Affinage

Showing INPP5D — SHIP is a alias.

INPP5D

Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 1 · UniProt Q92835

Length
1189 aa
Mass
133.3 kDa
Annotated
2026-06-10
100 papers in source corpus 36 papers cited in narrative 36 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 6/6 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INPP5D (SHIP1) is a hematopoietic and microglial inositol 5'-phosphatase that hydrolyzes PI(3,4,5)P3 to oppose PI3K/Akt signaling and thereby acts as a brake on immune cell activation (PMID:9586640, PMID:11222379, PMID:19148132). Its catalytic activity is genetically required: phosphatase-dead and active-site mutants fail to revert knockout phenotypes or to suppress proliferation, and the C-terminal proline-rich region is also essential for substrate hydrolysis (PMID:11222379, PMID:19148132). SHIP1 is recruited to inhibitory and activation receptors through its SH2 domain — including FcγRIIB co-ligated with the BCR, DAP12/TREM2, TIGIT (via Grb2), and the LAT adaptor — where it lowers membrane PIP3 and dampens membrane recruitment of PH-domain kinases such as Btk and Tec, calcium flux, and granule/degranulation responses (PMID:9244303, PMID:9586640, PMID:15492005, PMID:18322174, PMID:20484116, PMID:23154388). Beyond simple suppression, it functions as a spatial regulator of PIP3 polarity, directing leading-edge PIP3 accumulation during neutrophil adhesion and chemotaxis and restricting its activity to early phagosome formation to control the oxidative burst and phagosome maturation (PMID:17173042, PMID:17442886, PMID:18490750, PMID:22323291). SHIP1 activity is tuned by Lyn/Src-family-dependent tyrosine phosphorylation, by PKA phosphorylation at Ser440, and by small-molecule allosteric activators acting through the C2 region, while its expression is set by Ikaros at the INPP5D promoter and repressed post-transcriptionally by miR-155 (PMID:12882960, PMID:19359473, PMID:20810657, PMID:23121445, PMID:20602434). In the brain it operates downstream of TREM2/TYROBP signaling, where loss of SHIP1 function in microglia triggers NLRP3 inflammasome assembly, CASP1 cleavage and IL-1β/IL-18 release, drives excess complement-mediated synaptic pruning during development, and shapes the microglial barrier against amyloid-β (PMID:38016942, PMID:37035000, PMID:39657671).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1997 High

    Established SHIP1 as the defining effector of one of two distinct inhibitory receptor pathways, separating FcγRIIB-driven inhibition from KIR/SHP-1 inhibition.

    Evidence SHIP-deficient B cell lines with BCR-triggered apoptosis and inhibitory signaling readouts

    PMID:9244303

    Open questions at the time
    • Did not define the lipid substrate or molecular mechanism of inhibition
    • Recruitment determinants to FcγRIIB not mapped
  2. 1998 High

    Defined the molecular mechanism: SHIP1 lowers PIP3 to limit PH-domain kinase membrane recruitment (Btk) and specifically restrains calcium mobilization without affecting ERK.

    Evidence FcγRIIB co-ligation, SHIP-deficient and DT40 B cells, Btk membrane-targeted chimera rescue, single-cell Ca2+ imaging

    PMID:9586640 PMID:9820480

    Open questions at the time
    • Did not address spatial control of PIP3
    • Other PH-domain effectors not enumerated
  3. 2001 High

    Showed that catalytic activity and the C-terminal proline-rich region are both required for SHIP1 function, defining a substrate-hydrolysis-dependent inhibitory output.

    Evidence Retroviral reconstitution of SHIP-/- mast cells with truncation and phosphatase-dead mutants; PIP3, calcium, degranulation readouts

    PMID:11222379

    Open questions at the time
    • Why the C-terminus is needed for catalysis in cells was not resolved
    • Structural basis not determined
  4. 2003 High

    Connected SHIP1 to receptor tyrosine kinase signaling and disease, showing Lyn-dependent phosphorylation/membrane stabilization and that an AML active-site mutation impairs catalysis and deregulates Akt.

    Evidence GST pulldown, reciprocal co-IP, knockout macrophages, in vitro 5'-phosphatase assay with V684E mutant, Akt and growth readouts

    PMID:12529653 PMID:12882960

    Open questions at the time
    • Frequency and pathogenic role of V684E in AML not established
    • Direct structural effect of the mutation not modeled
  5. 2004 High

    Generalized SHIP1's inhibitory mechanism across cell types, showing it restrains Tec-family kinase activity/membrane localization and integrin αIIbβ3 outside-in signaling in platelets.

    Evidence Co-IP, in vitro kinase inhibition, Tec SH3 mutagenesis and membrane-targeting rescue; Lyn/SHIP1 knockout platelets with PIP3, Ca2+, spreading and adhesion assays

    PMID:15166241 PMID:15492005

    Open questions at the time
    • Relative contribution of catalytic vs. scaffolding functions to platelet adhesion not separated
  6. 2006 High

    Revealed SHIP1 as a spatial regulator of PIP3 rather than a bulk suppressor, directing leading-edge polarity in neutrophil chemotaxis distinct from PTEN.

    Evidence SHIP1 knockout mice with AktPH-GFP PIP3 bioprobe live imaging; comparison with PTEN-null neutrophils; osteoclast precursor proliferation assays

    PMID:17142780 PMID:17173042

    Open questions at the time
    • Mechanism targeting SHIP1 to the leading edge not defined
    • Link between spatial PIP3 control and cytoskeletal machinery incomplete
  7. 2007 High

    Demonstrated pharmacologically tractable allosteric activation and refined the spatiotemporal model, showing SHIP1 acts at early phagocytic cups distinct from PTEN.

    Evidence In vitro recombinant enzyme assay with allosteric domain mapping plus in vivo endotoxemia/anaphylaxis; live-cell imaging of SHIP1/PTEN/PH-domain probes at phagosomes

    PMID:17442886 PMID:17502453

    Open questions at the time
    • Identity of the endogenous allosteric ligand not determined
    • Recruitment timing determinants at phagosomes not fully mapped
  8. 2008 High

    Linked SHIP1's local PI(3,4,5)P3-to-PI(3,4)P2 conversion to functional phagosome outcomes (oxidative burst, maturation) and identified LAT-mediated recruitment at FcεRI tuned by NTAL.

