Affinage

INPPL1

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

Length
1258 aa
Mass
138.6 kDa
Annotated
2026-04-28
100 papers in source corpus 55 papers cited in narrative 55 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

SHIP2 (INPPL1) is a broadly expressed inositol polyphosphate 5-phosphatase that hydrolyzes PI(3,4,5)P3 to PI(3,4)P2 and PI(4,5)P2 to PI4P, serving as a major negative regulator of PI3K/Akt signaling downstream of insulin, growth factor, and cytokine receptors (PMID:9660833, PMID:10958682, PMID:15316017, PMID:20679431). SHIP2 is recruited to activated receptors (EGFR, c-Met, EphA2 via SAM–SAM interaction, FcγRIIB via ITIM, FGFRs, M-CSF receptor) and to membrane scaffolds including filamin, intersectin, LL5β, and FBP17/CIP4, which direct its localized phosphatase activity to control clathrin-coated pit dynamics, fast endophilin-mediated endocytosis, invadopodium maturation, cell polarity, and actin-based cell spreading and migration (PMID:11739414, PMID:20679431, PMID:30061681, PMID:24206842, PMID:23699395, PMID:11158326). Beyond catalysis, SHIP2 functions as a scaffold protein—recruiting Src kinases to FGFRs to sustain ERK signaling independently of its phosphatase activity, and recruiting Mena to invadopodia to promote ECM degradation and metastasis—and is regulated by tyrosine phosphorylation (which increases catalytic activity 5–10-fold and redirects membrane association) and serine phosphorylation at Ser132 (which directs nuclear localization where it contacts lamin A/C), while an allosteric C2 domain enhances catalytic turnover through hydrophobic and polar interdomain signaling pathways (PMID:30228226, PMID:27597754, PMID:17672824, PMID:21770892, PMID:28792888). Loss-of-function INPPL1 mutations concentrated in the catalytic domain cause opsismodysplasia, establishing SHIP2 phosphatase activity as essential for endochondral ossification (PMID:23273569).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 1998 High

    Establishing SHIP2's enzymatic identity: the gene product was shown to be a PtdIns(3,4,5)P3 5-phosphatase that becomes tyrosine-phosphorylated upon growth factor stimulation and associates with the Shc adaptor, placing it in receptor tyrosine kinase signaling cascades.

    Evidence Immunoprecipitated and recombinant SHIP2 tested against PtdIns(3,4,5)P3 and InsP4 substrates in vitro; co-IP with Shc after EGF/PDGF/NGF/insulin stimulation

    PMID:9660833 PMID:9824312

    Open questions at the time
    • Physiological substrate hierarchy not yet defined
    • Mechanism of recruitment to receptor complexes unknown
    • In vivo function not established
  2. 2001 High

    SHIP2 was established as a negative regulator of PI3K/Akt signaling in insulin and growth factor pathways, and its knockout revealed a critical role in glucose homeostasis and insulin sensitivity in vivo.

    Evidence Overexpression in insulin-receptor-expressing cells and glioblastoma cells reduced PtdIns(3,4,5)P3, PKB activity, and caused G1 arrest; SHIP2 KO mice showed severe neonatal hypoglycemia with enhanced GLUT4 translocation and glycogen synthesis; SHIP2 co-immunoprecipitated with EGFR and insulin receptor

    PMID:10381377 PMID:10958682 PMID:11343120 PMID:11349134 PMID:11401540

    Open questions at the time
    • Original KO targeted a region also affecting Phox2a (later corrected)
    • Tissue-specific contributions not resolved
    • Whether SHIP2 has non-catalytic signaling roles unknown
  3. 2001 High

    SHIP2 was linked to the actin cytoskeleton and cell adhesion through its interaction with filamin and p130Cas, revealing that its phosphatase activity at the membrane regulates actin remodeling, focal contacts, and cell spreading.

