{"gene":"INPP5D","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1997,"finding":"SHIP (INPP5D) mediates FcγRIIB inhibitory signaling in B cells, distinct from SHP-1-mediated KIR inhibitory signaling; SHIP recruitment by FcγRIIB attenuates a proapoptotic signal initiated by FcγRIIB co-ligation to BCR, while SHP-1 blocks apoptosis via a separate pathway.","method":"Genetic deletion of SHIP or SHP-1 in B cell lines followed by functional inhibitory signaling assays and apoptosis measurements","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal genetic loss-of-function with orthogonal functional readouts, replicated across two distinct pathways","pmids":["9244303"],"is_preprint":false},{"year":1997,"finding":"SHIP/SIP enzymatic activity (inositol 5-phosphatase) is required to inhibit PI3K-dependent signaling in vivo; catalytically inactive SHIP cannot block insulin- or PI3K-induced germinal vesicle breakdown or MAPK phosphorylation in Xenopus oocytes, and SHIP specifically reduces PtdIns(3,4,5)P3 levels generated in response to insulin.","method":"Injection of wild-type vs. catalytically inactive SHIP cRNA into Xenopus oocytes; GVBD and MAPK assays; lipid phosphoinositide measurements","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 — in vivo catalytic activity requirement demonstrated with mutagenesis and multiple functional readouts","pmids":["9111325"],"is_preprint":false},{"year":1998,"finding":"SHIP reduces PIP3 levels upon FcγRIIB co-ligation with BCR, thereby regulating membrane association of Btk through PH domain–phosphoinositol lipid interactions; loss of SHIP increases Btk membrane association and hyperresponsive BCR signaling, while membrane-tethered Btk bypasses SHIP-mediated inhibition.","method":"Genetic deletion of SHIP in DT40 B cells; expression of membrane-anchored Btk chimera; PIP3 measurement; calcium flux assays","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — genetic loss-of-function combined with rescue experiments and mechanistic lipid measurements","pmids":["9586640"],"is_preprint":false},{"year":1998,"finding":"SHIP inhibits Akt/PKB activation downstream of BCR signaling by depleting PIP3; SHIP-deficient B cells show sustained Akt activity after FcγRIIB co-cross-linking, and PIP3 (not PI(3,4)P2) is the predominant in vivo activator of Akt.","method":"FcγRIIB ITIM mutants and SHIP-deficient B cells; Akt kinase activity assays; phosphatidylinositol 3-kinase-dependent signaling measurements","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — genetic and pharmacological approaches with multiple orthogonal readouts in a single study","pmids":["9852043"],"is_preprint":false},{"year":1998,"finding":"SHIP-deficient DT40 B cells display enhanced and sustained Ca2+ mobilization (long-lasting Ca2+ oscillations) in response to BCR ligation, while ERK activation is unaffected, demonstrating SHIP modulates Ca2+ signaling specifically.","method":"SHIP knockout DT40 B cells; single-cell Ca2+ imaging; ERK activation assays","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined cellular phenotype using direct single-cell imaging","pmids":["9820480"],"is_preprint":false},{"year":2000,"finding":"SHIP1 and SHIP2 are recruited to FcγRIIB via ITIM binding determined by the Y+2 leucine residue in the FcγRIIB ITIM (distinct from the Y-2 isoleucine that determines SHP-1/SHP-2 binding), defining separate SHIP- and SHP-binding sites on ITIMs.","method":"Loss-of-function and gain-of-function ITIM residue substitutions between FcγRIIB and KIR ITIMs; in vivo recruitment assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mutagenesis-based mapping of binding site with gain- and loss-of-function validation","pmids":["11016922"],"is_preprint":false},{"year":2000,"finding":"SHIP1 forms a novel signaling complex with DOK1, PI3K, and CRKL in BCR/ABL-transformed cells; DOK1 binds directly through its PTB domain to SHIP1, and CRKL binds via its SH2 domain; Tyr917 and Tyr1020 in SHIP1 mediate interactions with DOK1 and regulate cell migration.","method":"Co-immunoprecipitation; GST pulldown; SHIP1 tyrosine mutants; migration assays in Ba/F3 cells","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding mapping with mutants and functional migration readout, single study","pmids":["11031258"],"is_preprint":false},{"year":2000,"finding":"Ship1 is recruited to the erythropoietin receptor (EPO-R) in an SH2-dependent manner at Tyr401 (with redundancy at Tyr429/Tyr431); EPO activates tyrosine phosphorylation of Ship1, leading to formation of a ternary Ship1/Shc/Grb2 complex.","method":"EPO-R deletion and tyrosine mutants; co-immunoprecipitation; kinase assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — receptor mutagenesis with defined binding sites, single laboratory","pmids":["10660611"],"is_preprint":false},{"year":2001,"finding":"The C-terminus of SHIP (proline-rich region) is essential for its ability to hydrolyze PIP3 and inhibit mast cell degranulation; C-terminally truncated SHIP cannot revert SHIP-deficient BMMC responses even though the catalytic domain is intact. The catalytic phosphatase activity is required for inhibition; the NPXY motifs that bind Shc are dispensable.","method":"Retroviral infection of SHIP-/- bone marrow with wild-type, phosphatase-dead, C-terminal truncations, and NPXY mutant SHIP constructs; PIP3 measurement; calcium entry; degranulation assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — reconstitution with domain mutants and multiple functional readouts","pmids":["11222379"],"is_preprint":false},{"year":2003,"finding":"SHIP-1 is tyrosine-phosphorylated after M-CSF stimulation in a Src family kinase-dependent manner and binds Lyn via its SH2 domain (independently of Lyn kinase activity); SHIP-1 negatively regulates M-CSF-induced Akt activation and NF-κB-dependent transcription, with Lyn stabilizing SHIP-1 at the membrane.","method":"GST-SH2 fusion protein pulldown; co-immunoprecipitation; SHIP-1 overexpression/SH2-domain constructs in THP-1 cells; macrophages from SHIP-1−/− and Lyn−/− mice; Akt phosphorylation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — direct binding mapped with domain constructs, confirmed in genetic KO models, multiple functional readouts","pmids":["12882960"],"is_preprint":false},{"year":2003,"finding":"A somatic mutation in SHIP (V684E) within the phosphatase active-site signature motif reduces SHIP catalytic activity, leading to enhanced Akt phosphorylation and leukemic cell growth advantage, supporting SHIP as a tumor suppressor via the PI3K/Akt pathway.","method":"In vitro inositol 5-phosphatase assay with mutant SHIP; Akt phosphorylation assays; transfection of SHIP-V684E into K562 cells; proliferation and apoptosis assays","journal":"Leukemia","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro enzymatic assay with active-site mutant plus cellular phenotype, single study","pmids":["12529653"],"is_preprint":false},{"year":2004,"finding":"SHIP1 deficiency in mast cells leads to dysregulated FcεRI signaling characterized by prolonged PIP3 synthesis and Ca2+ mobilization, resulting from loss of SHIP phosphorylation and activity; this is dependent on Lyn kinase for SHIP activation in normal cells.","method":"Bone marrow-derived mast cells from Lyn−/− mice; PIP3 measurement; Ca2+ mobilization; SHIP tyrosine phosphorylation assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — defined KO phenotype with mechanistic phospholipid measurements, single study","pmids":["15210764"],"is_preprint":false},{"year":2004,"finding":"SHIP1 and Lyn act as negative regulators of integrin αIIbβ3 outside-in signaling in platelets; SHIP1 regulates PIP3 accumulation, Ca2+ responses, and platelet spreading, with Lyn-dependent SHIP1 phosphorylation modulating PtdIns(3,4,5)P3 metabolism and fibrinogen adhesion stability.","method":"SHIP1 knockout and Lyn knockout murine platelets; PIP3 measurement; calcium flux; platelet spreading and adhesion assays under physiological blood flow","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — two genetic KO models with multiple orthogonal functional readouts","pmids":["15166241"],"is_preprint":false},{"year":2004,"finding":"SHIP1 and SHIP2 interact preferentially with Tec (vs. other Tec family kinases) via the Tec SH3 domain, and SHIP1 inhibits Tec activity and membrane localization by depleting local PtdIns(3,4,5)P3; constitutively membrane-targeted Tec is resistant to SHIP1 inhibition.","method":"Co-immunoprecipitation; kinase activity assays; Tec SH3 domain mutants; membrane-targeting chimeras; SHIP phosphatase assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — four orthogonal lines of evidence including binding mapping, enzymatic inhibition, and rescue experiments","pmids":["15492005"],"is_preprint":false},{"year":2004,"finding":"SHIP1 negatively regulates monokine-induced IFN-γ production in NK cells; the inhibitory effect requires SHIP1 catalytic activity, as catalytic-dead SHIP1 overexpression does not suppress IFN-γ, and SHIP1−/− mice produce more IFN-γ from NK cells in vivo.","method":"SHIP1 overexpression (wild-type vs. catalytic-dead mutant) in CD56bright NK cells; SHIP1-/- mouse NK cells; IFN-γ production assays in vitro and in vivo","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — catalytic mutant combined with genetic KO, in vitro and in vivo validation","pmids":["15604218"],"is_preprint":false},{"year":2004,"finding":"LPS-induced endotoxin tolerance requires upregulation of SHIP (not SHIP2 or PTEN); this upregulation is mediated by LPS-induced autocrine TGFβ (via MyD88-dependent pathway), and neutralizing TGFβ blocks tolerance. SHIP-/- macrophages and mast cells cannot establish endotoxin tolerance.","method":"SHIP-/- bone marrow-derived macrophages and mast cells; LPS tolerance assays; TGFβ neutralizing antibodies; in vivo SHIP+/+ and SHIP-/- mouse models","journal":"Immunity","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with mechanistic antibody neutralization and in vivo confirmation","pmids":["15308103"],"is_preprint":false},{"year":2006,"finding":"SHIP1 controls neutrophil polarity and chemotaxis by governing where PtdIns(3,4,5)P3 accumulates; SHIP1-deficient neutrophils show diffuse PtdIns(3,4,5)P3 distribution and fail to form a leading edge, whereas PTEN deficiency does not affect neutrophil chemotaxis.","method":"SHIP1-/- mice; transgenic AktPH-GFP biosensor mice for live PtdIns(3,4,5)P3 imaging; time-lapse microscopy of chemotaxing primary neutrophils","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 — direct live-cell PIP3 imaging tied to functional chemotaxis phenotype in genetic KO, replicated vs. PTEN KO","pmids":["17173042"],"is_preprint":false},{"year":2006,"finding":"SHIP1 negatively regulates osteoclast precursor proliferation via Akt-dependent modulation of D-type cyclins and p27; SHIP1-null BMMs show enhanced M-CSF-induced Akt activation leading to cyclin D