    Evidence SHIP-1-deficient macrophages with phagosome-level phospholipid/ROS imaging; NTAL-deficient mast cells with co-IP and LAT tyrosine mapping

    PMID:18322174 PMID:18490750

    Open questions at the time
    • LAT recruitment (Medium) lacks reciprocal in vivo validation
    • Coupling of PI(3,4)P2 to NADPH oxidase effectors not resolved
  9. 2009 High

    Established transcriptional/post-transcriptional control and proved catalytic activity is required for tumor-suppressive function in primary AML cells.

    Evidence miR-155 gain/loss with 3'UTR reporters and in vivo phenocopy; lentiviral INPP5D vs. catalytically dead D672A in AML CD34+ cells

    PMID:19148132 PMID:19359473

    Open questions at the time
    • Full set of upstream regulators of INPP5D expression not catalogued
  10. 2010 High

    Defined direct biochemical regulation (PKA-Ser440 activation), receptor-blockade mechanism at DAP12/TREM2, transcriptional control by Ikaros, and a role in endotoxin tolerance.

    Evidence MS phospho-site mapping and S440A mutant rescue; TREM2/DAP12 co-IP with SH2-dependent PI3K-blockade; Ikaros ChIP at INPP5D promoter; SHIP-/- mice in LPS tolerance

    PMID:19139077 PMID:20484116 PMID:20602434 PMID:20810657

    Open questions at the time
    • Ikaros regulation (Medium) shown in DT40 only
    • Integration of multiple regulatory inputs on SHIP1 in vivo unresolved
  11. 2011 High

    Revealed SHIP1 has an enzymatically active nuclear pool and an autoinhibited SH2 domain, expanding its regulatory and localization repertoire.

    Evidence SHIP1-GFP confocal, nuclear fractionation with activity assay, NLS mutagenesis; FRET and phospho-ITAM pulldowns for SH2 auto-inhibition

    PMID:21864674 PMID:22182704

    Open questions at the time
    • Nuclear substrates and functions of SHIP1 not identified
    • SH2 auto-inhibition (Medium) not validated structurally
  12. 2012 High

    Extended the adaptor-recruitment paradigm to NK cell TIGIT inhibition (via Grb2), adhesion-specific PIP3 polarity control, and a positive ITAM-stabilizing role via CD2AP/Cbl.

    Evidence TIGIT/PVR phospho-mapping, co-IP, siRNA and mutant rescue in NK cells; SHIP1-/- neutrophil adhesion/PIP3 assays; CD2AP co-IP/MS and ubiquitination assays in pDCs

    PMID:22323291 PMID:22706086 PMID:23154388

    Open questions at the time
    • How SHIP1 switches between inhibitory and ITAM-stabilizing outputs not defined
  13. 2013 High

    Validated a clinical-candidate allosteric activator acting through the C2 region, confirming SHIP1 as a drug target with isogenic specificity.

    Evidence In vitro recombinant human SHIP1 assay with C2-deletion construct; SHIP1-proficient vs. deficient cells; Akt and functional readouts

    PMID:23121445

    Open questions at the time
    • Precise C2 binding site and conformational change not structurally resolved
  14. 2015 Medium

    Implicated SHIP1 in extrinsic apoptosis (CD95/Fas) for T-cell survival and in neutrophil IL-1β suppression via PSTPIP2 binding.

    Evidence SHIP1/CD95 co-IP with caspase-8 inhibitor rescue in SHIP1-/- mice; PSTPIP2 co-IP/phospho-mapping with IL-1β processing assays

    PMID:24781051 PMID:26304991

    Open questions at the time
    • Both interactions (Medium) from single labs without reciprocal in vivo validation
    • Mechanism linking SHIP1 to caspase-8 not defined
  15. 2020 Medium

    Placed SHIP1 within a defined macrophage polarization circuit, restraining M2 differentiation via a PI3K/Akt-STAT5-Trib1 axis during bacterial infection.

    Evidence SHIP-1-/- mice and siRNA with pathway phosphorylation, polarization markers, bacterial burden and survival

    PMID:32256487

    Open questions at the time
    • Single-lab axis (Medium); direct vs. indirect control of STAT5/Trib1 not separated
  16. 2022 High

    Distinguished a C2-independent activation mechanism (K306 agonist) and demonstrated SHIP1 activation enhances microglial phagolysosomal degradation and suppresses inflammation.

    Evidence In vitro enzyme assay with C2-deletion comparison, SHIP1-null cell controls, microglial cytokine/iNOS and phagolysosomal assays, in vivo LPS model

    PMID:35465359

    Open questions at the time
    • Binding site of the C2-independent activator not mapped
  17. 2023 High

    Established SHIP1 as a microglial node in neurodegeneration: loss of activity triggers NLRP3/CASP1 inflammasome activation, and it acts downstream of TREM2/TYROBP to shape the amyloid barrier.

    Evidence INPP5D-disrupted iPSC microglia with inflammasome/IL-1β/IL-18 assays and human AD brain analysis; Inpp5d-haploinsufficient × Tyrobp-deficient TREM2-LOF mice with plaque and phosphoproteomic analyses

    PMID:37035000 PMID:38016942

    Open questions at the time
    • Epistasis study (Medium) from single lab
    • Mechanistic link between disrupted autophagy and NLRP3 assembly not fully resolved
  18. 2024 High

    Defined a developmental neuronal function: microglial SHIP1 limits complement-mediated synaptic pruning, with loss causing aberrant pruning and adult cognitive deficits.