    Evidence Yeast two-hybrid and co-IP identified filamin A/B/C binding via C-terminal PRD; filamin-null cells showed mislocalized SHIP2; SHIP2 localized to focal contacts and lamellipodia; catalytic mutants impaired spreading

    PMID:11158326 PMID:11739414

    Open questions at the time
    • How SHIP2 lipid product (PI(3,4)P2) controls actin effectors not identified
    • Whether filamin interaction is regulated by stimulation unclear
  4. 2003 High

    SHIP2 was found to localize to nuclei (at SC35 speckles) and to form a tetrameric complex with filamin/actin/GPIb-IX-V in platelets, broadening its functional geography beyond the plasma membrane.

    Evidence Subcellular fractionation and confocal microscopy in smooth muscle cells showed nuclear SHIP2 with PtdIns(3,4,5)P3 phosphatase activity; IP from platelet fractions identified active filamin-actin-SHIP2-GPIb-IX-V complex

    PMID:12676785 PMID:12847108

    Open questions at the time
    • Nuclear function and substrates not defined
    • Mechanism of nuclear import unknown
  5. 2005 High

    A corrected SHIP2 null mouse revealed that the severe hypoglycemia of the original KO was confounded by Phox2a co-deletion; true SHIP2 nulls are viable with normal glucose but resistant to diet-induced obesity, reframing SHIP2's metabolic role.

    Evidence ATG-targeted SHIP2 null mice on high-fat diet; glucose/insulin tolerance testing showed normal basal glucose but obesity resistance

    PMID:15654325

    Open questions at the time
    • Mechanism of obesity resistance not determined
    • Whether catalytic versus scaffold function drives metabolic phenotype unknown
  6. 2005 High

    SHIP2 was shown to regulate EGFR trafficking and actin integrity: its depletion caused F-actin deformities, spreading defects, and enhanced EGFR ubiquitination and degradation, while hepatic SHIP2 overexpression in diabetic mice impaired insulin-Akt signaling in a tissue-specific manner.

    Evidence RNAi in HeLa cells assessed for actin morphology, EGFR ubiquitination, and c-Cbl association; adenoviral hepatic SHIP2 expression in db/db mice with Akt and gluconeogenic gene readouts

    PMID:15668240 PMID:15983195

    Open questions at the time
    • Direct mechanism linking SHIP2 to EGFR-c-Cbl ubiquitination not identified
    • Whether SHIP2 regulates other RTK degradation pathways unknown
  7. 2006 High

    SHIP2 was shown to engage the EphA2 receptor via a SAM–SAM domain interaction, regulating EphA2 endocytosis through PI3K-Rac1, and to be allosterically activated by phosphatidylserine in the membrane.

    Evidence SAM domain interaction assays plus OE/KD of SHIP2 measuring EphA2 internalization; in vitro phosphatase assays with PS vesicles of defined composition

    PMID:16824732 PMID:17135240

    Open questions at the time
    • How PS allosteric activation integrates with membrane recruitment in cells not tested
    • Other SAM-domain partners not surveyed
  8. 2007 High

    Tyrosine phosphorylation was established as an activating switch for SHIP2: EGF-stimulated or vanadate-induced phosphorylation increased catalytic activity 5–10-fold and promoted translocation to the Triton-insoluble fraction, converting PI3K output from PtdIns(3,4,5)P3 to PtdIns(3,4)P2.

    Evidence IP of endogenous SHIP2 from HeLa/1321N1 cells after vanadate or EGF treatment with in vitro phosphatase assay and subcellular fractionation

    PMID:17672824

    Open questions at the time
    • Specific activating phosphotyrosine sites not mapped in this study
    • Kinase(s) responsible in each context not fully resolved
  9. 2010 High

    SHIP2 was found to regulate clathrin-coated pit dynamics by hydrolyzing PI(4,5)P2 (not only PI(3,4,5)P3) at the plasma membrane, and to be exploited by EPEC bacteria that recruit SHIP2 to actin pedestals via Tir ITIM-like sequences to generate PI(3,4)P2 platforms.

