Affinage

INPPL1

Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2 · UniProt O15357

Length
1258 aa
Mass
138.6 kDa
Annotated
2026-06-10
100 papers in source corpus 46 papers cited in narrative 46 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

INPPL1 (SHIP2) is an inositol polyphosphate 5-phosphatase that hydrolyzes PtdIns(3,4,5)P3 to PtdIns(3,4)P2, acting as a negative regulator of PI3K/Akt signaling downstream of insulin and multiple growth factor receptors (PMID:9660833, PMID:10958682, PMID:11401540). Its catalytic activity is intrinsically modulated: an adjacent C2 domain greatly enhances 5-phosphatase turnover through allosteric interdomain contacts, both domains engage phosphatidylserine, and PtdSer vesicles specifically stimulate activity (PMID:28792888, PMID:16824732); tyrosine phosphorylation increases specific activity and drives translocation to a Triton-insoluble membrane fraction, switching the lipid output toward PtdIns(3,4)P2 (PMID:17672824). Beyond canonical PtdIns(3,4,5)P3 turnover, SHIP2 also dephosphorylates PI(4,5)P2 to PI4P, including in nuclear speckles where a Ser132-phosphorylated pool localizes (PMID:21770892, PMID:26826186). SHIP2 is recruited to activated receptors and signaling platforms through a modular set of interactions—to EGFR and c-Met, to FcγRIIB via the ITIM, and to EphA2 through a heterotypic SAM–SAM interaction whose structure has been defined (PMID:11349134, PMID:15735664, PMID:11016922, PMID:17135240, PMID:22244754)—and to endocytic clathrin-coated pits via intersectin, where its phosphoinositide turnover controls coated-pit maturation and FcγRIIB-dependent FEME priming (PMID:20679431, PMID:30061681). Through filamin-, p130Cas-, and Vinexin-dependent targeting and its lipid products, SHIP2 shapes the local phosphoinositide and actin landscape to govern cell spreading, adhesion, polarity, migration, and invadopodium maturation, the latter via local PI(3,4)P2 generation and direct recruitment of the actin regulator Mena (PMID:11739414, PMID:11158326, PMID:16302969, PMID:23699395, PMID:24206842, PMID:27597754). SHIP2 additionally functions as a catalysis-independent scaffold downstream of FGF receptors, recruiting Src-family kinases to sustain ERK activation (PMID:30228226). Catalytic-domain loss-of-function mutations in INPPL1 cause opsismodysplasia, a severe chondrodysplasia, establishing 5-phosphatase activity as essential for endochondral ossification (PMID:23273569).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1998 High

    Established the core biochemical identity of SHIP2 as a PtdIns(3,4,5)P3 5-phosphatase coupled to growth factor signaling, distinguishing it from SHIP1 by substrate handling.

    Evidence In vitro phosphatase assays on immunoprecipitates and recombinant protein, with tyrosine-phosphorylation and Shc Co-IP across multiple growth factor stimuli

    PMID:9660833 PMID:9824312

    Open questions at the time
    • In-cell substrate specificity inferred from in vitro assays
    • Mechanism coupling receptor activation to phosphatase recruitment not yet defined
  2. 1999 High

    Defined SHIP2 as a negative regulator of insulin-induced Akt and MAPK signaling and mapped selective SH3-domain binding (ABL, not Src or GRB2), clarifying its adaptor wiring.

    Evidence Overexpression in insulin-receptor fibroblasts with kinase readouts; SH3-domain in vitro binding and Co-IP in p210(bcr/abl) CML cells

    PMID:10194451 PMID:10381377

    Open questions at the time
    • Overexpression may not reflect endogenous stoichiometry
    • Physiological relevance of ABL SH3 binding not functionally tested
  3. 2000 High

    Showed SHIP2 can suppress Akt and impose G1 arrest independent of PTEN, linking lipid phosphatase output to cell-cycle control via p27.

    Evidence Gain- and loss-of-function in PTEN-null glioblastoma cells with lipid quantification, PKB assays, and cell-cycle analysis

    PMID:10958682

    Open questions at the time
    • Mechanism by which PtdIns(3,4)P2 versus PtdIns(3,4,5)P3 controls PKB not resolved
    • Single cell model
  4. 2001 High

    Identified the molecular adaptors targeting SHIP2 to the actin cytoskeleton and receptor platforms (filamin, p130Cas, EGFR, FcγRIIB ITIM), establishing it as a spatially regulated phosphatase.

    Evidence Yeast two-hybrid, Co-IP, ITIM mutagenesis, and localization/spreading assays across multiple cell types

    PMID:11016922 PMID:11158326 PMID:11349134 PMID:11401540 PMID:11739414

    Open questions at the time
    • Relative contribution of each adaptor in vivo unclear
    • How localization couples to catalytic output not quantified
  5. 2002 High

    Pinpointed Src-mediated phosphorylation of the SHIP2 NPXY motif during collagen-I adhesion as a regulatory switch coupling SHIP2 to Shc and lamellipodia control.

    Evidence In vitro Src kinase assay, NPXY mutagenesis, activated/dominant-negative Src, and lamellipodia readouts

    PMID:12235291

    Open questions at the time
    • Matrix-specificity mechanism (collagen I vs others) unexplained
    • Effect of phosphorylation on catalytic activity not measured here
  6. 2003 Medium

    Extended SHIP2 to nuclear speckle and platelet cytoskeletal contexts, showing it retains 5-phosphatase activity within native filamin–actin–GPIb complexes.

    Evidence Nuclear fractionation with phosphatase assay; platelet Co-IP and activity assays with immunofluorescence

    PMID:12676785 PMID:12847108

    Open questions at the time
    • Nuclear substrate and function not defined
    • Functional consequence of platelet complex dissociation untested
  7. 2004 High

    Broadened the recognized substrate repertoire of SHIP2 beyond PtdIns(3,4,5)P3 through comprehensive kinetic profiling.

    Evidence In vitro kinetic assay against 54 soluble inositol phosphates and 4 phosphoinositide lipids

    PMID:15316017

    Open questions at the time
    • In-cell relevance of non-canonical substrates unknown
    • No structural basis for broad specificity at this stage
  8. 2005 High

    Resolved the cell-type-dependent role of SHIP2 in insulin signaling and metabolism, showing hepatic relevance in vivo but no effect in 3T3-L1 adipocytes.

    Evidence Adenoviral liver overexpression/dominant-negative in mouse models versus efficient siRNA in adipocytes; metabolic and signaling readouts

    PMID:15668240 PMID:15824124 PMID:15983195 PMID:16302969

    Open questions at the time
    • Reconciling tissue-specific metabolic roles incomplete
    • Mechanistic basis for adipocyte non-responsiveness unexplained
  9. 2006 High

    Defined the EphA2 SAM–SAM recruitment mode and PtdSer-dependent activation, connecting SHIP2 localization to receptor endocytosis via PI3K/Rac1.