    Evidence Conditional microglial SHIP1 knockout at defined postnatal windows with proteomics, complement staining, pruning and behavioral assays, plus iPSC-microglia engulfment

    PMID:39657671

    Open questions at the time
    • Lipid-substrate vs. scaffolding contribution to pruning not separated
    • Link from PIP3 control to complement deposition not mechanistically defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • The nuclear function and substrates of SHIP1, and how its scaffolding (inhibitory vs. ITAM-stabilizing) outputs are switched in different receptor contexts, remain unresolved.
  • No nuclear substrate identified
  • No structural model for SH2 auto-inhibition or allosteric activation
  • Determinants selecting inhibitory vs. positive scaffolding output undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 5 GO:0008289 lipid binding 3 GO:0098772 molecular function regulator activity 3 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 4 GO:0031410 cytoplasmic vesicle 2 GO:0005634 nucleus 1 GO:0005829 cytosol 1
Pathway
R-HSA-168256 Immune System 5 R-HSA-162582 Signal Transduction 4 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-5357801 Programmed Cell Death 2
Partners
CD2APDAP12DOK1GRB2LATLYNPSTPIP2TIGIT

Evidence

Reading pass · 36 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1997 SHIP (INPP5D) is required for FcγRIIB-mediated inhibitory signaling in B cells but not for KIR-class inhibitory signaling (which requires SHP-1), defining two distinct inhibitory pathways; SHIP recruitment attenuates a pro-apoptotic signal initiated by FcγRIIB co-ligation with BCR. SHIP-deficient B cell lines generated by targeted deletion; functional inhibitory signaling assays; BCR-triggered apoptosis readouts Cell High 9244303
1998 SHIP1 controls BCR signaling by reducing PIP3 levels, thereby regulating membrane recruitment of the tyrosine kinase Btk through PH domain–phosphoinositol lipid interactions; deletion of SHIP increases PIP3, increases Btk membrane association, and causes hyperresponsive BCR signaling and elevated calcium flux. FcγRIIB co-ligation assays; SHIP membrane expression constructs; PI3K inhibition; SHIP-deficient cells; Btk membrane-targeted chimera rescue experiments Immunity High 9586640
1998 SHIP-deficient DT40 B cells display enhanced and prolonged intracellular Ca2+ mobilization (sustained increase or long-lasting oscillations) in response to BCR ligation, while ERK activation is unaffected, demonstrating that SHIP specifically modulates Ca2+ mobilization during B cell activation. SHIP-deficient DT40 B cell line; BCR cross-linking; single-cell Ca2+ imaging; ERK phosphorylation assays Journal of immunology High 9820480
1999 Upon FLT3 receptor activation, SHC binds to SHIP1 via the SHC PTB domain; SHC overexpression increases SHIP1 tyrosine phosphorylation and limits FLT3-dependent cell growth in a PTB domain-dependent manner. FLT3-activatable Ba/F3 cells; SHC overexpression; co-precipitation; phosphorylation mapping; cell growth assays Leukemia Medium 10482988
2000 SHIP1 forms a signaling complex with DOK1, PI3K, and CRKL in BCR/ABL-transformed cells; DOK1 binds SHIP1 directly through its PTB domain, and CRKL binds via the CRKL-SH2 domain. Tyr917 and Tyr1020 on SHIP1 mediate interactions with DOK1, and tyrosine mutations at these sites abrogate SHIP1-dependent suppression of cell migration. SHIP1 overexpression in BCR/ABL Ba/F3 cells; co-precipitation; domain mutants; migration assays The Journal of biological chemistry Medium 11031258
2001 The C-terminus (proline-rich region) of SHIP1 is essential for its ability to hydrolyze PIP3 and inhibit mast cell degranulation; C-terminally truncated SHIP1 constructs fail to revert the SHIP1-/- mast cell phenotype even when the 5'-phosphatase catalytic domain is intact. A phosphatase-dead mutant also cannot revert the phenotype, confirming catalytic activity is required. Retroviral reconstitution of SHIP-/- BMMCs with SHIP1 truncation and point mutants; PIP3 measurement; calcium entry assay; degranulation assay Blood High 11222379
2003 A somatic mutation at codon 684 (Val→Glu) in the phosphatase active site of SHIP1 found in AML reduces catalytic activity in vitro, and expression of SHIP1-V684E in K562 cells confers growth advantage and resistance to apoptosis through deregulated PI(3,4,5)P3/Akt signaling. In vitro inositol 5'-phosphatase assay; transfection of mutant SHIP1-V684E; cell growth and apoptosis assays; Akt phosphorylation measurement Leukemia Medium 12529653
2003 SHIP-1 becomes tyrosine-phosphorylated upon M-CSF stimulation in a Src family kinase-dependent manner and negatively regulates M-CSF-induced Akt activation. SHIP-1 binds Lyn via its SH2 domain (independent of Lyn kinase activity), and Lyn stabilizes SHIP-1 at the membrane to enhance its regulation of Akt. THP-1 cells; 3T3-Fms transfection; GST fusion protein pulldown; co-immunoprecipitation; SHIP-1 and Lyn knockout macrophages; Akt phosphorylation; NF-κB reporter assay The Journal of biological chemistry High 12882960
2004 SHIP1 and Lyn kinase negatively regulate integrin αIIbβ3 outside-in signaling in platelets by controlling PIP3 accumulation, cytosolic calcium response, and platelet spreading; SHIP1 phosphorylation is partially regulated by Lyn, and SHIP1-dependent PIP3 metabolism down-regulates the stability of integrin αIIbβ3-fibrinogen adhesive bonds. SHIP1 and Lyn knockout murine platelets; PIP3 measurement; calcium flux assay; platelet spreading; platelet adhesion under physiological blood flow The Journal of biological chemistry High 15166241
2004 SHIP1 and SHIP2 interact preferentially with the Tec kinase (vs. other Tec family members) through the Tec SH3 domain and inhibit Tec activity and membrane localization; inactivation of the Tec SH3 domain generates a hyperactive Tec, and constitutive targeting of Tec to the membrane relieves SHIP1-mediated inhibition. Co-immunoprecipitation; in vitro kinase inhibition assay; Tec SH3 domain mutagenesis; membrane-targeted Tec chimera rescue; Tec membrane localization imaging The Journal of biological chemistry High 15492005
2006 SHIP1 governs neutrophil polarization and chemotaxis by directing where PIP3 accumulates; genetic inactivation of SHIP1 leads to severe defects in neutrophil polarization and motility, with diffuse rather than leading-edge PIP3 distribution, while loss of PTEN has no impact on neutrophil chemotaxis. SHIP1 knockout mice; transgenic AktPH-GFP PIP3 bioprobe mice; time-lapse live imaging of chemotaxing neutrophils; comparison with PTEN-null neutrophils Nature cell biology High 17173042