upregulation, p27 downregulation, increased Rb phosphorylation, and proliferation.","method":"SHIP1-/- bone marrow macrophages; Akt activation assays; cyclin D and p27 protein levels; Rb phosphorylation; BrdU proliferation assays; inflammatory arthritis model","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — clean KO with defined mechanistic pathway through Akt/cyclins/p27","pmids":["17142780"],"is_preprint":false},{"year":2007,"finding":"SHIP-1 (YFP chimera) is recruited to forming phagosomes at the leading edge and dissociates earlier than PI3K (p85), restricting its inhibitory activity to early stages of phagocytosis; PTEN does not localize to phagosomes. This differential localization regulates when and where PIP3 accumulates.","method":"Live imaging of YFP-SHIP1, YFP-PTEN, and p85-CFP chimeras in macrophages; quantitative analysis of phagosome PH domain biosensors for PIP3 and PI(3,4)P2","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 — direct live-cell localization with functional lipid biosensors and quantitative analysis","pmids":["17442886"],"is_preprint":false},{"year":2007,"finding":"Small-molecule agonists of SHIP1 activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity in intact macrophages and mast cells by binding an allosteric activation domain distinct from the active site; in vivo administration is protective in endotoxemia and anaphylaxis models.","method":"In vitro enzyme activity assays with recombinant SHIP1; cellular phosphoinositide measurements in macrophages and mast cells; in vivo mouse models","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with identified allosteric site, validated in cells and in vivo","pmids":["17502453"],"is_preprint":false},{"year":2008,"finding":"SHIP-1 activity on phagosomal membranes enhances the early oxidative burst by converting PI(3,4,5)P3 to PI(3,4)P2, which activates NADPH oxidase; SHIP-1-deficient macrophages show elevated PI(3,4,5)P3/PI(3,4)P2 ratios on phagosomes and decreased early NADPH oxidase activity, and altered Rab5a/PI(3)P dynamics indicating disrupted phagosome maturation.","method":"SHIP-1-deficient macrophages; phagosomal phospholipid measurements; reactive oxygen species imaging; phagosome maturation markers","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with direct phagosomal organelle-level phospholipid and ROS measurements","pmids":["18490750"],"is_preprint":false},{"year":2008,"finding":"NTAL decreases the recruitment of SHIP1 by LAT in mast cell FcεRI signaling complexes; LAT provides two SHIP1 binding sites via its distal tyrosines; reduced SHIP1 recruitment leads to increased Akt phosphorylation and enhanced mast cell survival.","method":"Co-immunoprecipitation; NTAL-deficient mast cells; LAT tyrosine mutants; Akt phosphorylation and apoptosis assays","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — defined binding sites with KO and mutant studies, single laboratory","pmids":["18322174"],"is_preprint":false},{"year":2009,"finding":"SHIP1 is a bona fide target of onco-miR-155; elevated miR-155 driven by autocrine TNFα in DLBCL reduces SHIP1 protein expression, promoting B cell lymphoma proliferation; anti-TNFα treatment restores SHIP1 expression and reduces proliferation.","method":"miR-155 target validation in DLBCL cells; anti-TNFα treatment (etanercept/infliximab); SHIP1 protein measurement; tumor xenograft models","journal":"EMBO molecular medicine","confidence":"Medium","confidence_rationale":"Tier 2 — direct miR-155/SHIP1 targeting with rescue experiments and in vivo xenograft validation","pmids":["19890474"],"is_preprint":false},{"year":2009,"finding":"Lyn, PKC-δ, and SHIP-1 form a specific signaling complex downstream of GPVI (but not PAR) in platelets; Lyn-mediated phosphorylation of SHIP-1 at Y1020 and PKC-δ at Y311 occurs preferentially after GPVI stimulation, and this complex negatively regulates GPVI-mediated dense granule secretion.","method":"Co-immunoprecipitation; Lyn-/- and PKC-δ-/- murine platelets; SHIP-1 phosphorylation assays; dense granule secretion assays","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 — two genetic KO models with defined phosphorylation events and functional secretion readout","pmids":["19587372"],"is_preprint":false},{"year":2010,"finding":"TREM2/DAP12-induced PI3K signaling requires DAP10 for PI3K recruitment, and SHIP1 inhibits this pathway by binding to DAP12 in an SH2 domain-dependent manner, preventing PI3K recruitment to DAP12.","method":"Co-immunoprecipitation; SH2-domain mutants of SHIP1; SHIP1 knockdown; TREM2/DAP12/DAP10 reconstitution experiments; PI3K recruitment assays","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 — SH2-domain-dependent mechanism demonstrated by mutants and co-IP, multiple orthogonal approaches","pmids":["20484116"],"is_preprint":false},{"year":2010,"finding":"PKA phosphorylates SHIP1 at Ser440 within the catalytic domain, increasing SHIP1 enzymatic activity in hematopoietic cells; S440A mutation abolishes PKA-mediated SHIP1 activation and prevents inhibition of Akt downstream of BCR engagement.","method":"Mass spectrometry identification of phosphorylation sites; truncation mutants; S440A site-directed mutagenesis; SHIP1 activity assays; Akt phosphorylation by flow cytometry in DT40 B cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — mass spectrometry-identified site validated by mutagenesis in vitro and in cells with functional Akt readout","pmids":["20810657"],"is_preprint":false},{"year":2010,"finding":"Concomitant deletion of PTEN and SHIP in B cells results in spontaneous mature B cell lymphoma, demonstrating that SHIP is a tumor suppressor that cooperates with PTEN to suppress B cell malignancy; bPTEN/SHIP-/- B cells show enhanced survival with increased MCL1, decreased Bim, low p27, and high cyclin D3, and proliferate in response to BAFF.","method":"B cell-specific conditional PTEN and SHIP double-knockout mice (Cre-lox); tumor analysis; BCL2-family protein expression; cell cycle analysis; BAFF-dependent proliferation assays","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 — conditional double-KO genetic epistasis with multiple mechanistic cellular readouts","pmids":["20956547"],"is_preprint":false},{"year":2010,"finding":"In SHIP1-/- macrophages stimulated via TLR2/TLR4, enhanced PI3K pathway activation (due to SHIP1 loss) leads to reduced cytokine production, consistent with SHIP1's product PI(3,4)P2 promoting signaling differently from its substrate PIP3; Lyn interacts with PI3K downstream of TLR4/TLR2 as a negative regulatory module.","method":"SHIP1-/- bone marrow-derived macrophages; Lyn-/- macrophages; cytokine production assays; PI3K inhibitor treatment","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — genetic KO models with pharmacological validation, single laboratory","pmids":["20385881"],"is_preprint":false},{"year":2011,"finding":"SHIP1 SH2 domain undergoes intramolecular and intermolecular interaction with the SHIP1 C-terminus, which regulates the association between SHIP1 and the BCR component Ig-α (ITAM); full-length SHIP1 does not interact with phosphorylated Ig-α ITAM peptide in the same manner as the isolated SH2 domain, indicating autoinhibitory regulation.","method":"FRET in S2 cells; pulldown with phospho-ITAM peptides; fluorescently labeled SH2 domain membrane translocation assays; BCR mutants with C-terminally truncated Ig-α","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 2 — FRET and membrane translocation assays with mutant receptors, single laboratory","pmids":["22182704"],"is_preprint":false},{"year":2012,"finding":"TIGIT/PVR engagement phosphorylates Tyr225 in the ITT-like motif of TIGIT, which recruits Grb2, which in turn recruits SHIP1 to terminate PI3K and MAPK signaling in NK cells, leading to disrupted granule polarization and loss of cytotoxicity; Y225 or N227 mutation or SHIP1 silencing reverses TIGIT-mediated killing inhibition.","method":"TIGIT/PVR ligation; phospho-Tyr225 mutants; Grb2/SHIP1 co-immunoprecipitation; SHIP1 siRNA knockdown; granule polarization and cytotoxicity assays","journal":"Cell death and differentiation","confidence":"High","confidence_rationale":"Tier 2 — tyrosine mutants plus protein binding studies plus KD rescue with functional NK cytotoxicity readout","pmids":["23154388"],"is_preprint":false},{"year":2012,"finding":"CD2AP forms a complex with SHIP1, and this CD2AP/SHIP1 complex associates with Cbl after BDCA2/FcεR1γ cross-linking, inhibiting Cbl E3 ubiquitin ligase activity to prevent ubiquitination and degradation of Syk and FcεR1γ, thereby positively regulating ITAM signaling in pDCs.","method":"Immunoprecipitation and mass spectrometry; Cbl ubiquitin ligase activity assays; CD2AP/SHIP1 knockdown; immunofluorescence co-localization at plasma membrane","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP/MS identification with functional E3 ligase inhibition assay, single laboratory","pmids":["22706086"],"is_preprint":false},{"year":2014,"finding":"SHIP1 promotes osteoblast development from mesenchymal stem cells by limiting PI3K/Akt/β-catenin/Id2 pathway activation; SHIP1 deficiency in MSCs reduces bone mass and density, and is the primary cause of osteoporotic phenotype in SHIP1 germline KO mice (not osteoclast SHIP1 deficiency).","method":"MSC-specific SHIP1 conditional KO mice vs. myeloid/OC-specific KO; bone densitometry; PI3K/Akt/β-catenin/Id2 pathway analysis; SHIP1 inhibitor treatment","journal":"Stem cells and development","confidence":"Medium","confidence_rationale":"Tier 2 — cell-type-specific conditional KO with epistasis dissecting lineage contributions, single laboratory","pmids":["24857423"],"is_preprint":false},{"year":2014,"finding":"SHIP1 associates with the death receptor CD95/Fas and its loss promotes extrinsic T cell death via Caspase 8; Caspase 8 inhibitor treatment prevents SHIP1 inhibitor-mediated T cell death and reduces mucosal inflammation in SHIP1-/- mice.","method":"Co-immunoprecipitation of SHIP1 with Fas; Caspase 8 inhibitor treatment; CD4CreSHIP1flox/flox conditional KO mice; mucosal inflammation assays","journal":"Mucosal immunology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP binding partner with pharmacological rescue, single laboratory","pmids":["24781051"],"is_preprint":false},{"year":2015,"finding":"PSTPIP2 interacts with SHIP1 via PSTPIP2 C-terminal tyrosine residues (critical for PEST-phosphatase-independent inhibitory function); SHIP1 binding is important for PSTPIP2-mediated suppression of IL-1β processing in neutrophils, and SHIP1 inhibition enhances IL-1β processing.","method":"Co-immunoprecipitation; PSTPIP2 domain mutants; SHIP1 inhibitor treatment; IL-1β processing assays in neutrophils","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — binding mapped with domain mutants and functional IL-1β readout, single laboratory","pmids":["26304991"],"is_preprint":false},{"year":2023,"finding":"Reduction