    Evidence SAM-domain interaction assays, siRNA, Rac1-GTP pulldowns with dominant-negative Rac1; in vitro PtdSer-vesicle phosphatase assay

    PMID:16824732 PMID:17135240

    Open questions at the time
    • Structural detail of SAM-SAM interface not yet solved here
    • Link between membrane lipid environment and in vivo activity correlative
  10. 2007 Medium

    Showed tyrosine phosphorylation acts as an activity-and-localization switch and identified additional SAM-domain partner Arap3.

    Evidence PTP-inhibitor-induced phosphorylation with specific-activity measurement and fractionation; yeast two-hybrid and endogenous Co-IP

    PMID:17314030 PMID:17672824

    Open questions at the time
    • Physiological kinase/stimulus for activation not defined
    • Functional role of Arap3 interaction untested
  11. 2007 High

    Demonstrated SHIP2 as a negative-feedback node on PtdIns(3,4,5)P3 during NGF-driven neurite outgrowth using live imaging and validated modeling.

    Evidence siRNA, FRET biosensors for lipids and Rac1/Cdc42, and an experimentally validated kinetic model in PC12 cells

    PMID:17535963

    Open questions at the time
    • In vivo neuronal relevance not established
    • Molecular link from Rac1 to SHIP2 regulation inferred from modeling
  12. 2010 High

    Placed SHIP2 at clathrin-coated pits and bacterial actin pedestals via intersectin and Shc, defining its role in shaping endocytic and pathogen-driven phosphoinositide platforms.

    Evidence TIRF imaging of CCP dynamics, intersectin Co-IP, and Tir-ITIM mutagenesis with PI(3,4)P2/lamellipodin localization

    PMID:20114025 PMID:20679431

    Open questions at the time
    • Quantitative contribution of PI(4,5)P2 versus PI(3,4,5)P3 turnover to CCP maturation not fully separated
  13. 2011 Medium

    Connected SHIP2 to small-GTPase-driven polarity/migration (RhoA effector) and identified Ser132 phosphorylation governing nuclear localization, PI(4,5)P2 activity, and stability.

    Evidence GTP-RhoA pulldown with RhoA-binding-deficient rescue; MS phosphosite ID, phospho-specific staining, PI(4,5)P2 phosphatase assay, lamin A/C Co-IP

    PMID:21770892 PMID:22194892 PMID:22593208

    Open questions at the time
    • Kinase responsible for Ser132 phosphorylation unknown
    • Nuclear PI(4,5)P2 substrate function not mechanistically linked to phenotypes
  14. 2012 High

    Provided structural definition of SHIP2's catalytic domain and SAM-SAM recognition, and established INPPL1 catalytic mutations as causative for opsismodysplasia.

    Evidence X-ray structure of phosphatase domain with inhibitor; NMR of EphA2-SHIP2 SAM complex; exome sequencing of 10 unrelated families

    PMID:18991394 PMID:22244754 PMID:22330088 PMID:23273569

    Open questions at the time
    • Mechanism linking phosphatase loss to growth-plate disorganization not detailed
    • Tissue-specific substrate in cartilage unidentified
  15. 2013 High

    Established PtdIns(3,4)P2 as an effector lipid: SHIP2 controls epithelial apicobasal polarity via Dlg1 binding and is required for invadopodium maturation.

    Evidence Direct lipid-protein binding, catalytic-dead mutant and rescue with polarity/Rho-GTPase readouts; live-cell PI(3,4)P2 biosensor imaging with matrix-degradation assays

    PMID:23699395 PMID:24206842

    Open questions at the time
    • How SHIP2 is spatially restricted to invadopodium cores not fully resolved
  16. 2016 High

    Defined catalysis-coupled and protein-protein-coupled invasive functions (Mena recruitment), neuronal disease relevance (FcγRIIb–SHIP2 in tau pathology), and a PI(4,5)P2-to-PI4P role at focal adhesions.

    Evidence Co-IP and structure-function for Mena with in vivo metastasis; FcγRIIb Tyr273 complex with multiple interventions in AD mice; siRNA with PI(4,5)P2/PI4P imaging and myosin-1c Co-IP

    PMID:26826186 PMID:27597754 PMID:27834631

    Open questions at the time
    • Selectivity of Mena over VASP recruitment mechanistically unexplained
    • Causality of PI(4,5)P2 control on adhesion turnover correlative in single model
  17. 2018 High

    Separated SHIP2's catalytic and scaffolding functions: it acts as a phosphatase-independent adaptor sustaining FGFR-ERK signaling and as a catalysis-dependent primer for FEME.

    Evidence Phosphatase-dead mutants, siRNA, FGFR complex Co-IP, and phospho-ERK/FRS2/PTPN11 readouts; Cdc42-FBP17/CIP4-SHIP2 axis ordering with endocytosis assays

    PMID:30061681 PMID:30228226

    Open questions at the time
    • How a single protein partitions between adaptor and catalytic roles in cells unresolved
  18. 2019 Medium

    Identified upstream regulators of SHIP2 abundance and activity in cancer (PLEK2-driven degradation; IQGAP2-driven activation).

    Evidence Co-IP/MS, ubiquitination and stability assays, domain mapping, and migration/invasion rescue in cancer cell lines

    PMID:31498891 PMID:32183047

    Open questions at the time
    • Single-lab findings without in vivo validation
    • Mechanism of IQGAP2-mediated activity enhancement not structurally defined

Open questions

Synthesis pass · forward-looking unresolved questions
  • How the multiple regulatory inputs (tyrosine/Ser132 phosphorylation, C2 allostery, membrane lipid environment, and competing adaptor partners) are integrated to determine SHIP2 localization, substrate choice, and the balance between its catalytic and scaffolding roles in a given cellular context remains unresolved.
  • No unified model coupling phosphorylation state to in-cell substrate selection
  • Tissue-specific substrate in cartilage relevant to opsismodysplasia unidentified
  • Endogenous kinases driving regulatory phosphorylation undefined

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 6 GO:0140098 catalytic activity, acting on RNA 5 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 3 GO:0060090 molecular adaptor activity 3
Localization
GO:0005886 plasma membrane 5 GO:0005856 cytoskeleton 4 GO:0005829 cytosol 3 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2
Pathway
R-HSA-162582 Signal Transduction 5 R-HSA-5653656 Vesicle-mediated transport 4 R-HSA-1430728 Metabolism 2 R-HSA-1266738 Developmental Biology 1
Partners
BCAR1ENAHEPHA2FCGR2BFLNAITSN1METSHC1
Complex memberships
FGFR–Src–FRS2–PTPN11 signaling complexNephrin–Filamin–Lamellipodin complexfilamin–actin–GPIb-IX-V platelet complex