2006 SHIP1 negatively regulates osteoclast precursor proliferation through the Akt pathway by controlling D-type cyclin upregulation and p27 downregulation; SHIP1-null BMMs show increased Akt activation and retinoblastoma protein phosphorylation specifically in response to M-CSF, without altered cell survival. SHIP1-null mouse bone marrow macrophages; Akt phosphorylation; cyclin D and p27 western blotting; retinoblastoma phosphorylation; cell proliferation and survival assays Journal of immunology High 17142780
2007 Small-molecule activators of SHIP1 bind an allosteric activation domain within SHIP1 (not the catalytic site), activate recombinant SHIP1 in vitro, stimulate SHIP1 activity in intact macrophage and mast cells, and inhibit the PI3K pathway in hematopoietic cells in vivo. In vitro enzyme assay with recombinant SHIP1; intact cell PI3K pathway readouts; allosteric domain mapping; in vivo mouse models of endotoxemia and anaphylaxis Blood High 17502453
2007 SHIP-1 is recruited to forming phagosomes and sequestered at the leading edge, dissociating from phagocytic cups earlier than PI3K, restricting its inhibitory activity to early stages of phagocytosis; PTEN-YFP does not localize to phagosomes, indicating spatially distinct roles for the two phosphatases. YFP chimeras of SHIP-1, PTEN, p85; PH domain chimeras for PIP3/PI(3,4)P2 mapping; live-cell quantitative fluorescence imaging of phagosome formation Molecular biology of the cell High 17442886
2008 SHIP-1 promotes an early phagosomal oxidative burst through localized conversion of PI(3,4,5)P3 to PI(3,4)P2; SHIP-1-deficient macrophages have elevated PI(3,4,5)P3/PI(3,4)P2 ratios on phagosomal membranes, decreased early NADPH oxidase activity, persistent PI(3)P elevation, and early Rab5a phagosomal localization, indicating altered phagosome maturation. SHIP-1-deficient mouse macrophages; phospholipid dynamics imaging on individual phagosomes; reactive oxygen intermediate assay in phagosomes; membrane trafficking markers Journal of immunology High 18490750
2008 SHIP1 is recruited to FcεRI signaling complexes through binding to two tyrosines on the LAT adaptor protein; this recruitment is dampened by NTAL, which reduces LAT-mediated SHIP1 recruitment leading to increased Akt phosphorylation and enhanced mast cell survival. NTAL-deficient mast cells; co-immunoprecipitation; Akt phosphorylation; mast cell survival assays; LAT tyrosine mapping Journal of immunology Medium 18322174
2009 SHIP1 is a direct target of miR-155; miR-155 represses SHIP1 through direct 3'UTR interactions conserved through evolution. Repression of SHIP1 by miR-155 results in increased Akt activation following LPS stimulation, and specific knockdown of SHIP1 in hematopoietic cells reproduces the myeloproliferative disorder seen in miR-155-expressing mice. Gain- and loss-of-function miR-155 in hematopoietic cells in vitro and in vivo; 3'UTR reporter assays; retroviral miR-155-formatted siRNA against SHIP1; Akt phosphorylation; LPS-treated WT vs. miR-155-/- macrophages Proceedings of the National Academy of Sciences of the United States of America High 19359473
2009 Lyn and SHIP-1 associate with PKC-δ specifically upon GPVI (but not PAR) agonist stimulation of platelets; Lyn-mediated phosphorylation of SHIP-1 (Y1020) and PKC-δ (Y311) and their association negatively regulate GPVI-mediated dense granule secretion; in Lyn-null platelets, GPVI-mediated SHIP-1 phosphorylation is inhibited. Human platelet stimulation; co-immunoprecipitation; Lyn-null and SHIP-1-null mouse platelets; phosphorylation site mapping; dense granule secretion assay Blood High 19587372
2010 SHIP1 inhibits TREM2/DAP12-dependent PI3K activation by binding to DAP12 in an SH2 domain-dependent manner and blocking PI3K recruitment to DAP12; DAP10 is required for DAP12-dependent PI3K recruitment, while SHIP1 directly prevents this interaction. TREM2 ligation assays; co-immunoprecipitation; SH2 domain-dependent binding assays; PI3K, ERK, Vav3 activation readouts; Ca2+ mobilization; actin reorganization; apoptosis assays Science signaling High 20484116
2010 PKA phosphorylates SHIP1 at Ser440 within the catalytic region, and this phosphorylation increases SHIP1 enzymatic activity; the S440A mutant abolishes PKA-mediated SHIP1 activation and the resulting inhibition of Akt downstream of BCR engagement. Mass spectrometry identification of PKA phosphorylation sites; SHIP1 truncation and point mutants; in vitro kinase assay; mammalian cell Akt phosphorylation; SHIP1-null DT40 cells reconstituted with SHIP1 mutants; flow cytometry The Journal of biological chemistry High 20810657
2010 LPS stimulation of macrophages upregulates SHIP via MyD88-dependent TGFβ autocrine signaling; elevated SHIP then inhibits both MyD88-dependent and independent signaling to mediate endotoxin tolerance and cross-tolerance, and restrains LPS-induced IFN-β production. SHIP-/- mice overproduce IFN-β in response to LPS. SHIP-/- macrophages and mice; isoform-specific PI3K inhibitors; MyD88 pathway analysis; TGFβ neutralization; IFN-β measurement in vivo Blood High 19139077
2011 SHIP1 is a nucleo-cytoplasmic shuttling protein actively imported into and exported from the nucleus via two canonical NLS sequences (K327KSK and K547KLR); nuclear SHIP1 is enzymatically active with similar specific activity to cytoplasmic SHIP1, and mutational inactivation of either NLS reduces nuclear import and decreases cell proliferation. Confocal microscopy of SHIP1-GFP; nuclear fractionation; enzyme activity assay on nuclear fractions; NLS point mutagenesis; nuclear import/export inhibitor studies; cell proliferation assay Cellular signalling High 21864674
2012 The ITT-like motif of TIGIT is phosphorylated at Tyr225 upon TIGIT/PVR engagement and recruits cytosolic adaptor Grb2, which then recruits SHIP1 to prematurely terminate PI3K and MAPK signaling, suppressing granule polarization and NK cell cytotoxicity; SHIP1 silencing dramatically abolishes TIGIT/PVR-mediated killing inhibition. NK cell TIGIT/PVR engagement; phosphorylation mapping; co-immunoprecipitation; SHIP1 siRNA knockdown; granule polarization imaging; cytotoxicity assay; Tyr225/Asn227 mutant rescue Cell death and differentiation High 23154388
2012 SHIP1 regulates PIP3 production specifically in response to cell adhesion (not in suspension) and prevents formation of top-down PIP3 polarity; SHIP1-/- neutrophils lose polarity upon adhesion, are extremely adherent, and show elevated Akt activation; chemotaxis can be restored by reducing adhesion. SHIP1-/- neutrophils; cell adhesion vs. suspension PIP3 measurement; Akt activation assay; cell polarity imaging; adhesion and chemotaxis assays Molecular biology of the cell High 22323291
