \"pmids\": [\"32256487\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"A novel SHIP1 agonist (K306), identified via AI, activates SHIP1 through a mechanism that does not require the C2 domain (unlike other known SHIP1 agonists), suppresses inflammatory cytokines and iNOS in macrophages and microglia in a SHIP1-dependent manner, and enhances phagolysosomal degradation of synaptosomes and dead neurons by microglia.\",\n      \"method\": \"In vitro SHIP1 enzyme assay; SHIP1-/- macrophages/microglia as controls; C2 domain deletion constructs; cytokine and iNOS measurement; phagolysosomal degradation assay; in vivo LPS endotoxemia model\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro enzyme assay with domain comparison, SHIP1-null cell controls, and in vivo validation\",\n      \"pmids\": [\"35465359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Reduction in INPP5D (SHIP1) activity in iPSC-derived human microglia leads to formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18; this is associated with disrupted autophagy; evidence from human AD brain confirms that reduced SHIP1 function in microglia results in inflammasome activation.\",\n      \"method\": \"INPP5D-disrupted iPSC-derived human microglia; RNA and protein profiling; pharmacological SHIP1 inhibition; NLRP3 inflammasome assembly assay; CASP1 cleavage and IL-1β/IL-18 ELISA; multi-analytic analysis of human AD brain tissue\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (genetic disruption, pharmacological validation, iPSC human cells, and post-mortem human brain) converging on NLRP3/CASP1 mechanism\",\n      \"pmids\": [\"38016942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"INPP5D and TREM2/TYROBP exert opposing effects on PI(3,4,5)P3 signaling and phosphoproteins involved in actin assembly; Inpp5d haplodeficiency in a TREM2 loss-of-function mouse model restores microglial association with Aβ plaques and partially restores plaque compaction, placing INPP5D downstream of TREM2/TYROBP in regulating the microglial barrier against Aβ toxicity.\",\n      \"method\": \"Tyrobp-deficient TREM2 loss-of-function mice crossed with Inpp5d haplodeficient mice; microglial clustering; plaque compaction; astrogliosis; phosphorylated tau+ dystrophic neurites; mechanistic PI(3,4,5)P3 signaling and phosphoproteomic analyses\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in mouse model with phosphoproteomic mechanistic analysis, single lab\",\n      \"pmids\": [\"37035000\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"SHIP1 limits complement-mediated synaptic pruning in the developing hippocampus; conditional loss of microglial SHIP1 in early postnatal brain increases complement deposition and synapse loss, causes abnormal synaptic pruning, and leads to cognitive defects in adulthood; iPSC-derived microglia lacking SHIP1 also show increased engulfment of synaptic structures.\",\n      \"method\": \"Conditional microglial SHIP1 knockout mice (early vs. late postnatal deletion); proteomics; complement marker staining; synaptic pruning assays; cognitive behavioral tests; iPSC-derived microglia engulfment assay\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional in vivo genetic model at defined developmental windows with proteomics, human iPSC validation, and behavioral readouts\",\n      \"pmids\": [\"39657671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ikaros binds to the promoter of the INPP5D gene (demonstrated by ChIP) and transcriptionally regulates SHIP expression; loss of Ikaros upregulates SHIP while loss of Helios downregulates SHIP, and these expression changes underlie opposite BCR signaling phenotypes (calcium mobilization strength).\",\n      \"method\": \"Ikaros-deficient and Helios-deficient DT40 B cell lines; chromatin immunoprecipitation (ChIP) of Ikaros at INPP5D promoter; BCR cross-linking calcium assay; SHIP mRNA/protein measurement\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct ChIP establishes transcription factor binding with functional consequence, single lab\",\n      \"pmids\": [\"20602434\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INPP5D/SHIP1 is a hematopoietic-enriched (and microglial) inositol 5'-phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2 at the plasma membrane (and in the nucleus) to oppose PI3K signaling; it is recruited to inhibitory receptors (FcγRIIB, TIGIT, DAP12) and activation scaffolds (LAT, Ig-α, integrin αIIbβ3) via its SH2 domain and C-terminal proline-rich region, dampening Akt/Btk/Tec kinase membrane localization and calcium flux; its catalytic activity is allosterically enhanced by compounds binding the C2 domain and by PKA-mediated phosphorylation at Ser440; it acts as a spatial regulator of PIP3 polarity in neutrophil chemotaxis and phagosome maturation, a suppressor of NLRP3 inflammasome activation in microglia, a brake on complement-mediated synaptic pruning in developing brain, and a downstream effector of TREM2/TYROBP signaling.