Evidence

Reading pass · 46 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SHIP2 (51C/SHIP2) hydrolyzes phosphatidylinositol 3,4,5-trisphosphate (PtdIns(3,4,5)P3) to PtdIns(3,4)P2 in vitro, as confirmed by immunoprecipitation of phosphatase activity, and undergoes tyrosine phosphorylation in response to EGF, PDGF, NGF, IGF-1, and insulin. SHIP2 associates with the Shc adapter protein following EGF, NGF, and PDGF stimulation. Immunoprecipitation with phosphatase activity assay; immunoblot for tyrosine phosphorylation; co-immunoprecipitation with Shc The Journal of biological chemistry High 9660833
1998 SHIP2 displays both PtdIns(3,4,5)P3 5-phosphatase and inositol 1,3,4,5-tetrakisphosphate (InsP4) 5-phosphatase activities when expressed as a recombinant protein in E. coli and in COS-7 cells; unlike SHIP1, SHIP2 does not hydrolyze soluble Ins(1,3,4,5)P4 in COS-7 cell assays. In vitro enzymatic assay with recombinant truncated protein expressed in E. coli; transfection into COS-7 cells followed by phosphatase activity measurement FEBS letters High 9824312
1999 SHIP2 is constitutively tyrosine phosphorylated in CML progenitor cells expressing p210(bcr/abl) and associates with SHC via its PTB domain. SHIP2 selectively binds the SH3 domain of ABL (not Src), whereas SHIP1 binds Src. SHIP2 does not bind GRB2 SH3 domains. Both SHIP1 and SHIP2 hydrolyze PtdIns(3,4,5)P3 in vitro, but only SHIP1 hydrolyzes Ins(1,3,4,5)P4. Protein purification, mass spectrometry identification, co-immunoprecipitation, in vitro binding assays with SH3 domain constructs, in vitro phosphatase assay Blood High 10194451
1999 Overexpression of rat SHIP2 in insulin receptor-expressing Rat1 fibroblasts inhibits insulin-induced Akt activation and MAP kinase activation. SHIP2 inhibits Shc-Grb2 association by competing for Shc phosphotyrosine via its SH2 domain, without affecting insulin receptor or IRS-1 phosphorylation or PI3K activation. SHIP2 itself undergoes insulin-mediated tyrosine phosphorylation. Stable overexpression in Rat1-HIRc cells; immunoprecipitation; kinase assays; [3H]-thymidine incorporation Biochemical and biophysical research communications High 10381377
2000 SHIP2 overexpression in PTEN-null glioblastoma cells abolishes PtdIns(3,4,5)P3 levels while PtdIns(3,4)P2 remains elevated, yet reduces PKB phosphorylation (Thr308 and Ser473) and activity to a similar extent as PTEN re-expression. SHIP2 causes G1 cell cycle arrest and stabilizes p27(KIP1). Antisense reduction of SHIP2 increases PKB activity. SHIP2 undergoes tyrosine phosphorylation upon growth factor stimulation without significant alteration of its phosphatase activity. Overexpression and antisense knockdown; lipid quantification; PKB kinase assay; cell cycle analysis; immunoblot for p27 Molecular and cellular biology High 10958682
2000 The Y+2 leucine residue in the FcγRIIB ITIM motif specifically determines recruitment of both SHIP1 and SHIP2 (but not SHP-1 or SHP-2) in vivo; this residue is distinct from the Y-2 hydrophobic residue that determines SHP binding, defining a separate SHIP-binding site on the ITIM. Loss-of-function and gain-of-function ITIM substitution mutagenesis; in vivo co-immunoprecipitation from B cells The Journal of biological chemistry High 11016922
2001 SHIP2 negatively regulates insulin signaling and insulin sensitivity in vivo. SHIP2 knockout mice display severe neonatal hypoglycaemia, deregulated gluconeogenic gene expression, increased GLUT4 recruitment and glycogen synthesis in skeletal muscle. (Note: subsequent work showed this locus also inadvertently deleted Phox2a.) Gene knockout in mice; glucose/insulin tolerance tests; GLUT4 recruitment assay; glycogen synthesis assay Nature Medium 11343120
2001 SHIP2 binds filamin A, B, and C via its C-terminal proline-rich domain, as identified by yeast two-hybrid and confirmed by co-immunoprecipitation from COS-7 cells. Filamin-dependent localization is required for SHIP2 membrane ruffle targeting; in filamin-deficient cells SHIP2 is exclusively cytosolic. At membrane ruffles, SHIP2 catalytic activity regulates PtdIns(3,4,5)P3 levels and submembranous actin remodeling after growth factor stimulation. Yeast two-hybrid screening; co-immunoprecipitation; immunofluorescence; overexpression in filamin-deficient cells; lipid phosphatase assay The Journal of cell biology High 11739414
2001 SHIP2 associates with the p130(Cas) adapter protein via its SH2 domain in multiple cell types. The SHIP2-p130(Cas) interaction is stimulated by cell reattachment/spreading and correlates with p130(Cas) cleavage. SHIP2 localizes to focal contacts and lamellipodia; increased adhesion requires an intact SH2 domain, and a catalytic domain deletion mutant inhibits cell spreading. Co-immunoprecipitation; immunofluorescence; transient transfection of SH2 and catalytic domain mutants; adhesion/spreading assays Molecular and cellular biology High 11158326
2001 SHIP2 is recruited to and co-immunoprecipitates with the EGF receptor in EGF-stimulated COS-7 cells via its C-terminal region (not SH2 domain alone), and also with Shc. SHIP2 overexpression decreases EGF-stimulated PtdIns(3,4,5)P3 production and PKB activity. Co-immunoprecipitation; immunofluorescence double-staining; transfection with truncation mutants; lipid and PKB activity measurement The Journal of biological chemistry Medium 11349134
2001 SHIP2 overexpression in CHO-IR cells reduces insulin-stimulated PtdIns(3,4,5)P3 accumulation, Akt/PKB activation, and MAPK stimulation, confirming SHIP2 as a direct regulator of insulin-induced PI3K signaling. Stable overexpression; [32P]-lipid quantification; immunoblot for phospho-Akt and MAPK Biochemical and biophysical research communications Medium 11401540
2002 Src family tyrosine kinases phosphorylate SHIP2 on Tyr986-987 within the NPXY motif during cell attachment/spreading on collagen I (but not fibronectin, collagen IV, laminin, or poly-L-lysine). Src-phosphorylated SHIP2 recruits Shc via the NPXY/PTB interaction; a NPXY mutant of SHIP2 causes deregulated lamellipodia formation. Src inhibitor pharmacology; in vitro Src kinase assay with recombinant SHIP2; activated/dominant-negative Src overexpression; site-directed mutagenesis of NPXY; co-immunoprecipitation Journal of cell science High 12235291