in INPP5D/SHIP1 activity in human iPSC-derived microglia induces NLRP3 inflammasome formation, Caspase-1 cleavage, and secretion of IL-1β and IL-18; this is associated with disrupted autophagy; pharmacological inhibition of INPP5D recapitulates inflammasome activation, and evidence for INPP5D/NLRP3 inflammasome connection is confirmed in human AD brain tissue.","method":"INPP5D disruption in iPSC-derived human microglia; unbiased RNA/protein profiling; targeted pharmacological experiments; CASP1 cleavage and IL-1β/IL-18 secretion assays; multi-analytic human brain tissue analysis","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 — multiple orthogonal methods (genetic + pharmacological + human tissue) in human relevant model system","pmids":["38016942"],"is_preprint":false},{"year":2022,"finding":"SHIP1 agonist K306 activates SHIP1 without requiring the C2 domain (unlike previous agonists), suppresses inflammatory cytokines (TNF-α, 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 activation assays; SHIP1-deficient macrophage/microglia controls; cytokine assays; in vivo LPS endotoxemia; synaptosome degradation assays","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 1-2 — in vitro enzymatic activation with domain-specificity, SHIP1-KO controls, and in vivo validation","pmids":["35465359"],"is_preprint":false},{"year":2022,"finding":"Inpp5d haplodeficiency in microglia of 5xFAD mice enhances microglial phagocytosis and amyloid beta clearance, perturbs intracellular signaling pathways regulating immune response, and preserves cognitive function; spatial transcriptomics revealed altered synaptic regulation and immune activation pathways.","method":"5xFAD Inpp5d haploinsufficient mice; behavioral cognitive testing; amyloid plaque quantification; spatial transcriptomics; microglial phagocytosis assays","journal":"Alzheimer's & dementia","confidence":"Medium","confidence_rationale":"Tier 2 — genetic haploinsufficiency with multiple functional and transcriptomic readouts, single laboratory","pmids":["36524682"],"is_preprint":false},{"year":2023,"finding":"Microglial SHIP-1 deletion in 5xFAD mice substantially enhances microglial recruitment to Aβ plaques, improves plaque encapsulation and Aβ engulfment, alters microglial gene expression toward activation/phagocytosis programs, and protects against plaque-induced neuronal dystrophy.","method":"5xFAD Inpp5dfl/fl Cx3cr1Ert2Cre conditional microglial KO; microglial recruitment quantification; plaque engulfment assays; gene expression analysis; neuronal health markers","journal":"Alzheimer's & dementia","confidence":"High","confidence_rationale":"Tier 2 — inducible microglial-specific conditional KO with multiple orthogonal mechanistic readouts","pmids":["37061460"],"is_preprint":false},{"year":2010,"finding":"SHIP1 negatively regulates lentiviral gene transfer-demonstrated PI3K/AKT-driven proliferation of AML CD34+ cells; enzymatically inactive SHIP1 (D672A) has no effect, confirming the requirement for phosphatase activity.","method":"Lentiviral gene transfer of wild-type vs. catalytic-dead (D672A) SHIP1 into AML patient CD34+ cells; GM-CSF-dependent proliferation assays","journal":"Gene therapy","confidence":"Medium","confidence_rationale":"Tier 1 — catalytic-dead mutant establishes enzymatic activity requirement, replicated across 12 patient samples","pmids":["19148132"],"is_preprint":false},{"year":2010,"finding":"Ikaros binds to the promoter of the INPP5D gene (encoding SHIP) and is required for SHIP expression; Helios deficiency reduces SHIP expression while Ikaros deficiency upregulates it, providing transcriptional co-regulation of SHIP by Ikaros family factors that governs BCR signaling strength.","method":"Chromatin immunoprecipitation (ChIP) of Ikaros at INPP5D promoter; Helios-/- and Ikaros-/- DT40 B cell lines; SHIP mRNA/protein quantification; BCR-induced Ca2+ signaling assays","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — ChIP demonstrates direct promoter binding, complemented by genetic KO functional data","pmids":["20602434"],"is_preprint":false}],"current_model":"INPP5D/SHIP1 is a hematopoietic-enriched (and microglial-expressed) inositol 5-phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2 at the plasma membrane, thereby negatively regulating PI3K/Akt signaling downstream of immune receptors (BCR, FcγRIIB, FcεRI, TREM2/DAP12, GPVI, integrins, TLRs, TIGIT), controlling Btk membrane localization, Ca2+ mobilization, cell polarity, phagocytosis, NLRP3 inflammasome activation, and cell survival/proliferation; SHIP1 is recruited to receptors via its SH2 domain (binding ITIMs and phosphotyrosines), regulated by Lyn-mediated tyrosine phosphorylation and PKA-mediated phosphorylation at Ser440, and modulated by miR-155-mediated repression and allosteric small-molecule agonists/antagonists, with its catalytic C-terminus essential for full enzymatic function and tumor-suppressive activity."},"narrative":{"teleology":[{"year":1997,"claim":"Establishing that SHIP1 is an enzymatically active inositol 5-phosphatase that reduces PIP3 levels in vivo and that its catalytic activity is required to inhibit PI3K-dependent signaling resolved the question of whether SHIP1 functions as a lipid phosphatase rather than merely an adaptor protein.","evidence":"Injection of wild-type vs. catalytically inactive SHIP cRNA into Xenopus oocytes with GVBD, MAPK, and lipid measurements","pmids":["9111325"],"confidence":"High","gaps":["Structural basis of catalytic specificity not determined","In vivo relevance in mammalian hematopoietic cells not yet shown"]},{"year":1997,"claim":"Demonstrating that SHIP1 mediates FcγRIIB inhibitory signaling in B cells—distinct from SHP-1-mediated KIR signaling—established SHIP1 as the phosphatase specifically recruited by the FcγRIIB ITIM to modulate BCR co-inhibition.","evidence":"Genetic deletion of SHIP or SHP-1 in B cell lines with inhibitory signaling and apoptosis readouts","pmids":["9244303"],"confidence":"High","gaps":["Mechanism of SHIP1 recruitment to FcγRIIB ITIM not yet mapped at the residue level"]},{"year":1998,"claim":"Showing that SHIP1 controls Btk membrane association and Akt activation by depleting PIP3 downstream of BCR/FcγRIIB defined the core mechanistic axis: SHIP1 → PIP3 depletion → loss of PH-domain-dependent effector membrane recruitment → signal termination.","evidence":"SHIP-deficient DT40 B cells with membrane-anchored Btk rescue, PIP3 quantification, Ca²⁺ flux, and Akt kinase assays","pmids":["9586640","9852043","9820480"],"confidence":"High","gaps":["Whether PI(3,4)P2 generated by SHIP1 has independent signaling roles was unclear","Contribution of SHIP1 vs. SHIP2 not delineated"]},{"year":2000,"claim":"Residue-level mapping of ITIM determinants (Y+2 leucine for SHIP binding vs. Y−2 isoleucine for SHP binding) and identification of SH2-dependent recruitment to EPO-R and a DOK1/CRKL signaling complex defined how SHIP1 is recruited to multiple receptor systems and participates in multiprotein signaling complexes.","evidence":"ITIM residue substitution mutagenesis; EPO-R deletion/tyrosine mutants with co-IP; GST pulldown and migration assays in BCR/ABL-transformed cells","pmids":["11016922","10660611","11031258"],"confidence":"High","gaps":["Crystal structure of SH2/ITIM interaction not available","Relative contribution of DOK1/CRKL complex to SHIP1 function in vivo unknown"]},{"year":2001,"claim":"Reconstitution experiments with domain mutants in SHIP−/− mast cells revealed that the C-terminal proline-rich region is essential for PIP3 hydrolysis and degranulation inhibition, even though the catalytic domain is intact, indicating the C-terminus is required for full enzymatic activity in cells.","evidence":"Retroviral transduction of wild-type, phosphatase-dead, C-terminal truncation, and NPXY mutant SHIP constructs into SHIP−/− BMMCs with PIP3, Ca²⁺, and degranulation readouts","pmids":["11222379"],"confidence":"High","gaps":["Whether C-terminus acts through allosteric activation, membrane targeting, or protein–protein interactions not resolved"]},{"year":2003,"claim":"Identification of Lyn as a direct binding partner and activating kinase for SHIP1 via SH2-domain interaction, and discovery of a somatic V684E mutation reducing catalytic activity in leukemia, established the Lyn→SHIP1 activation axis and SHIP1's role as a tumor suppressor.","evidence":"GST-SH2 pulldowns, co-IP in macrophages, SHIP1−/− and Lyn−/− mice for Akt readouts; in vitro phosphatase assay with V684E mutant and proliferation assays in K562 cells","pmids":["12882960","12529653"],"confidence":"High","gaps":["Frequency of SHIP1 mutations across leukemia subtypes not established","Whether other Src kinases can substitute for Lyn in different cell types unclear"]},{"year":2004,"claim":"Multiple studies using SHIP1−/− and Lyn−/− cells across mast cells, platelets, and NK cells established that Lyn-dependent SHIP1 activation is a general negative regulatory module controlling PIP3/Ca²⁺ in FcεRI signaling, integrin outside-in signaling, and IFN-γ production, while LPS tolerance was shown to require SHIP1 upregulation by autocrine TGFβ.","evidence":"SHIP1−/− and Lyn−/− BMMCs, platelets, NK cells; PIP3 and Ca²⁺ measurements; IFN-γ assays with catalytic-dead mutant; LPS tolerance in SHIP−/− macrophages with TGFβ neutralization","pmids":["15210764","15166241","15604218","15308103","15492005"],"confidence":"High","gaps":["Endotoxin tolerance mechanism beyond SHIP1 upregulation (e.g., chromatin remodeling) not addressed","Whether SHIP1-Tec interaction is relevant in primary cells not confirmed"]},{"year":2006,"claim":"Live PIP3 biosensor imaging in SHIP1−/− neutrophils demonstrated that SHIP1 restricts PIP3 to the leading edge to establish cell polarity during chemotaxis—a function not shared by PTEN—resolving the question of which phosphatase controls spatial PIP3 distribution in neutrophils.","evidence":"SHIP1−/− mice crossed with AktPH-GFP transgenic biosensor mice; time-lapse chemotaxis imaging","pmids":["17173042"],"confidence":"High","gaps":["Whether SHIP1 and PTEN have cooperative roles in other migratory cell types not tested"]},{"year":2007,"claim":"Live imaging of YFP-SHIP1 at forming phagosomes showed SHIP1 is recruited early and dissociates before PI3K, establishing temporal control of PIP3 on phagosomes; separately, identification of allosteric small-molecule SHIP1 agonists protective in endotoxemia and anaphylaxis demonstrated druggability.","evidence":"Live-cell imaging of YFP-SHIP1 and PI3K-CFP chimeras during phagocytosis; in vitro enzyme assays with allosteric activators; in vivo mouse models","pmids":["17442886","17502453"],"confidence":"High","gaps":["Identity of the allosteric activation domain not structurally defined","SHIP1 agonist selectivity over SHIP2 not fully characterized"]},{"year":2008,"claim":"Demonstration that SHIP1-generated PI(3,4)P2 on