2012 CD2AP forms a complex with SHIP1 (identified by co-immunoprecipitation and mass spectrometry) in plasmacytoid dendritic cells; upon BDCA2 cross-linking, the CD2AP/SHIP1 complex associates with and inhibits the E3 ubiquitin ligase Cbl, preventing ubiquitination and degradation of Syk and FcεR1γ, thereby positively regulating BDCA2/FcεR1γ ITAM signaling. Co-immunoprecipitation; mass spectrometry; SHIP1 and CD2AP knockdown; ubiquitination assay; Syk/FcεR1γ stability assay; membrane co-localization imaging; IFN production assay Journal of immunology High 22706086
2013 AQX-1125, a small-molecule SHIP1 activator, increases the catalytic activity of recombinant human SHIP1 in vitro through a mechanism requiring the C2 region; deletion of the C2 region abolishes AQX-1125-mediated activation. The compound inhibits Akt phosphorylation in SHIP1-proficient but not SHIP1-deficient cells. In vitro recombinant human SHIP1 enzyme assay; C2-region deletion construct; SHIP1-proficient vs. deficient cell lines; Akt phosphorylation; cytokine production; mast cell activation; leukocyte chemotaxis British journal of pharmacology High 23121445
2011 The SH2 domain of SHIP1 can bind to the C-terminus of SHIP1 itself (inter- and intramolecularly), and this intramolecular interaction regulates the association between SHIP1 and Ig-α; the SH2 domain of SHIP1 interacts with Ig-α in an Ig-α-dependent manner in cells, but full-length SHIP1 does not interact with phosphorylated Ig-α ITAM, suggesting SH2 domain auto-inhibition. FRET in S2 cells; fluorescently labeled SH2 domain translocation assay; pulldown with phospho-ITAM peptides; mutant Ig-α BCR B cell lines; pervanadate stimulation; SHIP1 phosphorylation and Akt activation readouts Biochimica et biophysica acta Medium 22182704
2015 SHIP1 associates with the death receptor CD95/Fas and promotes T-cell survival at mucosal surfaces; treatment with a Caspase 8 inhibitor prevents SHIP1 inhibitor-mediated T-cell death and reduces mucosal inflammation in SHIP1-/- mice, placing SHIP1 in the extrinsic apoptosis pathway. Co-immunoprecipitation of SHIP1 with CD95/Fas; caspase 8 inhibitor treatment; SHIP1-/- and CD4CreSHIP1flox/flox mice; T-cell survival and mucosal inflammation assays Mucosal immunology Medium 24781051
2015 PSTPIP2 binds SHIP1 through critical tyrosine residues at the C-terminus of PSTPIP2; SHIP1 inhibition in neutrophils enhances IL-1β processing, demonstrating that the PSTPIP2-SHIP1 interaction is functionally important for suppressing neutrophil IL-1β production. Co-immunoprecipitation; phospho-site mapping; SHIP1 inhibitor in neutrophils; IL-1β processing assay; stimulation with silica, Ab aggregates, and LPS Journal of immunology Medium 26304991
2009 SHIP1 gene transfer (lentiviral INPP5D) into CD34+ AML cells reduces GM-CSF-dependent and autonomous cell proliferation; an enzymatically inactive SHIP1 mutant (D672A) has no effect, establishing that SHIP1's catalytic activity is required for its anti-proliferative function. Lentiviral INPP5D gene transfer into AML patient CD34+ cells; GM-CSF-dependent and autonomous proliferation assays; catalytically inactive SHIP1-D672A control Gene therapy High 19148132
2020 SHIP-1 regulates macrophage M2 polarization and phagocytosis during Pseudomonas aeruginosa infection through a PI3K/Akt-STAT5-Trib1 axis; SHIP-1 deficiency augments PI3K phosphorylation and nuclear STAT5 translocation, inducing Trib1 expression critical for M2 differentiation. SHIP-1-/- mice; siRNA silencing in macrophages; PI3K, Akt, STAT5, Trib1 expression and phosphorylation; macrophage polarization markers; bacterial burden; survival assays Frontiers in immunology Medium 32256487
2022 A novel SHIP1 agonist (K306), identified via AI, activates SHIP1 through a mechanism that does not require the C2 domain (unlike other known SHIP1 agonists), suppresses inflammatory cytokines and iNOS in macrophages and microglia in a SHIP1-dependent manner, and enhances phagolysosomal degradation of synaptosomes and dead neurons by microglia. In vitro SHIP1 enzyme assay; SHIP1-/- macrophages/microglia as controls; C2 domain deletion constructs; cytokine and iNOS measurement; phagolysosomal degradation assay; in vivo LPS endotoxemia model iScience High 35465359
2023 Reduction in INPP5D (SHIP1) activity in iPSC-derived human microglia leads to formation of the NLRP3 inflammasome, cleavage of CASP1, and secretion of IL-1β and IL-18; this is associated with disrupted autophagy; evidence from human AD brain confirms that reduced SHIP1 function in microglia results in inflammasome activation. INPP5D-disrupted iPSC-derived human microglia; RNA and protein profiling; pharmacological SHIP1 inhibition; NLRP3 inflammasome assembly assay; CASP1 cleavage and IL-1β/IL-18 ELISA; multi-analytic analysis of human AD brain tissue Nature communications High 38016942
2023 INPP5D and TREM2/TYROBP exert opposing effects on PI(3,4,5)P3 signaling and phosphoproteins involved in actin assembly; Inpp5d haplodeficiency in a TREM2 loss-of-function mouse model restores microglial association with Aβ plaques and partially restores plaque compaction, placing INPP5D downstream of TREM2/TYROBP in regulating the microglial barrier against Aβ toxicity. Tyrobp-deficient TREM2 loss-of-function mice crossed with Inpp5d haplodeficient mice; microglial clustering; plaque compaction; astrogliosis; phosphorylated tau+ dystrophic neurites; mechanistic PI(3,4,5)P3 signaling and phosphoproteomic analyses iScience Medium 37035000
2024 SHIP1 limits complement-mediated synaptic pruning in the developing hippocampus; conditional loss of microglial SHIP1 in early postnatal brain increases complement deposition and synapse loss, causes abnormal synaptic pruning, and leads to cognitive defects in adulthood; iPSC-derived microglia lacking SHIP1 also show increased engulfment of synaptic structures. Conditional microglial SHIP1 knockout mice (early vs. late postnatal deletion); proteomics; complement marker staining; synaptic pruning assays; cognitive behavioral tests; iPSC-derived microglia engulfment assay Immunity High 39657671
2010 Ikaros binds to the promoter of the INPP5D gene (demonstrated by ChIP) and transcriptionally regulates SHIP expression; loss of Ikaros upregulates SHIP while loss of Helios downregulates SHIP, and these expression changes underlie opposite BCR signaling phenotypes (calcium mobilization strength). Ikaros-deficient and Helios-deficient DT40 B cell lines; chromatin immunoprecipitation (ChIP) of Ikaros at INPP5D promoter; BCR cross-linking calcium assay; SHIP mRNA/protein measurement European journal of immunology Medium 20602434