2003 SHIP2 is expressed in the nuclei of vascular smooth muscle cells and displays PtdIns(3,4,5)P3 5-phosphatase activity in nuclear fractions. Nuclear SHIP2 co-localizes with the SC35 splicing factor at nuclear speckles, while PTEN does not. Nuclear fractionation; in vitro PtdIns(3,4,5)P3 phosphatase assay on nuclear extracts; immunoprecipitation from nuclear fractions; confocal microscopy The Journal of biological chemistry Medium 12847108
2003 SHIP2 forms a tetrameric complex with filamin, actin, and the platelet GPIb-IX-V receptor in unstimulated platelets. The complex dissociates from the Triton-soluble fraction upon thrombin or VWF activation. SHIP2 within this complex retains PtdIns(3,4,5)P3 5-phosphatase activity. In activated spreading platelets, SHIP2 colocalizes with actin at the central actin ring and at filopodia/lamellipodia. Co-immunoprecipitation from platelet lysates; phosphatase activity assay on immunoprecipitates; immunofluorescence on spread platelets Blood High 12676785
2003 SHIP2 associates with c-Cbl-associated protein (CAP) via its proline-rich C-terminus (interacting with CAP SH3C domain) as shown by yeast two-hybrid and GST pulldown, and co-immunoprecipitates with endogenous c-Cbl and with the insulin receptor in CHO-IR cells. Yeast two-hybrid; GST pulldown; co-immunoprecipitation Biochemical and biophysical research communications Medium 12504111
2004 Kinetic analysis defines the substrate specificity rank order for human SHIP2: Ins(1,2,3,4,5)P5 > Ins(1,3,4,5)P4 > PtdIns(3,4,5)P3 ≈ PtdIns(3,5)P2 ≈ several inositol tetrakisphosphate isomers. SHIP2 has broader substrate specificity than previously appreciated, acting on multiple inositol phosphate isomers. In vitro kinetic assay with 54 water-soluble inositol phosphates and 4 phosphatidylinositol lipids; comparative analysis with S. pombe synaptojanin The Journal of biological chemistry High 15316017
2005 SHIP2 RNAi in HeLa cells causes severe F-actin deformities (weak cortical actin, peripheral actin spikes), cell-spreading defects with absent focal contacts, altered distribution of EEA1-positive endocytic vesicles, enhanced EGF receptor degradation, increased EGFR ubiquitination, and increased EGFR association with c-Cbl ubiquitin ligase. siRNA knockdown; immunofluorescence (F-actin, EEA1, EGFR); receptor degradation assay; co-immunoprecipitation of EGFR/c-Cbl The Journal of biological chemistry High 15668240
2005 SHIP2 interacts with the cytoskeletal protein Vinexin via its C-terminal proline-rich domain (interaction with Vinexin SH3 domain), identified by yeast two-hybrid and confirmed by co-immunoprecipitation. The SHIP2-Vinexin interaction promotes SHIP2 localization at the cell periphery. Enhanced cell adhesion to collagen I requires both the catalytic activity and the C-terminus of SHIP2, and is SHIP2-specific (not seen with SHIP1). SHIP2-/- MEF cells show reduced adhesion to collagen I. Yeast two-hybrid; co-immunoprecipitation from COS-7 and MEF cells; immunofluorescence; adhesion assay; catalytic and C-terminal mutants; SHIP2-/- MEF cells The FEBS journal High 16302969
2005 In 3T3-L1 adipocytes, siRNA knockdown of SHIP2 by ~90% does not modulate insulin-stimulated Akt phosphorylation, GSK-3α phosphorylation, or deoxyglucose transport, in contrast to PTEN knockdown which markedly enhances these parameters. This is a negative finding for SHIP2 regulation of insulin signaling in this cell model. siRNA knockdown (~90% depletion); phospho-Akt, phospho-GSK-3α immunoblot; [3H]-deoxyglucose transport assay The Journal of biological chemistry High 15824124
2005 Hepatic SHIP2 overexpression in mice impairs insulin-induced Akt phosphorylation in liver, increases mRNA for G6Pase and PEPCK (gluconeogenic genes), decreases SREBP1 mRNA, and elevates blood glucose after oral glucose. Dominant-negative SHIP2 expression in diabetic db/db mice reverses these effects, demonstrating hepatic SHIP2 regulates gluconeogenic gene expression in vivo. Adenoviral vector-mediated liver-specific overexpression/dominant-negative expression; phospho-Akt immunoblot; qRT-PCR for metabolic genes; oral glucose tolerance test Diabetes High 15983195
2005 SHIP2 binds directly to the HGF receptor c-Met via phosphotyrosine 1356. HGF-induced lamellipodium formation requires both SHIP2 catalytic activity and the proline-rich domain; a catalytically inactive SHIP2 mutant suppresses HGF-potentiated cell scattering and spreading but still forms lamellipodia, while a proline-rich domain deletion mutant impairs lamellipodium formation. Co-immunoprecipitation; site-directed mutagenesis of c-Met Y1356; overexpression of catalytic and proline-rich domain mutants; cell scattering/spreading assays Oncogene Medium 15735664
2006 SHIP2 is recruited to activated EphA2 receptor via a heterotypic SAM-SAM domain interaction between SHIP2's SAM domain and EphA2's SAM domain. SHIP2 overexpression inhibits EphA2 receptor endocytosis, while SHIP2 siRNA knockdown promotes EphA2 internalization and degradation. SHIP2 regulates EphA2 endocytosis via PI3K-dependent Rac1 activation; PI3K inhibition reduces PtdIns(3,4,5)P3 and suppresses increased endocytosis; dominant-negative Rac1 inhibits EphA2 endocytosis. Co-immunoprecipitation; siRNA knockdown; SAM domain interaction assay; lipid quantification; Rac1-GTP pull-down; dominant-negative Rac1 overexpression; receptor internalization/degradation assay The Journal of biological chemistry High 17135240
2007 SHIP2 SAM domain interacts heterotypically with the Arap3 SAM domain in vitro and with endogenous Arap3 protein in cells, as shown by yeast two-hybrid and co-immunoprecipitation with endogenous proteins. Yeast two-hybrid screen; co-immunoprecipitation of endogenous proteins; in vitro SAM-SAM interaction assay Cellular signalling Medium 17314030