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"INPP5D (SHIP1) is a hematopoietic and microglial inositol 5'-phosphatase that hydrolyzes PI(3,4,5)P3 to oppose PI3K/Akt signaling and thereby acts as a brake on immune cell activation [#1, #5, #29]. Its catalytic activity is genetically required: phosphatase-dead and active-site mutants fail to revert knockout phenotypes or to suppress proliferation, and the C-terminal proline-rich region is also essential for substrate hydrolysis [#5, #29]. SHIP1 is recruited to inhibitory and activation receptors through its SH2 domain — including FcγRIIB co-ligated with the BCR, DAP12/TREM2, TIGIT (via Grb2), and the LAT adaptor — where it lowers membrane PIP3 and dampens membrane recruitment of PH-domain kinases such as Btk and Tec, calcium flux, and granule/degranulation responses [#0, #1, #9, #15, #18, #22]. Beyond simple suppression, it functions as a spatial regulator of PIP3 polarity, directing leading-edge PIP3 accumulation during neutrophil adhesion and chemotaxis and restricting its activity to early phagosome formation to control the oxidative burst and phagosome maturation [#10, #13, #14, #23]. SHIP1 activity is tuned by Lyn/Src-family-dependent tyrosine phosphorylation, by PKA phosphorylation at Ser440, and by small-molecule allosteric activators acting through the C2 region, while its expression is set by Ikaros at the INPP5D promoter and repressed post-transcriptionally by miR-155 [#7, #16, #19, #25, #35]. In the brain it operates downstream of TREM2/TYROBP signaling, where loss of SHIP1 function in microglia triggers NLRP3 inflammasome assembly, CASP1 cleavage and IL-1β/IL-18 release, drives excess complement-mediated synaptic pruning during development, and shapes the microglial barrier against amyloid-β [#32, #33, #34].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established SHIP1 as the defining effector of one of two distinct inhibitory receptor pathways, separating FcγRIIB-driven inhibition from KIR/SHP-1 inhibition.\",\n      \"evidence\": \"SHIP-deficient B cell lines with BCR-triggered apoptosis and inhibitory signaling readouts\",\n      \"pmids\": [\"9244303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the lipid substrate or molecular mechanism of inhibition\", \"Recruitment determinants to FcγRIIB not mapped\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Defined the molecular mechanism: SHIP1 lowers PIP3 to limit PH-domain kinase membrane recruitment (Btk) and specifically restrains calcium mobilization without affecting ERK.\",\n      \"evidence\": \"FcγRIIB co-ligation, SHIP-deficient and DT40 B cells, Btk membrane-targeted chimera rescue, single-cell Ca2+ imaging\",\n      \"pmids\": [\"9586640\", \"9820480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not address spatial control of PIP3\", \"Other PH-domain effectors not enumerated\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Showed that catalytic activity and the C-terminal proline-rich region are both required for SHIP1 function, defining a substrate-hydrolysis-dependent inhibitory output.\",\n      \"evidence\": \"Retroviral reconstitution of SHIP-/- mast cells with truncation and phosphatase-dead mutants; PIP3, calcium, degranulation readouts\",\n      \"pmids\": [\"11222379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Why the C-terminus is needed for catalysis in cells was not resolved\", \"Structural basis not determined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Connected SHIP1 to receptor tyrosine kinase signaling and disease, showing Lyn-dependent phosphorylation/membrane stabilization and that an AML active-site mutation impairs catalysis and deregulates Akt.\",\n      \"evidence\": \"GST pulldown, reciprocal co-IP, knockout macrophages, in vitro 5'-phosphatase assay with V684E mutant, Akt and growth readouts\",\n      \"pmids\": [\"12882960\", \"12529653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency and pathogenic role of V684E in AML not established\", \"Direct structural effect of the mutation not modeled\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Generalized SHIP1's inhibitory mechanism across cell types, showing it restrains Tec-family kinase activity/membrane localization and integrin αIIbβ3 outside-in signaling in platelets.