phagosomes activates NADPH oxidase for the early oxidative burst, and that SHIP1 loss disrupts Rab5a/PI(3)P dynamics, established that SHIP1's product PI(3,4)P2 has positive signaling functions beyond simply depleting PIP3.","evidence":"SHIP1−/− macrophages with phagosomal phospholipid quantification, ROS imaging, and phagosome maturation markers","pmids":["18490750"],"confidence":"High","gaps":["Direct PI(3,4)P2 effectors on the phagosome not identified","Whether PI(3,4)P2 signaling differs between phagosomes and plasma membrane not resolved"]},{"year":2009,"claim":"Identification of miR-155 as a direct repressor of SHIP1 mRNA driving DLBCL proliferation, and of a Lyn/PKC-δ/SHIP1 signaling complex specific to GPVI in platelets, expanded SHIP1 regulation to post-transcriptional control and receptor-specific signaling complexes.","evidence":"miR-155 target validation in DLBCL with anti-TNFα rescue and xenograft models; co-IP from Lyn−/− and PKC-δ−/− platelets with SHIP1 phosphorylation and dense granule secretion assays","pmids":["19890474","19587372"],"confidence":"High","gaps":["Whether miR-155/SHIP1 axis is relevant beyond DLBCL not established","Other miRNAs targeting SHIP1 not surveyed"]},{"year":2010,"claim":"Multiple 2010 studies established that SHIP1 cooperates with PTEN as a tumor suppressor in B cells (double KO causes spontaneous lymphoma), is activated by PKA at Ser440, inhibits TREM2/DAP12 signaling via SH2-dependent DAP12 binding, and suppresses AML progenitor proliferation in a catalytic-activity-dependent manner.","evidence":"B-cell-specific PTEN/SHIP conditional double-KO mice; mass spectrometry identification of Ser440 with S440A mutagenesis in DT40 cells; SHIP1 SH2-domain mutants and knockdown in TREM2/DAP12 reconstitution; lentiviral WT/D672A SHIP1 in AML CD34+ cells","pmids":["20956547","20810657","20484116","19148132"],"confidence":"High","gaps":["Structural basis for PKA-mediated allosteric activation not resolved","Whether SHIP1 loss alone is sufficient for lymphomagenesis without PTEN loss unknown"]},{"year":2011,"claim":"FRET-based studies revealed that the SHIP1 C-terminus engages in intramolecular interaction with the SH2 domain, creating an autoinhibited conformation that limits ITAM binding, providing a structural explanation for why the C-terminus is required for regulated enzymatic function.","evidence":"FRET in S2 cells; phospho-ITAM peptide pulldowns comparing full-length vs. isolated SH2 domain; membrane translocation assays","pmids":["22182704"],"confidence":"Medium","gaps":["No high-resolution structural data for autoinhibited SHIP1","Physiological signals that relieve autoinhibition not identified"]},{"year":2012,"claim":"SHIP1 was placed in the TIGIT inhibitory pathway (recruited via Grb2 to phospho-Y225) to terminate PI3K/MAPK signaling in NK cells, and in a CD2AP/SHIP1 complex that inhibits Cbl E3 ligase activity in pDCs, expanding SHIP1's non-catalytic scaffolding roles.","evidence":"TIGIT Y225 mutants, Grb2/SHIP1 co-IP, SHIP1 siRNA in NK cytotoxicity assays; CD2AP/SHIP1 co-IP/MS with Cbl ubiquitin ligase assays in pDCs","pmids":["23154388","22706086"],"confidence":"High","gaps":["Whether SHIP1 catalytic activity is required for TIGIT-mediated inhibition not tested","CD2AP/SHIP1 interaction not validated in other immune cell types"]},{"year":2014,"claim":"Cell-type-specific conditional knockouts revealed that SHIP1 in mesenchymal stem cells (not osteoclasts) drives the osteoporotic phenotype of SHIP1-null mice by limiting PI3K/Akt/β-catenin/Id2, and that SHIP1 associates with Fas to suppress Caspase-8-mediated T cell death, broadening SHIP1 biology beyond hematopoietic signaling.","evidence":"MSC-specific vs. myeloid-specific SHIP1 conditional KO mice with bone densitometry and pathway analysis; Fas co-IP and Caspase-8 inhibitor rescue in CD4Cre SHIP1 conditional KO mice","pmids":["24857423","24781051"],"confidence":"Medium","gaps":["Mechanism by which SHIP1 interacts with Fas not defined","Whether SHIP1 catalytic activity is required for Fas-associated function not tested"]},{"year":2022,"claim":"Studies in Alzheimer's disease models demonstrated that SHIP1 haploinsufficiency or microglial-specific deletion enhances microglial phagocytosis and amyloid-β clearance, preserves cognition, and protects against plaque-induced neuronal dystrophy, establishing microglial SHIP1 as a negative regulator of protective microglial responses in AD.","evidence":"5xFAD Inpp5d haploinsufficient mice and 5xFAD Inpp5dfl/fl Cx3cr1Ert2Cre conditional microglial KO with behavioral testing, plaque quantification, phagocytosis assays, and spatial transcriptomics","pmids":["36524682","37061460"],"confidence":"High","gaps":["Whether SHIP1 reduction is beneficial long-term or has adverse immune consequences not established","Downstream effectors of enhanced microglial phagocytosis upon SHIP1 loss not identified"]},{"year":2023,"claim":"INPP5D/SHIP1 loss in human iPSC-derived microglia was shown to activate the NLRP3 inflammasome (Caspase-1, IL-1β, IL-18 secretion) and disrupt autophagy, with confirmation in human AD brain tissue, linking SHIP1 to inflammasome regulation in neurodegeneration.","evidence":"INPP5D disruption and pharmacological inhibition in iPSC-derived microglia; unbiased RNA/protein profiling; CASP1/IL-1β/IL-18 assays; human AD brain tissue analysis","pmids":["38016942"],"confidence":"High","gaps":["Whether inflammasome activation is PIP3-dependent or involves a distinct SHIP1 mechanism not resolved","Relationship between enhanced phagocytosis and inflammasome activation upon SHIP1 loss not clarified"]},{"year":null,"claim":"Key unresolved questions include the high-resolution structure of full-length SHIP1 in autoinhibited and active conformations, the identity of direct PI(3,4)P2 effectors mediating SHIP1's product-dependent signaling, whether SHIP1 catalytic activity versus scaffolding functions are separable in vivo across cell types, and whether therapeutic SHIP1 modulation in microglia can be achieved without compromising peripheral immune homeostasis.","evidence":"","pmids":[],"confidence":"Low","gaps":["No full-length SHIP1 crystal or cryo-EM structure available","PI(3,4)P2-specific effectors downstream of SHIP1 not identified","Long-term consequences of microglial SHIP1 inhibition on peripheral immunity unknown"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[1,2,3,8,10,19,25,38]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[1,2,16,18,20]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,3,14,15,29]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[2,9,16,18,30]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[28]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[18,20]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,2,3,5,11,15,24,29,34]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[1,3,9,17,25,26]},{"term_id":"R-HSA-109582","term_label":"Hemostasis","supporting_discovery_ids":[12,23]},{"term_id":"R-HSA-5357801","term_label":"Programmed Cell Death","supporting_discovery_ids":[26,32]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[10,22,34,36,37]}],"complexes":["Lyn/SHIP1/PKC-δ (GPVI signaling complex)","DOK1/SHIP1/CRKL/PI3K","CD2AP/SHIP1/Cbl"],"partners":["LYN","DOK1","CRKL","GRB2","CD2AP","PRKCD","PSTPIP2","BTK"],"other_free_text":[]},"mechanistic_narrative":"INPP5D/SHIP1 is a hematopoietic-enriched inositol 5-phosphatase that hydrolyzes PtdIns(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane and on phagosomal membranes, thereby serving as a master negative regulator of PI3K/Akt signaling downstream of diverse immune receptors including BCR/FcγRIIB, FcεRI, TREM2/DAP12, GPVI, integrins, TLRs, and TIGIT [PMID:9586640, PMID:9852043, PMID:20484116, PMID:23154388]. SHIP1 is recruited to receptors via its SH2 domain binding to phosphorylated ITIMs and ITAMs, is activated by Lyn-mediated tyrosine phosphorylation and PKA-dependent Ser440 phosphorylation, and requires both its catalytic domain and C-terminal proline-rich region for full enzymatic function; its C-terminus also mediates autoinhibitory intramolecular interactions that regulate SH2-domain accessibility [PMID:11016922, PMID:12882960, PMID:20810657, PMID:11222379, PMID:22182704]. By controlling local PIP3 pools, SHIP1 governs Btk and Tec membrane localization, Ca²⁺ mobilization, neutrophil polarity and chemotaxis, phagosome maturation and NADPH oxidase activation, NLRP3 inflammasome suppression, NK cell cytotoxicity, endotoxin tolerance, and cell cycle progression through Akt-dependent cyclin D/p27 regulation [PMID:9820480, PMID:17173042, PMID:18490750, PMID:38016942, PMID:15604218, PMID:15308103, PMID:17142780]. SHIP1 functions as a tumor suppressor in B cells—cooperating with PTEN to prevent lymphomagenesis—and its reduced expression or activity in microglia enhances amyloid-β phagocytosis and inflammasome activation, linking INPP5D to Alzheimer's disease pathology [PMID:20956547, PMID:37061460, PMID:38016942]."},"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). Able also to hydrolyzes the 5-phosphate of phosphatidylinositol-4,5-bisphosphate (PtdIns(4,5)P3) and inositol 1,3,4,5-tetrakisphosphate (PubMed:10764818, PubMed:8769125, PubMed:9108392). Acts as a negative regulator of B-cell antigen receptor signaling. Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems. Acts as a negative regulator of myeloid cell proliferation/survival and chemotaxis, mast cell degranulation, immune cells homeostasis, integrin alpha-IIb/beta-3 signaling in platelets and JNK signaling in B-cells. Regulates proliferation of osteoclast precursors, macrophage programming, phagocytosis and activation and is required for endotoxin tolerance. Involved in the control of cell-cell junctions, CD32a signaling in neutrophils and modulation of EGF-induced phospholipase C activity (PubMed:16682172). 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":"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":340,"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":285,"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":261,"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":"15308103","id":"PMC_15308103","title":"LPS-induced upregulation of SHIP is essential for endotoxin tolerance.","date":"2004","source":"Immunity","url":"https://pubmed.ncbi.nlm.nih.gov/15308103","citation_count":234,"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":"19891860","id":"PMC_19891860","title":"Hepatitis E outbreak on cruise ship.","date":"2009","source":"Emerging infectious diseases","url":"https://pubmed.ncbi.nlm.nih.gov/19891860","citation_count":196,"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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  \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal genetic loss-of-function with orthogonal functional readouts, replicated across two distinct pathways\",\n      \"pmids\": [\"9244303\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"SHIP/SIP enzymatic activity (inositol 5-phosphatase) is required to inhibit PI3K-dependent signaling in vivo; catalytically inactive SHIP cannot block insulin- or PI3K-induced germinal vesicle breakdown or MAPK phosphorylation in Xenopus oocytes, and SHIP specifically reduces PtdIns(3,4,5)P3 levels generated in response to insulin.