2007 Tyrosine phosphorylation of SHIP2 (induced by PTP inhibitors) causes a 5-10 fold increase in SHIP2 specific activity and promotes its translocation from cytosol to a Triton-insoluble fraction. This switches PI3K signal output from PtdIns(3,4,5)P3 to PtdIns(3,4)P2. PTP inhibitor treatment; SHIP2 immunoprecipitation with specific activity measurement; subcellular fractionation; lipid quantification The Biochemical journal Medium 17672824
2007 SHIP2 depletion in PC12 cells markedly potentiates NGF-induced Rac1/Cdc42 activation and PtdIns(3,4,5)P3 accumulation, and increases neurite number and length. FRET imaging reveals SHIP2 mediates negative feedback on PtdIns(3,4,5)P3 during neurite outgrowth; a computational model validated experimentally shows Rac1 regulation of both PI3K (positive feedback) and SHIP2 (negative feedback). siRNA knockdown; FRET-based biosensors for PtdIns(3,4,5)P3, PtdIns(3,4)P2, Rac1/Cdc42; live-cell imaging; computational kinetic modeling with experimental validation The Journal of cell biology High 17535963
2008 NMR solution structure of the SHIP2 SAM domain was determined; its interface with EphA2 SAM was mapped showing a heterotypic SAM-SAM interaction mode, and a minimal SHIP2 peptide region retaining EphA2-SAM binding affinity was identified. NMR spectroscopy; ITC (isothermal titration calorimetry); chemical shift perturbation mapping Biochemistry High 18991394
2008 SHIP2 associates with intersectin-1 (ITSN1) via the SH3D, A, C, and E domains of ITSN1 in vivo; SHIP2 overexpression recruits the ITSN1 short form to the cell membrane in response to EGF. Co-immunoprecipitation; domain mapping with ITSN1 SH3 domain constructs; immunofluorescence after EGF stimulation FEBS letters Medium 18692052
2010 SHIP2 is concentrated at endocytic clathrin-coated pits (CCPs) via interaction with the scaffold protein intersectin. SHIP2 is recruited early to CCPs and dissociates before fission. SHIP2 knockdown and acute PtdIns(3,4,5)P3 production both shorten CCP lifetime by enhancing maturation rate, consistent with both SHIP2 substrates (PI(4,5)P2 and PI(3,4,5)P3) positively affecting coat assembly. SHIP2 also negatively regulates plasma membrane PI(4,5)P2 levels. TIRF live-cell imaging of CCP dynamics; siRNA knockdown; intersectin co-immunoprecipitation; lipid level measurement The Journal of cell biology High 20679431
2010 SHIP2 controls F-actin-pedestal formation by EPEC by recruiting SHC adapter and generating PI(3,4)P2 at a lipid platform that recruits lamellipodin/RIAM for cytoskeletal regulator engagement. SHIP2 is recruited to EPEC Tir ITIM-like sequences at Y483/Y511, requiring both SHC scaffolding and phosphatase activity for compartmentalized actin dynamics. siRNA knockdown; mutagenesis of Tir ITIM sequences; PI(3,4)P2 localization; co-immunoprecipitation with SHC; lamellipodin localization assay Cell host & microbe High 20114025
2010 SHIP2 is an effector of RhoA small GTPase; SHIP2 interacts with active GTP-RhoA (GTP-dependent manner) in spreading and migrating U251 glioma cells. SHIP2 depletion impairs cell polarization and migration; these defects are rescued by wild-type SHIP2 but not by a RhoA-binding-deficient SHIP2 mutant. SHIP2 depletion also impairs proper PtdIns(3,4,5)P3 localization, not rescued by the RhoA-binding mutant. GTP-agarose pulldown for RhoA-active binding; co-immunoprecipitation; siRNA knockdown; rescue with wild-type vs. RhoA-binding mutant; cell polarity and migration assays; PtdIns(3,4,5)P3 localization Molecular biology of the cell High 22593208
2011 Nephrin activation in podocytes recruits a complex containing SHIP2, Filamin, and Lamellipodin. Knockdown of SHIP2 (as well as Filamin or Lamellipodin) impairs lamellipodia formation and cell migration. SHIP2, Filamin, and Lamellipodin are individually required for normal actin tail architecture in a CD16-Nephrin clustering model. Co-immunoprecipitation of Nephrin complex; siRNA knockdown of SHIP2, Filamin, Lamellipodin; immunofluorescence of actin; cell migration assay PloS one Medium 22194892
2011 SHIP2 phosphorylation at Ser132 was identified by MS in astrocytoma cells; Ser132-phosphorylated SHIP2 localizes to cytoplasm, nucleus, and nuclear speckles in a cell-cycle-dependent manner. SHIP2 phosphorylated on Ser132 displays PtdIns(4,5)P2 phosphatase activity. Nuclear lamin A/C was identified as a novel SHIP2 interactor. SHIP2 S132A mutant shows reduced sensitivity to C-terminal degradation and increased resistance to calpain. Mass spectrometry phosphosite identification; immunostaining with phospho-Ser132 specific antibody; nuclear fractionation; in vitro phosphatase assay with PtdIns(4,5)P2; co-immunoprecipitation with lamin A/C; calpain degradation assay The Biochemical journal Medium 21770892
2012 NMR structure of the EphA2-SHIP2 SAM:SAM heterodimeric complex was determined. Specific contacts differ significantly from a prior model. EphA family members (EphA1 and EphA2) bind SHIP2 SAM, whereas EphB2 does not; an engineered EphB2 SAM variant was designed that does bind SHIP2. A mutant EphA2 compromised in SHIP2 binding revealed two previously unrecognized SHIP2 functions: suppressing ligand-induced EphA2 activation and promoting receptor-coordinated chemotactic cell migration. NMR with NOE/RDC restraints; molecular dynamics/docking; ITC; binding assays with EphA1, EphB2 and designed EphB2 variant; functional cell assays with SHIP2-binding-deficient EphA2 mutant Structure High 22244754
2012 INPPL1 loss-of-function mutations (premature stops, splice site, and catalytic-domain missense) cause opsismodysplasia (OPS), a severe chondrodysplasia with major growth plate disorganization, establishing SHIP2 phosphatase activity as essential for endochondral ossification. Exome sequencing; Sanger sequencing confirmation; 12 distinct mutations in 10 unrelated families at homozygous or compound heterozygous state American journal of human genetics High 23273569
2012 A 2.1 Å crystal structure of the SHIP2 phosphatase domain bound to the synthetic ligand biphenyl 2,3',4,5',6-pentakisphosphate (BiPh(2,3',4,5',6)P5) was determined, revealing the active site architecture and a flexible loop that closes over ligand. BiPh(2,3',4,5',6)P5 inhibits Ins(1,3,4,5)P4 hydrolysis by SHIP2 with IC50 of 24.8 µM. X-ray crystallography at 2.1 Å; molecular dynamics simulation; in vitro phosphatase inhibition assay ACS chemical biology High 22330088