\",\n      \"evidence\": \"Co-IP, in vitro kinase inhibition, Tec SH3 mutagenesis and membrane-targeting rescue; Lyn/SHIP1 knockout platelets with PIP3, Ca2+, spreading and adhesion assays\",\n      \"pmids\": [\"15492005\", \"15166241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of catalytic vs. scaffolding functions to platelet adhesion not separated\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Revealed SHIP1 as a spatial regulator of PIP3 rather than a bulk suppressor, directing leading-edge polarity in neutrophil chemotaxis distinct from PTEN.\",\n      \"evidence\": \"SHIP1 knockout mice with AktPH-GFP PIP3 bioprobe live imaging; comparison with PTEN-null neutrophils; osteoclast precursor proliferation assays\",\n      \"pmids\": [\"17173042\", \"17142780\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism targeting SHIP1 to the leading edge not defined\", \"Link between spatial PIP3 control and cytoskeletal machinery incomplete\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated pharmacologically tractable allosteric activation and refined the spatiotemporal model, showing SHIP1 acts at early phagocytic cups distinct from PTEN.\",\n      \"evidence\": \"In vitro recombinant enzyme assay with allosteric domain mapping plus in vivo endotoxemia/anaphylaxis; live-cell imaging of SHIP1/PTEN/PH-domain probes at phagosomes\",\n      \"pmids\": [\"17502453\", \"17442886\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the endogenous allosteric ligand not determined\", \"Recruitment timing determinants at phagosomes not fully mapped\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Linked SHIP1's local PI(3,4,5)P3-to-PI(3,4)P2 conversion to functional phagosome outcomes (oxidative burst, maturation) and identified LAT-mediated recruitment at FcεRI tuned by NTAL.\",\n      \"evidence\": \"SHIP-1-deficient macrophages with phagosome-level phospholipid/ROS imaging; NTAL-deficient mast cells with co-IP and LAT tyrosine mapping\",\n      \"pmids\": [\"18490750\", \"18322174\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"LAT recruitment (Medium) lacks reciprocal in vivo validation\", \"Coupling of PI(3,4)P2 to NADPH oxidase effectors not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Established transcriptional/post-transcriptional control and proved catalytic activity is required for tumor-suppressive function in primary AML cells.\",\n      \"evidence\": \"miR-155 gain/loss with 3'UTR reporters and in vivo phenocopy; lentiviral INPP5D vs. catalytically dead D672A in AML CD34+ cells\",\n      \"pmids\": [\"19359473\", \"19148132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Full set of upstream regulators of INPP5D expression not catalogued\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Defined direct biochemical regulation (PKA-Ser440 activation), receptor-blockade mechanism at DAP12/TREM2, transcriptional control by Ikaros, and a role in endotoxin tolerance.\",\n      \"evidence\": \"MS phospho-site mapping and S440A mutant rescue; TREM2/DAP12 co-IP with SH2-dependent PI3K-blockade; Ikaros ChIP at INPP5D promoter; SHIP-/- mice in LPS tolerance\",\n      \"pmids\": [\"20810657\", \"20484116\", \"20602434\", \"19139077\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Ikaros regulation (Medium) shown in DT40 only\", \"Integration of multiple regulatory inputs on SHIP1 in vivo unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Revealed SHIP1 has an enzymatically active nuclear pool and an autoinhibited SH2 domain, expanding its regulatory and localization repertoire.\",\n      \"evidence\": \"SHIP1-GFP confocal, nuclear fractionation with activity assay, NLS mutagenesis; FRET and phospho-ITAM pulldowns for SH2 auto-inhibition\",\n      \"pmids\": [\"21864674\", \"22182704\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nuclear substrates and functions of SHIP1 not identified\", \"SH2 auto-inhibition (Medium) not validated structurally\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Extended the adaptor-recruitment paradigm to NK cell TIGIT inhibition (via Grb2), adhesion-specific PIP3 polarity control, and a positive ITAM-stabilizing role via CD2AP/Cbl.\",\n      \"evidence\": \"TIGIT/PVR phospho-mapping, co-IP, siRNA and mutant rescue in NK cells; SHIP1-/- neutrophil adhesion/PIP3 assays; CD2AP co-IP/MS and ubiquitination assays in pDCs\",\n      \"pmids\": [\"23154388\", \"22323291\", \"22706086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SHIP1 switches between inhibitory and ITAM-stabilizing outputs not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Validated a clinical-candidate allosteric activator acting through the C2 region, confirming SHIP1 as a drug target with isogenic specificity.