\",\n      \"method\": \"Injection of wild-type vs. catalytically inactive SHIP cRNA into Xenopus oocytes; GVBD and MAPK assays; lipid phosphoinositide measurements\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vivo catalytic activity requirement demonstrated with mutagenesis and multiple functional readouts\",\n      \"pmids\": [\"9111325\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SHIP reduces PIP3 levels upon FcγRIIB co-ligation with BCR, thereby regulating membrane association of Btk through PH domain–phosphoinositol lipid interactions; loss of SHIP increases Btk membrane association and hyperresponsive BCR signaling, while membrane-tethered Btk bypasses SHIP-mediated inhibition.\",\n      \"method\": \"Genetic deletion of SHIP in DT40 B cells; expression of membrane-anchored Btk chimera; PIP3 measurement; calcium flux assays\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic loss-of-function combined with rescue experiments and mechanistic lipid measurements\",\n      \"pmids\": [\"9586640\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SHIP inhibits Akt/PKB activation downstream of BCR signaling by depleting PIP3; SHIP-deficient B cells show sustained Akt activity after FcγRIIB co-cross-linking, and PIP3 (not PI(3,4)P2) is the predominant in vivo activator of Akt.\",\n      \"method\": \"FcγRIIB ITIM mutants and SHIP-deficient B cells; Akt kinase activity assays; phosphatidylinositol 3-kinase-dependent signaling measurements\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic and pharmacological approaches with multiple orthogonal readouts in a single study\",\n      \"pmids\": [\"9852043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"SHIP-deficient DT40 B cells display enhanced and sustained Ca2+ mobilization (long-lasting Ca2+ oscillations) in response to BCR ligation, while ERK activation is unaffected, demonstrating SHIP modulates Ca2+ signaling specifically.\",\n      \"method\": \"SHIP knockout DT40 B cells; single-cell Ca2+ imaging; ERK activation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined cellular phenotype using direct single-cell imaging\",\n      \"pmids\": [\"9820480\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SHIP1 and SHIP2 are recruited to FcγRIIB via ITIM binding determined by the Y+2 leucine residue in the FcγRIIB ITIM (distinct from the Y-2 isoleucine that determines SHP-1/SHP-2 binding), defining separate SHIP- and SHP-binding sites on ITIMs.\",\n      \"method\": \"Loss-of-function and gain-of-function ITIM residue substitutions between FcγRIIB and KIR ITIMs; in vivo recruitment assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mutagenesis-based mapping of binding site with gain- and loss-of-function validation\",\n      \"pmids\": [\"11016922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SHIP1 forms a novel signaling complex with DOK1, PI3K, and CRKL in BCR/ABL-transformed cells; DOK1 binds directly through its PTB domain to SHIP1, and CRKL binds via its SH2 domain; Tyr917 and Tyr1020 in SHIP1 mediate interactions with DOK1 and regulate cell migration.\",\n      \"method\": \"Co-immunoprecipitation; GST pulldown; SHIP1 tyrosine mutants; migration assays in Ba/F3 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding mapping with mutants and functional migration readout, single study\",\n      \"pmids\": [\"11031258\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"Ship1 is recruited to the erythropoietin receptor (EPO-R) in an SH2-dependent manner at Tyr401 (with redundancy at Tyr429/Tyr431); EPO activates tyrosine phosphorylation of Ship1, leading to formation of a ternary Ship1/Shc/Grb2 complex.\",\n      \"method\": \"EPO-R deletion and tyrosine mutants; co-immunoprecipitation; kinase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — receptor mutagenesis with defined binding sites, single laboratory\",\n      \"pmids\": [\"10660611\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"The C-terminus of SHIP (proline-rich region) is essential for its ability to hydrolyze PIP3 and inhibit mast cell degranulation; C-terminally truncated SHIP cannot revert SHIP-deficient BMMC responses even though the catalytic domain is intact. The catalytic phosphatase activity is required for inhibition; the NPXY motifs that bind Shc are dispensable.\",\n      \"method\": \"Retroviral infection of SHIP-/- bone marrow with wild-type, phosphatase-dead, C-terminal truncations, and NPXY mutant SHIP constructs; PIP3 measurement; calcium entry; degranulation assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — reconstitution with domain mutants and multiple functional readouts\",\n      \"pmids\": [\"11222379\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"SHIP-1 is tyrosine-phosphorylated after M-CSF stimulation in a Src family kinase-dependent manner and binds Lyn via its SH2 domain (independently of Lyn kinase activity); SHIP-1 negatively regulates M-CSF-induced Akt activation and NF-κB-dependent transcription, with Lyn stabilizing SHIP-1 at the membrane.\",\n      \"method\": \"GST-SH2 fusion protein pulldown; co-immunoprecipitation; SHIP-1 overexpression/SH2-domain constructs in THP-1 cells; macrophages from SHIP-1−/− and Lyn−/− mice; Akt phosphorylation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct binding mapped with domain constructs, confirmed in genetic KO models, multiple functional readouts\",\n      \"pmids\": [\"12882960\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"A somatic mutation in SHIP (V684E) within the phosphatase active-site signature motif reduces SHIP catalytic activity, leading to enhanced Akt phosphorylation and leukemic cell growth advantage, supporting SHIP as a tumor suppressor via the PI3K/Akt pathway.\",\n      \"method\": \"In vitro inositol 5-phosphatase assay with mutant SHIP; Akt phosphorylation assays; transfection of SHIP-V684E into K562 cells; proliferation and apoptosis assays\",\n      \"journal\": \"Leukemia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic assay with active-site mutant plus cellular phenotype, single study\",\n      \"pmids\": [\"12529653\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 deficiency in mast cells leads to dysregulated FcεRI signaling characterized by prolonged PIP3 synthesis and Ca2+ mobilization, resulting from loss of SHIP phosphorylation and activity; this is dependent on Lyn kinase for SHIP activation in normal cells.\",\n      \"method\": \"Bone marrow-derived mast cells from Lyn−/− mice; PIP3 measurement; Ca2+ mobilization; SHIP tyrosine phosphorylation assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined KO phenotype with mechanistic phospholipid measurements, single study\",\n      \"pmids\": [\"15210764\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 and Lyn act as negative regulators of integrin αIIbβ3 outside-in signaling in platelets; SHIP1 regulates PIP3 accumulation, Ca2+ responses, and platelet spreading, with Lyn-dependent SHIP1 phosphorylation modulating PtdIns(3,4,5)P3 metabolism and fibrinogen adhesion stability.\",\n      \"method\": \"SHIP1 knockout and Lyn knockout murine platelets; PIP3 measurement; calcium flux; platelet spreading and adhesion assays under physiological blood flow\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two genetic KO models with multiple orthogonal functional readouts\",\n      \"pmids\": [\"15166241\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 and SHIP2 interact preferentially with Tec (vs. other Tec family kinases) via the Tec SH3 domain, and SHIP1 inhibits Tec activity and membrane localization by depleting local PtdIns(3,4,5)P3; constitutively membrane-targeted Tec is resistant to SHIP1 inhibition.\",\n      \"method\": \"Co-immunoprecipitation; kinase activity assays; Tec SH3 domain mutants; membrane-targeting chimeras; SHIP phosphatase assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — four orthogonal lines of evidence including binding mapping, enzymatic inhibition, and rescue experiments\",\n      \"pmids\": [\"15492005\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"SHIP1 negatively regulates monokine-induced IFN-γ production in NK cells; the inhibitory effect requires SHIP1 catalytic activity, as catalytic-dead SHIP1 overexpression does not suppress IFN-γ, and SHIP1−/− mice produce more IFN-γ from NK cells in vivo.\",\n      \"method\": \"SHIP1 overexpression (wild-type vs. catalytic-dead mutant) in CD56bright NK cells; SHIP1-/- mouse NK cells; IFN-γ production assays in vitro and in vivo\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — catalytic mutant combined with genetic KO, in vitro and in vivo validation\",\n      \"pmids\": [\"15604218\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"LPS-induced endotoxin tolerance requires upregulation of SHIP (not SHIP2 or PTEN); this upregulation is mediated by LPS-induced autocrine TGFβ (via MyD88-dependent pathway), and neutralizing TGFβ blocks tolerance. SHIP-/- macrophages and mast cells cannot establish endotoxin tolerance.\",\n      \"method\": \"SHIP-/- bone marrow-derived macrophages and mast cells; LPS tolerance assays; TGFβ neutralizing antibodies; in vivo SHIP+/+ and SHIP-/- mouse models\",\n      \"journal\": \"Immunity\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with mechanistic antibody neutralization and in vivo confirmation\",\n      \"pmids\": [\"15308103\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SHIP1 controls neutrophil polarity and chemotaxis by governing where PtdIns(3,4,5)P3 accumulates; SHIP1-deficient neutrophils show diffuse PtdIns(3,4,5)P3 distribution and fail to form a leading edge, whereas PTEN deficiency does not affect neutrophil chemotaxis.\",\n      \"method\": \"SHIP1-/- mice; transgenic AktPH-GFP biosensor mice for live PtdIns(3,4,5)P3 imaging; time-lapse microscopy of chemotaxing primary neutrophils\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live-cell PIP3 imaging tied to functional chemotaxis phenotype in genetic KO, replicated vs. PTEN KO\",\n      \"pmids\": [\"17173042\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SHIP1 negatively regulates osteoclast precursor proliferation via Akt-dependent modulation of D-type cyclins and p27; SHIP1-null BMMs show enhanced M-CSF-induced Akt activation leading to cyclin D upregulation, p27 downregulation, increased Rb phosphorylation, and proliferation.