2013 SHIP2 regulates epithelial cell apicobasal polarity through its lipid product PtdIns(3,4)P2, which binds to the polarity protein Dlg1. SHIP2 is mainly localized at the basolateral membrane of polarized MDCK cells. SHIP2 siRNA or catalytically dead SHIP2 mutant disrupts polarity, inhibits RhoA, and activates Rac1 similarly to HCV core protein; SHIP2 re-expression rescues polarity and RhoA activation. siRNA knockdown; catalytic dead mutant overexpression; direct lipid-protein binding assay (PtdIns(3,4)P2 binding to Dlg1); immunofluorescence of polarity markers; RhoA/Rac1 activity assays Molecular biology of the cell High 23699395
2013 SHIP2 localizes at the invadopodium core and regulates PI(3,4)P2 levels locally. SHIP2 arrives at invadopodium precursors coinciding with PI(3,4)P2 accumulation. SHIP2 inhibition reduces mature invadopodia and matrix degradation; SHIP2 overexpression increases matrix degradation. SHIP2 does not affect precursor initiation but is required for maturation. High-resolution spatiotemporal live-cell imaging; pharmacological SHIP2 inhibition; SHIP2 overexpression; PI(3,4)P2 biosensor imaging; matrix degradation assay Current biology High 24206842
2016 SHIP2 SHIP2 recruits Mena (an Ena/VASP actin regulatory protein) to invadopodia through a specific SHIP2-Mena protein-protein interaction; SHIP2 does not recruit VASP. Disruption of the SHIP2-Mena interaction attenuates ECM degradation and invasion in vitro and reduces metastasis in vivo. Co-immunoprecipitation; structure-function analysis of SHIP2-Mena interaction; siRNA/mutant rescue assays; in vitro invasion assay; in vivo metastasis mouse model The Journal of cell biology High 27597754
2016 FcγRIIb phosphorylation at Tyr273 recruits SHIP2 to form a complex in neurons exposed to Aβ1-42. This leads to increased PtdIns(3,4)P2 production, which mediates tau hyperphosphorylation. Fcgr2b knockout, antagonistic FcγRIIb antibody, or SHIP2 knockdown/pharmacological inhibition rescues tau hyperphosphorylation and memory impairment in AD mouse models. Co-immunoprecipitation; phospho-specific antibody detection of FcγRIIb Tyr273; lipid quantification; lentiviral siRNA knockdown; pharmacological SHIP2 inhibition; behavioral memory tests in 3xTg-AD mice eLife High 27834631
2016 SHIP2 controls plasma membrane PI(4,5)P2 levels in glioblastoma 1321 N1 cells; SHIP2 depletion increases PI(4,5)P2 and decreases PI4P, demonstrating SHIP2 dephosphorylates PI(4,5)P2 to PI4P in intact cells. The PI(4,5)P2-binding protein myosin-1c was identified as a novel SHIP2 interactor. SHIP2-mediated control of PI(4,5)P2/PI4P regulates focal adhesion organization and cell migration. siRNA knockdown; immunofluorescence with PI(4,5)P2/PI4P antibodies; co-immunoprecipitation with myosin-1c; cell migration assay; focal adhesion staining Journal of cell science Medium 26826186
2017 Crystal structures of the SHIP2 5-phosphatase domain together with an adjacent C2 domain reveal an extensive interdomain interface that induces structural changes in the phosphatase domain. Both domains bind phosphatidylserine lipids. The C2 domain greatly enhances catalytic turnover despite being distant from the active site, acting via two allosteric pathways (hydrophobic and polar interdomain interactions) that differentially affect the lipid chain and headgroup moieties of PtdIns(3,4,5)P3. X-ray crystallography; mutagenesis of interdomain contacts; molecular dynamics simulation; in vitro phosphatase activity assay; cell biology assays eLife High 28792888
2018 SHIP2 functions as an adaptor (not through its phosphatase activity) to enable sustained ERK activation downstream of FGF receptors. SHIP2 recruits Src family kinases to FGFRs, promoting FGFR-mediated phosphorylation of FRS2 and recruitment of PTPN11. Loss of SHIP2 converts FGF-induced sustained ERK activation into a transient signal. Phosphatase-dead SHIP2 mutants still associate with FGFRs and do not prevent sustained ERK activation. siRNA knockdown; phosphatase-dead mutant expression; co-immunoprecipitation of FGFR complexes; phospho-ERK/FRS2/PTPN11 immunoblot; rescue experiments Science signaling High 30228226
2018 FBP17 and CIP4 (BAR domain proteins activated by membrane-bound GTP-Cdc42) recruit SHIP2 and lamellipodin to prime the plasma membrane for fast endophilin-mediated endocytosis (FEME) by locally producing PI(3,4)P2 and enabling endophilin pre-enrichment. SHIP2 5'-lipid phosphatase activity is essential for this priming function. Co-localization imaging; co-immunoprecipitation; siRNA knockdown; live-cell endocytosis assays; GTPase activity manipulation Nature cell biology High 30061681
2019 PLEK2 directly interacts with SHIP2 and promotes its ubiquitination and degradation in NSCLC cells, activating SHIP2-associated TGF-β/PI3K/AKT signaling and promoting EMT and invasion. Co-immunoprecipitation; ubiquitination assay; SHIP2 protein stability assay; SHIP2 overexpression rescue experiment; signaling pathway analysis International journal of cancer Medium 31498891
2006 SHIP2 PtdIns(3,4,5)P3 5-phosphatase activity is specifically stimulated by phosphatidylserine (PtdSer) vesicles (but not by PtdCho to the same extent), dependent on the fatty acid composition of the substrate. This stimulation is not seen with soluble Ins(1,3,4,5)P4 substrate or with the related phosphatase SKIP. In vitro phosphatase assay with lipid vesicles; recombinant minimal catalytic construct and full-length SHIP2 Cellular signalling Medium 16824732
2020 IQGAP2 binds SHIP2 via the PRD and SAM domains of SHIP2, colocalizes with SHIP2 in the cytoplasm, and increases SHIP2 phosphatase activity; knockdown of IQGAP2 in SHIP2-overexpressing cells suppresses elevated SHIP2 phosphatase activity and restores cell migration and invasion. Co-immunoprecipitation and mass spectrometry; domain deletion mutant analysis; SHIP2 phosphatase activity assay; siRNA knockdown of IQGAP2; migration/invasion assay International journal of molecular sciences Medium 32183047