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2009 Inositol phosphatase SHIP1 is a primary target of miR-155. Proceedings of the National Academy of Sciences of the United States of America 688 19359473
1997 Deletion of SHIP or SHP-1 reveals two distinct pathways for inhibitory signaling. Cell 380 9244303
2010 TREM2- and DAP12-dependent activation of PI3K requires DAP10 and is inhibited by SHIP1. Science signaling 348 20484116
1998 SHIP modulates immune receptor responses by regulating membrane association of Btk. Immunity 286 9586640
2012 Recruitment of Grb2 and SHIP1 by the ITT-like motif of TIGIT suppresses granule polarization and cytotoxicity of NK cells. Cell death and differentiation 263 23154388
2006 Control of cell polarity and motility by the PtdIns(3,4,5)P3 phosphatase SHIP1. Nature cell biology 240 17173042
2007 Functional selectivity through protean and biased agonism: who steers the ship? Molecular pharmacology 216 17901198
2009 Onco-miR-155 targets SHIP1 to promote TNFalpha-dependent growth of B cell lymphomas. EMBO molecular medicine 177 19890474
2010 The engine driving the ship: metabolic steering of cell proliferation and death. Nature reviews. Molecular cell biology 176 20861880
2007 Small-molecule agonists of SHIP1 inhibit the phosphoinositide 3-kinase pathway in hematopoietic cells. Blood 127 17502453
2010 SHIP1 inhibition increases immunoregulatory capacity and triggers apoptosis of hematopoietic cancer cells. Journal of immunology (Baltimore, Md. : 1950) 119 20200281
2003 Possible dominant-negative mutation of the SHIP gene in acute myeloid leukemia. Leukemia 105 12529653
2017 Regulation of immune cell signaling by SHIP1: A phosphatase, scaffold protein, and potential therapeutic target. European journal of immunology 99 28480512
2010 Inhibitor and activator: dual functions for SHIP in immunity and cancer. Annals of the New York Academy of Sciences 90 21155837
2021 INPP5D expression is associated with risk for Alzheimer's disease and induced by plaque-associated microglia. Neurobiology of disease 89 33631273
2003 SHIP, SHIP2, and PTEN activities are regulated in vivo by modulation of their protein levels: SHIP is up-regulated in macrophages and mast cells by lipopolysaccharide. Experimental hematology 78 14662322
2003 The inositol 5'-phosphatase SHIP-1 and the Src kinase Lyn negatively regulate macrophage colony-stimulating factor-induced Akt activity. The Journal of biological chemistry 76 12882960
2010 Coordinate suppression of B cell lymphoma by PTEN and SHIP phosphatases. The Journal of experimental medicine 74 20956547
2004 SHIP1 and Lyn Kinase Negatively Regulate Integrin alpha IIb beta 3 signaling in platelets. The Journal of biological chemistry 73 15166241
2007 Differential association of phosphatidylinositol 3-kinase, SHIP-1, and PTEN with forming phagosomes. Molecular biology of the cell 72 17442886
2013 Class I PI 3-kinases signaling in platelet activation and thrombosis: PDK1/Akt/GSK3 axis and impact of PTEN and SHIP1. Advances in biological regulation 71 24095650
2003 The role of SHIP in cytokine-induced signaling. Reviews of physiology, biochemistry and pharmacology 68 12692707
2023 Microglial function, INPP5D/SHIP1 signaling, and NLRP3 inflammasome activation: implications for Alzheimer's disease. Molecular neurodegeneration 65 38017562
2022 Microglial INPP5D limits plaque formation and glial reactivity in the PSAPP mouse model of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 64 36448627
1998 Role of the inositol phosphatase SHIP in B cell receptor-induced Ca2+ oscillatory response. Journal of immunology (Baltimore, Md. : 1950) 63 9820480
2023 INPP5D regulates inflammasome activation in human microglia. Nature communications 61 38016942
1999 SHC and SHIP phosphorylation and interaction in response to activation of the FLT3 receptor. Leukemia 58 10482988
2010 SHIP deficiency causes Crohn's disease-like ileitis. Gut 57 20940287
2018 Targeting SHP-1, 2 and SHIP Pathways: A Novel Strategy for Cancer Treatment? Oncology 56 29925063
2010 Role of SHIP in cancer. Experimental hematology 56 21056081
2020 Pan-SHIP1/2 inhibitors promote microglia effector functions essential for CNS homeostasis. Journal of cell science 55 31780579
2012 Phosphoinositide lipid phosphatase SHIP1 and PTEN coordinate to regulate cell migration and adhesion. Molecular biology of the cell 54 22323291
2004 The role of SHIP1 in macrophage programming and activation. Biochemical Society transactions 54 15494015
2009 SHIP limits immunoregulatory capacity in the T-cell compartment. Blood 52 19136659
2009 Lyn, PKC-delta, SHIP-1 interactions regulate GPVI-mediated platelet-dense granule secretion. Blood 52 19587372