\",\n      \"method\": \"SHIP1-/- bone marrow macrophages; Akt activation assays; cyclin D and p27 protein levels; Rb phosphorylation; BrdU proliferation assays; inflammatory arthritis model\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — clean KO with defined mechanistic pathway through Akt/cyclins/p27\",\n      \"pmids\": [\"17142780\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"SHIP-1 (YFP chimera) is recruited to forming phagosomes at the leading edge and dissociates earlier than PI3K (p85), restricting its inhibitory activity to early stages of phagocytosis; PTEN does not localize to phagosomes. This differential localization regulates when and where PIP3 accumulates.\",\n      \"method\": \"Live imaging of YFP-SHIP1, YFP-PTEN, and p85-CFP chimeras in macrophages; quantitative analysis of phagosome PH domain biosensors for PIP3 and PI(3,4)P2\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — direct live-cell localization with functional lipid biosensors and quantitative analysis\",\n      \"pmids\": [\"17442886\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Small-molecule agonists of SHIP1 activate recombinant SHIP1 enzyme in vitro and stimulate SHIP1 activity in intact macrophages and mast cells by binding an allosteric activation domain distinct from the active site; in vivo administration is protective in endotoxemia and anaphylaxis models.\",\n      \"method\": \"In vitro enzyme activity assays with recombinant SHIP1; cellular phosphoinositide measurements in macrophages and mast cells; in vivo mouse models\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with identified allosteric site, validated in cells and in vivo\",\n      \"pmids\": [\"17502453\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"SHIP-1 activity on phagosomal membranes enhances the early oxidative burst by converting PI(3,4,5)P3 to PI(3,4)P2, which activates NADPH oxidase; SHIP-1-deficient macrophages show elevated PI(3,4,5)P3/PI(3,4)P2 ratios on phagosomes and decreased early NADPH oxidase activity, and altered Rab5a/PI(3)P dynamics indicating disrupted phagosome maturation.\",\n      \"method\": \"SHIP-1-deficient macrophages; phagosomal phospholipid measurements; reactive oxygen species imaging; phagosome maturation markers\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with direct phagosomal organelle-level phospholipid and ROS measurements\",\n      \"pmids\": [\"18490750\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"NTAL decreases the recruitment of SHIP1 by LAT in mast cell FcεRI signaling complexes; LAT provides two SHIP1 binding sites via its distal tyrosines; reduced SHIP1 recruitment leads to increased Akt phosphorylation and enhanced mast cell survival.\",\n      \"method\": \"Co-immunoprecipitation; NTAL-deficient mast cells; LAT tyrosine mutants; Akt phosphorylation and apoptosis assays\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — defined binding sites with KO and mutant studies, single laboratory\",\n      \"pmids\": [\"18322174\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"SHIP1 is a bona fide target of onco-miR-155; elevated miR-155 driven by autocrine TNFα in DLBCL reduces SHIP1 protein expression, promoting B cell lymphoma proliferation; anti-TNFα treatment restores SHIP1 expression and reduces proliferation.\",\n      \"method\": \"miR-155 target validation in DLBCL cells; anti-TNFα treatment (etanercept/infliximab); SHIP1 protein measurement; tumor xenograft models\",\n      \"journal\": \"EMBO molecular medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct miR-155/SHIP1 targeting with rescue experiments and in vivo xenograft validation\",\n      \"pmids\": [\"19890474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"Lyn, PKC-δ, and SHIP-1 form a specific signaling complex downstream of GPVI (but not PAR) in platelets; Lyn-mediated phosphorylation of SHIP-1 at Y1020 and PKC-δ at Y311 occurs preferentially after GPVI stimulation, and this complex negatively regulates GPVI-mediated dense granule secretion.\",\n      \"method\": \"Co-immunoprecipitation; Lyn-/- and PKC-δ-/- murine platelets; SHIP-1 phosphorylation assays; dense granule secretion assays\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — two genetic KO models with defined phosphorylation events and functional secretion readout\",\n      \"pmids\": [\"19587372\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"TREM2/DAP12-induced PI3K signaling requires DAP10 for PI3K recruitment, and SHIP1 inhibits this pathway by binding to DAP12 in an SH2 domain-dependent manner, preventing PI3K recruitment to DAP12.\",\n      \"method\": \"Co-immunoprecipitation; SH2-domain mutants of SHIP1; SHIP1 knockdown; TREM2/DAP12/DAP10 reconstitution experiments; PI3K recruitment assays\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — SH2-domain-dependent mechanism demonstrated by mutants and co-IP, multiple orthogonal approaches\",\n      \"pmids\": [\"20484116\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"PKA phosphorylates SHIP1 at Ser440 within the catalytic domain, increasing SHIP1 enzymatic activity in hematopoietic cells; S440A mutation abolishes PKA-mediated SHIP1 activation and prevents inhibition of Akt downstream of BCR engagement.\",\n      \"method\": \"Mass spectrometry identification of phosphorylation sites; truncation mutants; S440A site-directed mutagenesis; SHIP1 activity assays; Akt phosphorylation by flow cytometry in DT40 B cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — mass spectrometry-identified site validated by mutagenesis in vitro and in cells with functional Akt readout\",\n      \"pmids\": [\"20810657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Concomitant deletion of PTEN and SHIP in B cells results in spontaneous mature B cell lymphoma, demonstrating that SHIP is a tumor suppressor that cooperates with PTEN to suppress B cell malignancy; bPTEN/SHIP-/- B cells show enhanced survival with increased MCL1, decreased Bim, low p27, and high cyclin D3, and proliferate in response to BAFF.\",\n      \"method\": \"B cell-specific conditional PTEN and SHIP double-knockout mice (Cre-lox); tumor analysis; BCL2-family protein expression; cell cycle analysis; BAFF-dependent proliferation assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — conditional double-KO genetic epistasis with multiple mechanistic cellular readouts\",\n      \"pmids\": [\"20956547\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"In SHIP1-/- macrophages stimulated via TLR2/TLR4, enhanced PI3K pathway activation (due to SHIP1 loss) leads to reduced cytokine production, consistent with SHIP1's product PI(3,4)P2 promoting signaling differently from its substrate PIP3; Lyn interacts with PI3K downstream of TLR4/TLR2 as a negative regulatory module.\",\n      \"method\": \"SHIP1-/- bone marrow-derived macrophages; Lyn-/- macrophages; cytokine production assays; PI3K inhibitor treatment\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO models with pharmacological validation, single laboratory\",\n      \"pmids\": [\"20385881\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"SHIP1 SH2 domain undergoes intramolecular and intermolecular interaction with the SHIP1 C-terminus, which regulates the association between SHIP1 and the BCR component Ig-α (ITAM); full-length SHIP1 does not interact with phosphorylated Ig-α ITAM peptide in the same manner as the isolated SH2 domain, indicating autoinhibitory regulation.\",\n      \"method\": \"FRET in S2 cells; pulldown with phospho-ITAM peptides; fluorescently labeled SH2 domain membrane translocation assays; BCR mutants with C-terminally truncated Ig-α\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — FRET and membrane translocation assays with mutant receptors, single laboratory\",\n      \"pmids\": [\"22182704\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"TIGIT/PVR engagement phosphorylates Tyr225 in the ITT-like motif of TIGIT, which recruits Grb2, which in turn recruits SHIP1 to terminate PI3K and MAPK signaling in NK cells, leading to disrupted granule polarization and loss of cytotoxicity; Y225 or N227 mutation or SHIP1 silencing reverses TIGIT-mediated killing inhibition.\",\n      \"method\": \"TIGIT/PVR ligation; phospho-Tyr225 mutants; Grb2/SHIP1 co-immunoprecipitation; SHIP1 siRNA knockdown; granule polarization and cytotoxicity assays\",\n      \"journal\": \"Cell death and differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — tyrosine mutants plus protein binding studies plus KD rescue with functional NK cytotoxicity readout\",\n      \"pmids\": [\"23154388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"CD2AP forms a complex with SHIP1, and this CD2AP/SHIP1 complex associates with Cbl after BDCA2/FcεR1γ cross-linking, inhibiting Cbl E3 ubiquitin ligase activity to prevent ubiquitination and degradation of Syk and FcεR1γ, thereby positively regulating ITAM signaling in pDCs.\",\n      \"method\": \"Immunoprecipitation and mass spectrometry; Cbl ubiquitin ligase activity assays; CD2AP/SHIP1 knockdown; immunofluorescence co-localization at plasma membrane\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP/MS identification with functional E3 ligase inhibition assay, single laboratory\",\n      \"pmids\": [\"22706086\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SHIP1 promotes osteoblast development from mesenchymal stem cells by limiting PI3K/Akt/β-catenin/Id2 pathway activation; SHIP1 deficiency in MSCs reduces bone mass and density, and is the primary cause of osteoporotic phenotype in SHIP1 germline KO mice (not osteoclast SHIP1 deficiency).\",\n      \"method\": \"MSC-specific SHIP1 conditional KO mice vs. myeloid/OC-specific KO; bone densitometry; PI3K/Akt/β-catenin/Id2 pathway analysis; SHIP1 inhibitor treatment\",\n      \"journal\": \"Stem cells and development\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cell-type-specific conditional KO with epistasis dissecting lineage contributions, single laboratory\",\n      \"pmids\": [\"24857423\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"SHIP1 associates with the death receptor CD95/Fas and its loss promotes extrinsic T cell death via Caspase 8; Caspase 8 inhibitor treatment prevents SHIP1 inhibitor-mediated T cell death and reduces mucosal inflammation in SHIP1-/- mice.\",\n      \"method\": \"Co-immunoprecipitation of SHIP1 with Fas; Caspase 8 inhibitor treatment; CD4CreSHIP1flox/flox conditional KO mice; mucosal inflammation assays\",\n      \"journal\": \"Mucosal immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP binding partner with pharmacological rescue, single laboratory\",\n      \"pmids\": [\"24781051\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"PSTPIP2 interacts with SHIP1 via PSTPIP2 C-terminal tyrosine residues (critical for PEST-phosphatase-independent inhibitory function); SHIP1 binding is important for PSTPIP2-mediated suppression of IL-1β processing in neutrophils, and SHIP1 inhibition enhances IL-1β processing.