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2001 The lipid phosphatase SHIP2 controls insulin sensitivity. Nature 292 11343120
2008 MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia. Proceedings of the National Academy of Sciences of the United States of America 240 19033458
2005 Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity. Nature medicine 207 15654325
2000 5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells. Molecular and cellular biology 151 10958682
2013 Tks5 and SHIP2 regulate invadopodium maturation, but not initiation, in breast carcinoma cells. Current biology : CB 134 24206842
2010 MicroRNA-205 promotes keratinocyte migration via the lipid phosphatase SHIP2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 134 20530248
1999 A novel SH2-containing phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase (SHIP2) is constitutively tyrosine phosphorylated and associated with src homologous and collagen gene (SHC) in chronic myelogenous leukemia progenitor cells. Blood 132 10194451
2001 The SH2-containing inositol polyphosphate 5-phosphatase, SHIP-2, binds filamin and regulates submembraneous actin. The Journal of cell biology 128 11739414
2006 Regulation of EphA2 receptor endocytosis by SHIP2 lipid phosphatase via phosphatidylinositol 3-Kinase-dependent Rac1 activation. The Journal of biological chemistry 117 17135240
1999 Molecular cloning of rat SH2-containing inositol phosphatase 2 (SHIP2) and its role in the regulation of insulin signaling. Biochemical and biophysical research communications 114 10381377
2001 SH2-containing inositol 5'-phosphatase SHIP2 associates with the p130(Cas) adapter protein and regulates cellular adhesion and spreading. Molecular and cellular biology 108 11158326
1998 Growth factors and insulin stimulate tyrosine phosphorylation of the 51C/SHIP2 protein. The Journal of biological chemistry 106 9660833
2002 The gene INPPL1, encoding the lipid phosphatase SHIP2, is a candidate for type 2 diabetes in rat and man. Diabetes 100 12086927
1998 The SH2 domain containing inositol 5-phosphatase SHIP2 displays phosphatidylinositol 3,4,5-trisphosphate and inositol 1,3,4,5-tetrakisphosphate 5-phosphatase activity. FEBS letters 99 9824312
2012 Therapeutic potential of SH2 domain-containing inositol-5'-phosphatase 1 (SHIP1) and SHIP2 inhibition in cancer. Molecular medicine (Cambridge, Mass.) 97 22033675
2010 The inositol 5-phosphatase SHIP2 regulates endocytic clathrin-coated pit dynamics. The Journal of cell biology 91 20679431
2005 PTEN, but not SHIP2, suppresses insulin signaling through the phosphatidylinositol 3-kinase/Akt pathway in 3T3-L1 adipocytes. The Journal of biological chemistry 87 15824124
1999 Distribution of the src-homology-2-domain-containing inositol 5-phosphatase SHIP-2 in both non-haemopoietic and haemopoietic cells and possible involvement of SHIP-2 in negative signalling of B-cells. The Biochemical journal 87 10477282
2003 SHIP-2 and PTEN are expressed and active in vascular smooth muscle cell nuclei, but only SHIP-2 is associated with nuclear speckles. The Journal of biological chemistry 84 12847108
2005 SH2-containing 5'-inositol phosphatase, SHIP2, regulates cytoskeleton organization and ligand-dependent down-regulation of the epidermal growth factor receptor. The Journal of biological chemistry 83 15668240
2002 PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells. Oncogene 82 12149650
2018 FBP17 and CIP4 recruit SHIP2 and lamellipodin to prime the plasma membrane for fast endophilin-mediated endocytosis. Nature cell biology 78 30061681
2009 Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2. British journal of pharmacology 78 19694723
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
2001 The Src homology 2 domain containing inositol 5-phosphatase SHIP2 is recruited to the epidermal growth factor (EGF) receptor and dephosphorylates phosphatidylinositol 3,4,5-trisphosphate in EGF-stimulated COS-7 cells. The Journal of biological chemistry 69 11349134
2000 Molecular basis of the recruitment of the SH2 domain-containing inositol 5-phosphatases SHIP1 and SHIP2 by fcgamma RIIB. The Journal of biological chemistry 69 11016922
2004 Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome. Diabetes 67 15220217
2007 Phosphoinositol phosphatase SHIP2 promotes cancer development and metastasis coupled with alterations in EGF receptor turnover. Carcinogenesis 62 17893231
2010 SHIP2 and its involvement in various diseases. Expert opinion on therapeutic targets 61 20536411
2012 NMR structure of a heterodimeric SAM:SAM complex: characterization and manipulation of EphA2 binding reveal new cellular functions of SHIP2. Structure (London, England : 1993) 57 22244754
2008 NMR studies of a heterotypic Sam-Sam domain association: the interaction between the lipid phosphatase Ship2 and the EphA2 receptor. Biochemistry 57 18991394
2007 An essential role for the SHIP2-dependent negative feedback loop in neuritogenesis of nerve growth factor-stimulated PC12 cells. The Journal of cell biology 56 17535963
2001 The SH2 domain containing inositol 5-phosphatase SHIP2 controls phosphatidylinositol 3,4,5-trisphosphate levels in CHO-IR cells stimulated by insulin. Biochemical and biophysical research communications 56 11401540
2019 PLEK2 mediates metastasis and vascular invasion via the ubiquitin-dependent degradation of SHIP2 in non-small cell lung cancer. International journal of cancer 55 31498891
2005 Impact of the liver-specific expression of SHIP2 (SH2-containing inositol 5'-phosphatase 2) on insulin signaling and glucose metabolism in mice. Diabetes 54 15983195
2010 Enteropathogenic Escherichia coli recruits the cellular inositol phosphatase SHIP2 to regulate actin-pedestal formation. Cell host & microbe 53 20114025
2005 SHIP2 interaction with the cytoskeletal protein Vinexin. The FEBS journal 53 16302969
2005 PPAR-gamma inhibits ANG II-induced cell growth via SHIP2 and 4E-BP1. American journal of physiology. Heart and circulatory physiology 52 16155101
2000 The SH2 domain containing inositol 5-phosphatase SHIP2 associates to the immunoreceptor tyrosine-based inhibition motif of Fc gammaRIIB in B cells under negative signaling. Immunology letters 51 10789675
2016 FcγRIIb-SHIP2 axis links Aβ to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model. eLife 49 27834631
2011 SHIP2 multiple functions: a balance between a negative control of PtdIns(3,4,5)P₃ level, a positive control of PtdIns(3,4)P₂ production, and intrinsic docking properties. Journal of cellular biochemistry 49 21503961
2005 The SH2-domian-containing inositol 5-phosphatase (SHIP)-2 binds to c-Met directly via tyrosine residue 1356 and involves hepatocyte growth factor (HGF)-induced lamellipodium formation, cell scattering and cell spreading. Oncogene 49 15735664
2009 SHIP2 phosphoinositol phosphatase positively regulates EGFR-Akt pathway, CXCR4 expression, and cell migration in MDA-MB-231 breast cancer cells. International journal of oncology 48 19082482
2002 Src family tyrosine kinases regulate adhesion-dependent tyrosine phosphorylation of 5'-inositol phosphatase SHIP2 during cell attachment and spreading on collagen I. Journal of cell science 48 12235291
2003 The c-Cbl-associated protein and c-Cbl are two new partners of the SH2-containing inositol polyphosphate 5-phosphatase SHIP2. Biochemical and biophysical research communications 47 12504111
2007 The PI3K effector Arap3 interacts with the PI(3,4,5)P3 phosphatase SHIP2 in a SAM domain-dependent manner. Cellular signalling 46 17314030
2005 The SH2 domain containing inositol polyphosphate 5-phosphatase-2: SHIP2. The international journal of biochemistry & cell biology 46 15964236
2016 Lipid phosphatase SHIP2 functions as oncogene in colorectal cancer by regulating PKB activation. Oncotarget 44 27716613
2012 The inositol 5-phosphatase SHIP2 is an effector of RhoA and is involved in cell polarity and migration. Molecular biology of the cell 44 22593208
2012 Exome sequencing identifies INPPL1 mutations as a cause of opsismodysplasia. American journal of human genetics 44 23273569