2022 INPP5D deficiency attenuates amyloid pathology in a mouse model of Alzheimer's disease. Alzheimer's & dementia : the journal of the Alzheimer's Association 51 36524682
2007 The role of SHIP in macrophages. Frontiers in bioscience : a journal and virtual library 51 17485263
2013 Characterization of AQX-1125, a small-molecule SHIP1 activator: Part 1. Effects on inflammatory cell activation and chemotaxis in vitro and pharmacokinetic characterization in vivo. British journal of pharmacology 50 23121445
2006 SHIP1 negatively regulates proliferation of osteoclast precursors via Akt-dependent alterations in D-type cyclins and p27. Journal of immunology (Baltimore, Md. : 1950) 49 17142780
2013 Discovery and development of small molecule SHIP phosphatase modulators. Medicinal research reviews 47 24302498
2000 SHIP1, an SH2 domain containing polyinositol-5-phosphatase, regulates migration through two critical tyrosine residues and forms a novel signaling complex with DOK1 and CRKL. The Journal of biological chemistry 47 11031258
1999 The role of SHIP in growth factor induced signalling. Progress in biophysics and molecular biology 47 10354708
2014 SHIP1 is targeted by miR-155 in acute myeloid leukemia. Oncology reports 46 25175984
2001 SHIP's C-terminus is essential for its hydrolysis of PIP3 and inhibition of mast cell degranulation. Blood 46 11222379
2009 SHIP1 is a repressor of mast cell hyperplasia, cytokine production, and allergic inflammation in vivo. Journal of immunology (Baltimore, Md. : 1950) 45 19542434
2003 Role of Src homology 2-containing-inositol 5'-phosphatase (SHIP) in mast cells and macrophages. Biochemical Society transactions 43 12546703
2011 Murine pancreatic adenocarcinoma dampens SHIP-1 expression and alters MDSC homeostasis and function. PloS one 42 22132131
2008 A novel germ cell-specific protein, SHIP1, forms a complex with chromatin remodeling activity during spermatogenesis. The Journal of biological chemistry 41 18849567
2004 SHIP family inositol phosphatases interact with and negatively regulate the Tec tyrosine kinase. The Journal of biological chemistry 41 15492005
2012 CD2AP/SHIP1 complex positively regulates plasmacytoid dendritic cell receptor signaling by inhibiting the E3 ubiquitin ligase Cbl. Journal of immunology (Baltimore, Md. : 1950) 40 22706086
2003 Homeostasis and regeneration of the hematopoietic stem cell pool are altered in SHIP-deficient mice. Blood 40 12855581
2009 Differential roles for the inositol phosphatase SHIP in the regulation of macrophages and lymphocytes. Immunologic research 39 18989630
2008 SHIP-1 increases early oxidative burst and regulates phagosome maturation in macrophages. Journal of immunology (Baltimore, Md. : 1950) 39 18490750
2004 Mutation analysis of SHIP gene in acute leukemia. Zhongguo shi yan xue ye xue za zhi 39 15363123
2013 Role of SHIP1 in cancer and mucosal inflammation. Annals of the New York Academy of Sciences 38 23551094
2019 Triptolide Inhibits Preformed Fibril-Induced Microglial Activation by Targeting the MicroRNA155-5p/SHIP1 Pathway. Oxidative medicine and cellular longevity 37 31182996
2017 INPP5D mRNA Expression and Cognitive Decline in Japanese Alzheimer's Disease Subjects. Journal of Alzheimer's disease : JAD 37 28482637
2023 The Alzheimer's disease risk factor INPP5D restricts neuroprotective microglial responses in amyloid beta-mediated pathology. Alzheimer's & dementia : the journal of the Alzheimer's Association 36 37061460
2020 Apigenin Increases SHIP-1 Expression, Promotes Tumoricidal Macrophages and Anti-Tumor Immune Responses in Murine Pancreatic Cancer. Cancers 36 33291556
2019 Targeted genetic analysis of cerebral blood flow imaging phenotypes implicates the INPP5D gene. Neurobiology of aging 34 31319229
2019 SHIP-1, a target of miR-155, regulates endothelial cell responses in lung fibrosis. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 31907997
2011 Enzymatic and non-enzymatic activities of SHIP-1 in signal transduction and cancer. Biochemical pharmacology 34 21672530
2009 SHIP prevents lipopolysaccharide from triggering an antiviral response in mice. Blood 34 19139077
2021 Targeting SHIP1 and SHIP2 in Cancer. Cancers 32 33672717
2002 The role of SHIP in mast cell degranulation and IgE-induced mast cell survival. Immunology letters 32 12008029
2015 SHIP1 intrinsically regulates NK cell signaling and education, resulting in tolerance of an MHC class I-mismatched bone marrow graft in mice. Journal of immunology (Baltimore, Md. : 1950) 31 25687756
2014 Impaired T-cell survival promotes mucosal inflammatory disease in SHIP1-deficient mice. Mucosal immunology 31 24781051
2002 SHIP represses mast cell activation and reveals that IgE alone triggers signaling pathways which enhance normal mast cell survival. Molecular immunology 31 12217384