\",\n      \"method\": \"Co-immunoprecipitation; PSTPIP2 domain mutants; SHIP1 inhibitor treatment; IL-1β processing assays in neutrophils\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — binding mapped with domain mutants and functional IL-1β readout, single laboratory\",\n      \"pmids\": [\"26304991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Reduction in INPP5D/SHIP1 activity in human iPSC-derived microglia induces NLRP3 inflammasome formation, Caspase-1 cleavage, and secretion of IL-1β and IL-18; this is associated with disrupted autophagy; pharmacological inhibition of INPP5D recapitulates inflammasome activation, and evidence for INPP5D/NLRP3 inflammasome connection is confirmed in human AD brain tissue.\",\n      \"method\": \"INPP5D disruption in iPSC-derived human microglia; unbiased RNA/protein profiling; targeted pharmacological experiments; CASP1 cleavage and IL-1β/IL-18 secretion assays; multi-analytic human brain tissue analysis\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — multiple orthogonal methods (genetic + pharmacological + human tissue) in human relevant model system\",\n      \"pmids\": [\"38016942\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SHIP1 agonist K306 activates SHIP1 without requiring the C2 domain (unlike previous agonists), suppresses inflammatory cytokines (TNF-α, 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 activation assays; SHIP1-deficient macrophage/microglia controls; cytokine assays; in vivo LPS endotoxemia; synaptosome degradation assays\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro enzymatic activation with domain-specificity, SHIP1-KO controls, and in vivo validation\",\n      \"pmids\": [\"35465359\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Inpp5d haplodeficiency in microglia of 5xFAD mice enhances microglial phagocytosis and amyloid beta clearance, perturbs intracellular signaling pathways regulating immune response, and preserves cognitive function; spatial transcriptomics revealed altered synaptic regulation and immune activation pathways.\",\n      \"method\": \"5xFAD Inpp5d haploinsufficient mice; behavioral cognitive testing; amyloid plaque quantification; spatial transcriptomics; microglial phagocytosis assays\",\n      \"journal\": \"Alzheimer's & dementia\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic haploinsufficiency with multiple functional and transcriptomic readouts, single laboratory\",\n      \"pmids\": [\"36524682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Microglial SHIP-1 deletion in 5xFAD mice substantially enhances microglial recruitment to Aβ plaques, improves plaque encapsulation and Aβ engulfment, alters microglial gene expression toward activation/phagocytosis programs, and protects against plaque-induced neuronal dystrophy.\",\n      \"method\": \"5xFAD Inpp5dfl/fl Cx3cr1Ert2Cre conditional microglial KO; microglial recruitment quantification; plaque engulfment assays; gene expression analysis; neuronal health markers\",\n      \"journal\": \"Alzheimer's & dementia\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — inducible microglial-specific conditional KO with multiple orthogonal mechanistic readouts\",\n      \"pmids\": [\"37061460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SHIP1 negatively regulates lentiviral gene transfer-demonstrated PI3K/AKT-driven proliferation of AML CD34+ cells; enzymatically inactive SHIP1 (D672A) has no effect, confirming the requirement for phosphatase activity.\",\n      \"method\": \"Lentiviral gene transfer of wild-type vs. catalytic-dead (D672A) SHIP1 into AML patient CD34+ cells; GM-CSF-dependent proliferation assays\",\n      \"journal\": \"Gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 — catalytic-dead mutant establishes enzymatic activity requirement, replicated across 12 patient samples\",\n      \"pmids\": [\"19148132\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Ikaros binds to the promoter of the INPP5D gene (encoding SHIP) and is required for SHIP expression; Helios deficiency reduces SHIP expression while Ikaros deficiency upregulates it, providing transcriptional co-regulation of SHIP by Ikaros family factors that governs BCR signaling strength.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP) of Ikaros at INPP5D promoter; Helios-/- and Ikaros-/- DT40 B cell lines; SHIP mRNA/protein quantification; BCR-induced Ca2+ signaling assays\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ChIP demonstrates direct promoter binding, complemented by genetic KO functional data\",\n      \"pmids\": [\"20602434\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"INPP5D/SHIP1 is a hematopoietic-enriched (and microglial-expressed) inositol 5-phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2 at the plasma membrane, thereby negatively regulating PI3K/Akt signaling downstream of immune receptors (BCR, FcγRIIB, FcεRI, TREM2/DAP12, GPVI, integrins, TLRs, TIGIT), controlling Btk membrane localization, Ca2+ mobilization, cell polarity, phagocytosis, NLRP3 inflammasome activation, and cell survival/proliferation; SHIP1 is recruited to receptors via its SH2 domain (binding ITIMs and phosphotyrosines), regulated by Lyn-mediated tyrosine phosphorylation and PKA-mediated phosphorylation at Ser440, and modulated by miR-155-mediated repression and allosteric small-molecule agonists/antagonists, with its catalytic C-terminus essential for full enzymatic function and tumor-suppressive activity.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"INPP5D/SHIP1 is a hematopoietic-enriched inositol 5-phosphatase that hydrolyzes PtdIns(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane and on phagosomal membranes, thereby serving as a master negative regulator of PI3K/Akt signaling downstream of diverse immune receptors including BCR/FcγRIIB, FcεRI, TREM2/DAP12, GPVI, integrins, TLRs, and TIGIT [PMID:9586640, PMID:9852043, PMID:20484116, PMID:23154388]. SHIP1 is recruited to receptors via its SH2 domain binding to phosphorylated ITIMs and ITAMs, is activated by Lyn-mediated tyrosine phosphorylation and PKA-dependent Ser440 phosphorylation, and requires both its catalytic domain and C-terminal proline-rich region for full enzymatic function; its C-terminus also mediates autoinhibitory intramolecular interactions that regulate SH2-domain accessibility [PMID:11016922, PMID:12882960, PMID:20810657, PMID:11222379, PMID:22182704]. By controlling local PIP3 pools, SHIP1 governs Btk and Tec membrane localization, Ca²⁺ mobilization, neutrophil polarity and chemotaxis, phagosome maturation and NADPH oxidase activation, NLRP3 inflammasome suppression, NK cell cytotoxicity, endotoxin tolerance, and cell cycle progression through Akt-dependent cyclin D/p27 regulation [PMID:9820480, PMID:17173042, PMID:18490750, PMID:38016942, PMID:15604218, PMID:15308103, PMID:17142780]. SHIP1 functions as a tumor suppressor in B cells—cooperating with PTEN to prevent lymphomagenesis—and its reduced expression or activity in microglia enhances amyloid-β phagocytosis and inflammasome activation, linking INPP5D to Alzheimer's disease pathology [PMID:20956547, PMID:37061460, PMID:38016942].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Establishing that SHIP1 is an enzymatically active inositol 5-phosphatase that reduces PIP3 levels in vivo and that its catalytic activity is required to inhibit PI3K-dependent signaling resolved the question of whether SHIP1 functions as a lipid phosphatase rather than merely an adaptor protein.\",\n      \"evidence\": \"Injection of wild-type vs. catalytically inactive SHIP cRNA into Xenopus oocytes with GVBD, MAPK, and lipid measurements\",\n      \"pmids\": [\"9111325\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of catalytic specificity not determined\", \"In vivo relevance in mammalian hematopoietic cells not yet shown\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Demonstrating that SHIP1 mediates FcγRIIB inhibitory signaling in B cells—distinct from SHP-1-mediated KIR signaling—established SHIP1 as the phosphatase specifically recruited by the FcγRIIB ITIM to modulate BCR co-inhibition.\",\n      \"evidence\": \"Genetic deletion of SHIP or SHP-1 in B cell lines with inhibitory signaling and apoptosis readouts\",\n      \"pmids\": [\"9244303\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of SHIP1 recruitment to FcγRIIB ITIM not yet mapped at the residue level\"]\n    },\n    {\n      \"year\": 1998,\n      \"claim\": \"Showing that SHIP1 controls Btk membrane association and Akt activation by depleting PIP3 downstream of BCR/FcγRIIB defined the core mechanistic axis: SHIP1 → PIP3 depletion → loss of PH-domain-dependent effector membrane recruitment → signal termination.\",\n      \"evidence\": \"SHIP-deficient DT40 B cells with membrane-anchored Btk rescue, PIP3 quantification, Ca²⁺ flux, and Akt kinase assays\",\n      \"pmids\": [\"9586640\", \"9852043\", \"9820480\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PI(3,4)P2 generated by SHIP1 has independent signaling roles was unclear\", \"Contribution of SHIP1 vs. SHIP2 not delineated\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Residue-level mapping of ITIM determinants (Y+2 leucine for SHIP binding vs. Y−2 isoleucine for SHP binding) and identification of SH2-dependent recruitment to EPO-R and a DOK1/CRKL signaling complex defined how SHIP1 is recruited to multiple receptor systems and participates in multiprotein signaling complexes.\",\n      \"evidence\": \"ITIM residue substitution mutagenesis; EPO-R deletion/tyrosine mutants with co-IP; GST pulldown and migration assays in BCR/ABL-transformed cells\",\n      \"pmids\": [\"11016922\", \"10660611\", \"11031258\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Crystal structure of SH2/ITIM interaction not available\", \"Relative contribution of DOK1/CRKL complex to SHIP1 function in vivo unknown\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"Reconstitution experiments with domain mutants in SHIP−/− mast cells revealed that the C-terminal proline-rich region is essential for PIP3 hydrolysis and degranulation inhibition, even though the catalytic domain is intact, indicating the C-terminus is required for full enzymatic activity in cells.\",\n      \"evidence\": \"Retroviral transduction of wild-type, phosphatase-dead, C-terminal truncation, and NPXY mutant SHIP constructs into SHIP−/− BMMCs with PIP3, Ca²⁺, and degranulation readouts\",\n      \"pmids\": [\"11222379\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether C-terminus acts through allosteric activation, membrane targeting, or protein–protein interactions not resolved\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Identification of Lyn as a direct binding partner and activating kinase for SHIP1 via SH2-domain interaction, and discovery of a somatic V684E mutation reducing catalytic activity in leukemia, established the Lyn→SHIP1 activation axis and SHIP1's role as a tumor suppressor.