2010 Lipid phosphatase SHIP2 downregulates insulin signalling in podocytes. Molecular and cellular endocrinology 43 20654688
2005 The inositol phosphatase SHIP-2 down-regulates FcgammaR-mediated phagocytosis in murine macrophages independently of SHIP-1. Blood 43 16179375
2004 SHIP2 is recruited to the cell membrane upon macrophage colony-stimulating factor (M-CSF) stimulation and regulates M-CSF-induced signaling. Journal of immunology (Baltimore, Md. : 1950) 43 15557176
2004 Comparative mechanistic and substrate specificity study of inositol polyphosphate 5-phosphatase Schizosaccharomyces pombe Synaptojanin and SHIP2. The Journal of biological chemistry 42 15316017
2002 SHIP2 overexpression strongly reduces the proliferation rate of K562 erythroleukemia cell line. Biochemical and biophysical research communications 42 12147234
2015 Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt. Journal of gastroenterology 41 26201869
2017 SHIP2: Structure, Function and Inhibition. Chembiochem : a European journal of chemical biology 40 27907247
2011 Nephrin regulates lamellipodia formation by assembling a protein complex that includes Ship2, filamin and lamellipodin. PloS one 40 22194892
2003 SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V: localization of SHIP-2 to the activated platelet actin cytoskeleton. Blood 39 12676785
2016 SHIP2 controls plasma membrane PI(4,5)P2 thereby participating in the control of cell migration in 1321 N1 glioblastoma cells. Journal of cell science 38 26826186
2009 PTEN and SHIP2 regulates PI3K/Akt pathway through focal adhesion kinase. Molecular and cellular endocrinology 38 19501627
2007 The inositol 5'-phosphatase SHIP-2 negatively regulates IgE-induced mast cell degranulation and cytokine production. Journal of immunology (Baltimore, Md. : 1950) 38 17579026
2011 Evidence of SHIP2 Ser132 phosphorylation, its nuclear localization and stability. The Biochemical journal 37 21770892
2009 Cultured peripheral blood mast cells from chronic idiopathic urticaria patients spontaneously degranulate upon IgE sensitization: Relationship to expression of Syk and SHIP-2. Clinical immunology (Orlando, Fla.) 37 19477690
2017 Structural basis for interdomain communication in SHIP2 providing high phosphatase activity. eLife 36 28792888
2015 SH2 domain-containing inositol 5-phosphatase (SHIP2) inhibition ameliorates high glucose-induced de-novo lipogenesis and VLDL production through regulating AMPK/mTOR/SREBP1 pathway and ROS production in HepG2 cells. Free radical biology & medicine 36 26456051
2014 A novel oncogenic role of inositol phosphatase SHIP2 in ER-negative breast cancer stem cells: involvement of JNK/vimentin activation. Stem cells (Dayton, Ohio) 36 24802135
2006 Regulation of protein kinase B activity by PTEN and SHIP2 in human prostate-derived cell lines. Cellular signalling 36 16842970
2022 LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2. Cell death discovery 35 36344496
2013 SHIP2 regulates epithelial cell polarity through its lipid product, which binds to Dlg1, a pathway subverted by hepatitis C virus core protein. Molecular biology of the cell 35 23699395
2012 A synthetic polyphosphoinositide headgroup surrogate in complex with SHIP2 provides a rationale for drug discovery. ACS chemical biology 35 22330088
2010 The inositol phosphatase SHIP2 negatively regulates insulin/IGF-I actions implicated in neuroprotection and memory function in mouse brain. Molecular endocrinology (Baltimore, Md.) 35 20829391
2003 SHIP-2 inositol phosphatase is inducibly expressed in human monocytes and serves to regulate Fcgamma receptor-mediated signaling. The Journal of biological chemistry 35 12690104
2009 Inhibitors of the lipid phosphatase SHIP2 discovered by high-throughput affinity selection-mass spectrometry screening of combinatorial libraries. Combinatorial chemistry & high throughput screening 34 19531013
2007 The control of phosphatidylinositol 3,4-bisphosphate concentrations by activation of the Src homology 2 domain containing inositol polyphosphate 5-phosphatase 2, SHIP2. The Biochemical journal 33 17672824
2021 Targeting SHIP1 and SHIP2 in Cancer. Cancers 32 33672717
2010 LL5beta directs the translocation of filamin A and SHIP2 to sites of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) accumulation, and PtdIns(3,4,5)P3 localization is mutually modified by co-recruited SHIP2. The Journal of biological chemistry 32 20236936
2005 Phosphatidylinositol 3,4,5-trisphosphate modulation in SHIP2-deficient mouse embryonic fibroblasts. The FEBS journal 32 15885100
2020 Small molecule targeting of SHIP1 and SHIP2. Biochemical Society transactions 30 32049315
2013 SHIP2 signaling in normal and pathological situations: Its impact on cell proliferation. Advances in biological regulation 30 24091101
2009 The Sam domain of the lipid phosphatase Ship2 adopts a common model to interact with Arap3-Sam and EphA2-Sam. BMC structural biology 29 19765305
2007 Significance of glucose intolerance and SHIP2 expression in hepatocellular carcinoma patients with HCV infection. Oncology reports 29 17671700
2017 Endothelial SHIP2 Suppresses Nox2 NADPH Oxidase-Dependent Vascular Oxidative Stress, Endothelial Dysfunction, and Systemic Insulin Resistance. Diabetes 28 28830894
2022 OxLDL-stimulated macrophage exosomes promote proatherogenic vascular smooth muscle cell viability and invasion via delivering miR-186-5p then inactivating SHIP2 mediated PI3K/AKT/mTOR pathway. Molecular immunology 27 35421738
2018 Inhibition of SHIP2 activity inhibits cell migration and could prevent metastasis in breast cancer cells. Journal of cell science 27 30012834
2018 The inositol phosphatase SHIP2 enables sustained ERK activation downstream of FGF receptors by recruiting Src kinases. Science signaling 27 30228226
2012 SHIP2 signalling at the plasma membrane, in the nucleus and at focal contacts. Advances in biological regulation 27 23040614
2016 5'-Inositol phosphatase SHIP2 recruits Mena to stabilize invadopodia for cancer cell invasion. The Journal of cell biology 26 27597754
2008 SHIP2 associates with intersectin and recruits it to the plasma membrane in response to EGF. FEBS letters 26 18692052
2006 The influence of anionic lipids on SHIP2 phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase activity. Cellular signalling 26 16824732
2020 IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity. International journal of molecular sciences 24 32183047
2007 Serum withdrawal-induced accumulation of phosphoinositide 3-kinase lipids in differentiating 3T3-L6 myoblasts: distinct roles for Ship2 and PTEN. Molecular and cellular biology 24 17893321
2012 Developmental defects and rescue from glucose intolerance of a catalytically-inactive novel Ship2 mutant mouse. Cellular signalling 23 22750293
2011 The host phosphoinositide 5-phosphatase SHIP2 regulates dissemination of vaccinia virus. Journal of virology 23 21543482
2010 Glucose metabolism activation by SHIP2 inhibitors via up-regulation of GLUT1 gene in L6 myotubes. European journal of pharmacology 23 20558154
2007 Normalization of prandial blood glucose and improvement of glucose tolerance by liver-specific inhibition of SH2 domain containing inositol phosphatase 2 (SHIP2) in diabetic KKAy mice: SHIP2 inhibition causes insulin-mimetic effects on glycogen metabolism, gluconeogenesis, and glycolysis. Diabetes 23 17596404
2017 ZIC2 promotes viability and invasion of human osteosarcoma cells by suppressing SHIP2 expression and activating PI3K/AKT pathways. Journal of cellular biochemistry 22 28857346
2017 The Sam-Sam interaction between Ship2 and the EphA2 receptor: design and analysis of peptide inhibitors. Scientific reports 21 29234063
2010 SHIP2, a factor associated with diet-induced obesity and insulin sensitivity, attenuates FGF signaling in vivo. Disease models & mechanisms 21 20616095
2006 APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2. Circulation research 21 16973905

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