2023 INPP5D modulates TREM2 loss-of-function phenotypes in a β-amyloidosis mouse model. iScience 30 37035000
2021 Bortezomib Sustains T Cell Function by Inducing miR-155-Mediated Downregulation of SOCS1 and SHIP1. Frontiers in immunology 30 33717088
2020 Small molecule targeting of SHIP1 and SHIP2. Biochemical Society transactions 30 32049315
2015 PSTPIP2, a Protein Associated with Autoinflammatory Disease, Interacts with Inhibitory Enzymes SHIP1 and Csk. Journal of immunology (Baltimore, Md. : 1950) 29 26304991
2010 Concerted action of Helios and Ikaros controls the expression of the inositol 5-phosphatase SHIP. European journal of immunology 29 20602434
2012 Lineage extrinsic and intrinsic control of immunoregulatory cell numbers by SHIP. European journal of immunology 28 22535653
2009 Reduced proliferation of CD34(+) cells from patients with acute myeloid leukemia after gene transfer of INPP5D. Gene therapy 25 19148132
2020 SHIP-1 Regulates Phagocytosis and M2 Polarization Through the PI3K/Akt-STAT5-Trib1 Circuit in Pseudomonas aeruginosa Infection. Frontiers in immunology 24 32256487
2018 SHIP1 Deficiency in Inflammatory Bowel Disease Is Associated With Severe Crohn's Disease and Peripheral T Cell Reduction. Frontiers in immunology 24 29872435
2017 IVIG activates FcγRIIB-SHIP1-PIP3 Pathway to stabilize mast cells and suppress inflammation after ICH in mice. Scientific reports 24 29138419
2014 TLR signaling that induces weak inflammatory response and SHIP1 enhances osteogenic functions. Bone research 24 26273527
2012 Mouse natural killer cell development and maturation are differentially regulated by SHIP-1. Blood 24 23034281
2008 Non-T cell activation linker promotes mast cell survival by dampening the recruitment of SHIP1 by linker for activation of T cells. Journal of immunology (Baltimore, Md. : 1950) 24 18322174
2025 ACSL4 at the helm of the lipid peroxidation ship: a deep-sea exploration towards ferroptosis. Frontiers in pharmacology 22 40932861
2022 Discovery of a novel SHIP1 agonist that promotes degradation of lipid-laden phagocytic cargo by microglia. iScience 22 35465359
2022 Apigenin Targets MicroRNA-155, Enhances SHIP-1 Expression, and Augments Anti-Tumor Responses in Pancreatic Cancer. Cancers 21 35892872
2013 Role of SHIP1 in bone biology. Annals of the New York Academy of Sciences 21 23551095
2013 How does SHIP1/2 balance PtdIns(3,4)P2 and does it signal independently of its phosphatase activity? BioEssays : news and reviews in molecular, cellular and developmental biology 21 23650141
2010 A key role for the phosphorylation of Ser440 by the cyclic AMP-dependent protein kinase in regulating the activity of the Src homology 2 domain-containing Inositol 5'-phosphatase (SHIP1). The Journal of biological chemistry 21 20810657
2017 SHIP1, but not an AML-derived SHIP1 mutant, suppresses myeloid leukemia growth in a xenotransplantation mouse model. Gene therapy 20 29143813
2011 The SH2-domain of SHIP1 interacts with the SHIP1 C-terminus: impact on SHIP1/Ig-α interaction. Biochimica et biophysica acta 20 22182704
2024 Microglial lipid phosphatase SHIP1 limits complement-mediated synaptic pruning in the healthy developing hippocampus. Immunity 19 39657671
2023 CircRNA_0075723 protects against pneumonia-induced sepsis through inhibiting macrophage pyroptosis by sponging miR-155-5p and regulating SHIP1 expression. Frontiers in immunology 19 36923408
2020 Effective inhibition of miR-330/SHIP1/NF-κB signaling pathway via miR-330 sponge repolarizes microglia differentiation. Cell biology international 19 33325083
2018 Effects of guluronic acid (G2013) on SHIP1, SOCS1 induction and related molecules in TLR4 signaling pathway. International immunopharmacology 19 29310108
2016 Overexpression of JARID1B promotes differentiation via SHIP1/AKT signaling in human hypopharyngeal squamous cell carcinoma. Cell death & disease 19 27584795
2023 Expression of INPP5D Isoforms in Human Brain: Impact of Alzheimer's Disease Neuropathology and Genetics. Genes 18 36981033
2023 Kaempferol Suppresses the Activation of Mast Cells by Modulating the Expression of FcεRI and SHIP1. International journal of molecular sciences 18 36983066
2019 Regulation of hematopoietic cell signaling by SHIP-1 inositol phosphatase: growth factors and beyond. Growth factors (Chur, Switzerland) 18 30764683
2015 SHIP1-expressing mesenchymal stem cells regulate hematopoietic stem cell homeostasis and lineage commitment during aging. Stem cells and development 18 25525673
2011 The inositol 5-phosphatase SHIP1 is a nucleo-cytoplasmic shuttling protein and enzymatically active in cell nuclei. Cellular signalling 18 21864674
2017 Analysis of SHIP1 expression and activity in Crohn's disease patients. PloS one 17 28767696

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