\",\n      \"evidence\": \"GST-SH2 pulldowns, co-IP in macrophages, SHIP1−/− and Lyn−/− mice for Akt readouts; in vitro phosphatase assay with V684E mutant and proliferation assays in K562 cells\",\n      \"pmids\": [\"12882960\", \"12529653\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Frequency of SHIP1 mutations across leukemia subtypes not established\", \"Whether other Src kinases can substitute for Lyn in different cell types unclear\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Multiple studies using SHIP1−/− and Lyn−/− cells across mast cells, platelets, and NK cells established that Lyn-dependent SHIP1 activation is a general negative regulatory module controlling PIP3/Ca²⁺ in FcεRI signaling, integrin outside-in signaling, and IFN-γ production, while LPS tolerance was shown to require SHIP1 upregulation by autocrine TGFβ.\",\n      \"evidence\": \"SHIP1−/− and Lyn−/− BMMCs, platelets, NK cells; PIP3 and Ca²⁺ measurements; IFN-γ assays with catalytic-dead mutant; LPS tolerance in SHIP−/− macrophages with TGFβ neutralization\",\n      \"pmids\": [\"15210764\", \"15166241\", \"15604218\", \"15308103\", \"15492005\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Endotoxin tolerance mechanism beyond SHIP1 upregulation (e.g., chromatin remodeling) not addressed\", \"Whether SHIP1-Tec interaction is relevant in primary cells not confirmed\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Live PIP3 biosensor imaging in SHIP1−/− neutrophils demonstrated that SHIP1 restricts PIP3 to the leading edge to establish cell polarity during chemotaxis—a function not shared by PTEN—resolving the question of which phosphatase controls spatial PIP3 distribution in neutrophils.\",\n      \"evidence\": \"SHIP1−/− mice crossed with AktPH-GFP transgenic biosensor mice; time-lapse chemotaxis imaging\",\n      \"pmids\": [\"17173042\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SHIP1 and PTEN have cooperative roles in other migratory cell types not tested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Live imaging of YFP-SHIP1 at forming phagosomes showed SHIP1 is recruited early and dissociates before PI3K, establishing temporal control of PIP3 on phagosomes; separately, identification of allosteric small-molecule SHIP1 agonists protective in endotoxemia and anaphylaxis demonstrated druggability.\",\n      \"evidence\": \"Live-cell imaging of YFP-SHIP1 and PI3K-CFP chimeras during phagocytosis; in vitro enzyme assays with allosteric activators; in vivo mouse models\",\n      \"pmids\": [\"17442886\", \"17502453\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Identity of the allosteric activation domain not structurally defined\", \"SHIP1 agonist selectivity over SHIP2 not fully characterized\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Demonstration that SHIP1-generated PI(3,4)P2 on phagosomes activates NADPH oxidase for the early oxidative burst, and that SHIP1 loss disrupts Rab5a/PI(3)P dynamics, established that SHIP1's product PI(3,4)P2 has positive signaling functions beyond simply depleting PIP3.\",\n      \"evidence\": \"SHIP1−/− macrophages with phagosomal phospholipid quantification, ROS imaging, and phagosome maturation markers\",\n      \"pmids\": [\"18490750\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct PI(3,4)P2 effectors on the phagosome not identified\", \"Whether PI(3,4)P2 signaling differs between phagosomes and plasma membrane not resolved\"]\n    },\n    {\n      \"year\": 2009,\n      \"claim\": \"Identification of miR-155 as a direct repressor of SHIP1 mRNA driving DLBCL proliferation, and of a Lyn/PKC-δ/SHIP1 signaling complex specific to GPVI in platelets, expanded SHIP1 regulation to post-transcriptional control and receptor-specific signaling complexes.\",\n      \"evidence\": \"miR-155 target validation in DLBCL with anti-TNFα rescue and xenograft models; co-IP from Lyn−/− and PKC-δ−/− platelets with SHIP1 phosphorylation and dense granule secretion assays\",\n      \"pmids\": [\"19890474\", \"19587372\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether miR-155/SHIP1 axis is relevant beyond DLBCL not established\", \"Other miRNAs targeting SHIP1 not surveyed\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Multiple 2010 studies established that SHIP1 cooperates with PTEN as a tumor suppressor in B cells (double KO causes spontaneous lymphoma), is activated by PKA at Ser440, inhibits TREM2/DAP12 signaling via SH2-dependent DAP12 binding, and suppresses AML progenitor proliferation in a catalytic-activity-dependent manner.\",\n      \"evidence\": \"B-cell-specific PTEN/SHIP conditional double-KO mice; mass spectrometry identification of Ser440 with S440A mutagenesis in DT40 cells; SHIP1 SH2-domain mutants and knockdown in TREM2/DAP12 reconstitution; lentiviral WT/D672A SHIP1 in AML CD34+ cells\",\n      \"pmids\": [\"20956547\", \"20810657\", \"20484116\", \"19148132\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for PKA-mediated allosteric activation not resolved\", \"Whether SHIP1 loss alone is sufficient for lymphomagenesis without PTEN loss unknown\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"FRET-based studies revealed that the SHIP1 C-terminus engages in intramolecular interaction with the SH2 domain, creating an autoinhibited conformation that limits ITAM binding, providing a structural explanation for why the C-terminus is required for regulated enzymatic function.\",\n      \"evidence\": \"FRET in S2 cells; phospho-ITAM peptide pulldowns comparing full-length vs. isolated SH2 domain; membrane translocation assays\",\n      \"pmids\": [\"22182704\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No high-resolution structural data for autoinhibited SHIP1\", \"Physiological signals that relieve autoinhibition not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"SHIP1 was placed in the TIGIT inhibitory pathway (recruited via Grb2 to phospho-Y225) to terminate PI3K/MAPK signaling in NK cells, and in a CD2AP/SHIP1 complex that inhibits Cbl E3 ligase activity in pDCs, expanding SHIP1's non-catalytic scaffolding roles.\",\n      \"evidence\": \"TIGIT Y225 mutants, Grb2/SHIP1 co-IP, SHIP1 siRNA in NK cytotoxicity assays; CD2AP/SHIP1 co-IP/MS with Cbl ubiquitin ligase assays in pDCs\",\n      \"pmids\": [\"23154388\", \"22706086\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SHIP1 catalytic activity is required for TIGIT-mediated inhibition not tested\", \"CD2AP/SHIP1 interaction not validated in other immune cell types\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Cell-type-specific conditional knockouts revealed that SHIP1 in mesenchymal stem cells (not osteoclasts) drives the osteoporotic phenotype of SHIP1-null mice by limiting PI3K/Akt/β-catenin/Id2, and that SHIP1 associates with Fas to suppress Caspase-8-mediated T cell death, broadening SHIP1 biology beyond hematopoietic signaling.\",\n      \"evidence\": \"MSC-specific vs. myeloid-specific SHIP1 conditional KO mice with bone densitometry and pathway analysis; Fas co-IP and Caspase-8 inhibitor rescue in CD4Cre SHIP1 conditional KO mice\",\n      \"pmids\": [\"24857423\", \"24781051\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SHIP1 interacts with Fas not defined\", \"Whether SHIP1 catalytic activity is required for Fas-associated function not tested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Studies in Alzheimer's disease models demonstrated that SHIP1 haploinsufficiency or microglial-specific deletion enhances microglial phagocytosis and amyloid-β clearance, preserves cognition, and protects against plaque-induced neuronal dystrophy, establishing microglial SHIP1 as a negative regulator of protective microglial responses in AD.\",\n      \"evidence\": \"5xFAD Inpp5d haploinsufficient mice and 5xFAD Inpp5dfl/fl Cx3cr1Ert2Cre conditional microglial KO with behavioral testing, plaque quantification, phagocytosis assays, and spatial transcriptomics\",\n      \"pmids\": [\"36524682\", \"37061460\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether SHIP1 reduction is beneficial long-term or has adverse immune consequences not established\", \"Downstream effectors of enhanced microglial phagocytosis upon SHIP1 loss not identified\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"INPP5D/SHIP1 loss in human iPSC-derived microglia was shown to activate the NLRP3 inflammasome (Caspase-1, IL-1β, IL-18 secretion) and disrupt autophagy, with confirmation in human AD brain tissue, linking SHIP1 to inflammasome regulation in neurodegeneration.\",\n      \"evidence\": \"INPP5D disruption and pharmacological inhibition in iPSC-derived microglia; unbiased RNA/protein profiling; CASP1/IL-1β/IL-18 assays; human AD brain tissue analysis\",\n      \"pmids\": [\"38016942\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether inflammasome activation is PIP3-dependent or involves a distinct SHIP1 mechanism not resolved\", \"Relationship between enhanced phagocytosis and inflammasome activation upon SHIP1 loss not clarified\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"Key unresolved questions include the high-resolution structure of full-length SHIP1 in autoinhibited and active conformations, the identity of direct PI(3,4)P2 effectors mediating SHIP1's product-dependent signaling, whether SHIP1 catalytic activity versus scaffolding functions are separable in vivo across cell types, and whether therapeutic SHIP1 modulation in microglia can be achieved without compromising peripheral immune homeostasis.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No full-length SHIP1 crystal or cryo-EM structure available\", \"PI(3,4)P2-specific effectors downstream of SHIP1 not identified\", \"Long-term consequences of microglial SHIP1 inhibition on peripheral immunity unknown\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [1, 2, 3, 8, 10, 19, 25, 38]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [1, 2, 16, 18, 20]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 3, 14, 15, 29]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [2, 9, 16, 18, 30]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [18, 20]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 2, 3, 5, 11, 15, 24, 29, 34]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [1, 3, 9, 17, 25, 26]},\n      {\"term_id\": \"R-HSA-109582\", \"supporting_discovery_ids\": [12, 23]},\n      {\"term_id\": \"R-HSA-5357801\", \"supporting_discovery_ids\": [26, 32]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [10, 22, 34, 36, 37]}\n    ],\n    \"complexes\": [\n      \"Lyn/SHIP1/PKC-δ (GPVI signaling complex)\",\n      \"DOK1/SHIP1/CRKL/PI3K\",\n      \"CD2AP/SHIP1/Cbl\"\n    ],\n    \"partners\": [\n      \"LYN\",\n      \"DOK1\",\n      \"CRKL\",\n      \"GRB2\",\n      \"CD2AP\",\n      \"PRKCD\",\n      \"PSTPIP2\",\n      \"BTK\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}