\",\n      \"evidence\": \"In vitro recombinant human SHIP1 assay with C2-deletion construct; SHIP1-proficient vs. deficient cells; Akt and functional readouts\",\n      \"pmids\": [\"23121445\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Precise C2 binding site and conformational change not structurally resolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Implicated SHIP1 in extrinsic apoptosis (CD95/Fas) for T-cell survival and in neutrophil IL-1β suppression via PSTPIP2 binding.\",\n      \"evidence\": \"SHIP1/CD95 co-IP with caspase-8 inhibitor rescue in SHIP1-/- mice; PSTPIP2 co-IP/phospho-mapping with IL-1β processing assays\",\n      \"pmids\": [\"24781051\", \"26304991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Both interactions (Medium) from single labs without reciprocal in vivo validation\", \"Mechanism linking SHIP1 to caspase-8 not defined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Placed SHIP1 within a defined macrophage polarization circuit, restraining M2 differentiation via a PI3K/Akt-STAT5-Trib1 axis during bacterial infection.\",\n      \"evidence\": \"SHIP-1-/- mice and siRNA with pathway phosphorylation, polarization markers, bacterial burden and survival\",\n      \"pmids\": [\"32256487\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab axis (Medium); direct vs. indirect control of STAT5/Trib1 not separated\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Distinguished a C2-independent activation mechanism (K306 agonist) and demonstrated SHIP1 activation enhances microglial phagolysosomal degradation and suppresses inflammation.\",\n      \"evidence\": \"In vitro enzyme assay with C2-deletion comparison, SHIP1-null cell controls, microglial cytokine/iNOS and phagolysosomal assays, in vivo LPS model\",\n      \"pmids\": [\"35465359\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding site of the C2-independent activator not mapped\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Established SHIP1 as a microglial node in neurodegeneration: loss of activity triggers NLRP3/CASP1 inflammasome activation, and it acts downstream of TREM2/TYROBP to shape the amyloid barrier.\",\n      \"evidence\": \"INPP5D-disrupted iPSC microglia with inflammasome/IL-1β/IL-18 assays and human AD brain analysis; Inpp5d-haploinsufficient × Tyrobp-deficient TREM2-LOF mice with plaque and phosphoproteomic analyses\",\n      \"pmids\": [\"38016942\", \"37035000\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Epistasis study (Medium) from single lab\", \"Mechanistic link between disrupted autophagy and NLRP3 assembly not fully resolved\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a developmental neuronal function: microglial SHIP1 limits complement-mediated synaptic pruning, with loss causing aberrant pruning and adult cognitive deficits.\",\n      \"evidence\": \"Conditional microglial SHIP1 knockout at defined postnatal windows with proteomics, complement staining, pruning and behavioral assays, plus iPSC-microglia engulfment\",\n      \"pmids\": [\"39657671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Lipid-substrate vs. scaffolding contribution to pruning not separated\", \"Link from PIP3 control to complement deposition not mechanistically defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"The nuclear function and substrates of SHIP1, and how its scaffolding (inhibitory vs. ITAM-stabilizing) outputs are switched in different receptor contexts, remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No nuclear substrate identified\", \"No structural model for SH2 auto-inhibition or allosteric activation\", \"Determinants selecting inhibitory vs. positive scaffolding output undefined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 5, 6, 14, 29]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 14, 23]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [1, 9, 18]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [22, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [1, 7, 13, 23]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [21]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [13, 14]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 1, 18, 22, 32]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 7, 18, 20]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [0, 27]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [13, 14, 31]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LYN\", \"DAP12\", \"TIGIT\", \"LAT\", \"GRB2\", \"CD2AP\", \"DOK1\", \"PSTPIP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":6,"faith_total":6,"faith_pct":100.0}}