    Evidence Live-cell imaging of CCP lifetime after SHIP2 KD; Tir ITIM-like tyrosine mutagenesis with PI(3,4)P2 and lamellipodin recruitment; SHIP2 co-IP with intersectin at CCPs

    PMID:20114025 PMID:20679431

    Open questions at the time
    • Whether PI(4,5)P2 hydrolysis at CCPs is the primary or secondary substrate in vivo unresolved
    • Relative contributions of SHIP2 vs. synaptojanin at CCPs not quantified
  10. 2011 High

    Ser132 phosphorylation was identified as a regulatory PTM that directs SHIP2 to nuclear speckles where it interacts with lamin A/C and exhibits PI(4,5)P2 phosphatase activity, while also modulating calpain-mediated degradation.

    Evidence Mass spectrometry of phospho-SHIP2, phospho-specific immunostaining, co-IP with lamin A/C, calpain digestion assay with S132A mutant

    PMID:21770892

    Open questions at the time
    • Kinase responsible for Ser132 phosphorylation not identified
    • Functional consequences of nuclear PI(4,5)P2 hydrolysis undefined
  11. 2012 High

    Loss-of-function INPPL1 mutations were shown to cause opsismodysplasia, and a catalytically-inactive knock-in mouse distinguished SHIP2's enzymatic from scaffolding functions in vivo—catalytic loss impaired growth and development but not glucose homeostasis, implying scaffold roles for metabolism.

    Evidence Exome sequencing of 10 opsismodysplasia families identified catalytic-domain mutations; catalytic-dead knock-in mice showed growth/developmental but not metabolic defects; crystal structure of phosphatase domain solved at 2.1 Å

    PMID:22330088 PMID:22750293 PMID:23273569

    Open questions at the time
    • Mechanism by which SHIP2 catalytic activity controls chondrocyte biology not determined
    • Which scaffolding interactions drive metabolic phenotype not identified
  12. 2013 High

    SHIP2 was established as a key determinant of invadopodium maturation and epithelial apicobasal polarity through local PI(3,4)P2 generation, with its product binding the polarity protein Dlg1.

    Evidence Live-cell imaging of invadopodium dynamics with PI(3,4)P2 biosensors; SHIP2 KD/catalytic-dead experiments in polarized MDCK and Huh7 cells with polarity marker analysis

    PMID:23699395 PMID:24206842

    Open questions at the time
    • Whether PI(3,4)P2-Dlg1 interaction is direct or scaffold-mediated in vivo not resolved
    • How invadopodium maturation signal integrates with Mena recruitment not yet connected
  13. 2017 High

    Structural and allosteric regulation was clarified: crystal structures revealed that the C2 domain forms an extensive interface with the phosphatase domain and enhances catalytic turnover through dual allosteric pathways, providing a structural basis for SHIP2's membrane-proximal activation.

    Evidence X-ray crystallography of phosphatase-C2 domain construct, mutagenesis of interdomain contacts, MD simulation, in vitro kinetic assays

    PMID:28792888

    Open questions at the time
    • Full-length SHIP2 structure including SH2, PRD, and SAM domains not available
    • How allosteric activation integrates with PS and tyrosine-phosphorylation activation in cells unknown
  14. 2018 High

    SHIP2 was shown to function as a catalysis-independent scaffold that recruits Src kinases to FGFRs for sustained ERK signaling, and separately to be recruited by FBP17/CIP4 to prime fast endophilin-mediated endocytosis by generating PI(3,4)P2.

    Evidence Phosphatase-dead SHIP2 rescued sustained ERK in SHIP2-KO cells stimulated by FGF; SHIP2 co-IP with FBP17/CIP4 and endophilin localization imaging with SHIP2 depletion

    PMID:30061681 PMID:30228226

    Open questions at the time
    • Which Src family member is scaffolded to FGFRs not specified
    • Whether scaffold and catalytic functions operate simultaneously at the same receptor complex unknown

Open questions

Synthesis pass · forward-looking unresolved questions
  • Major unresolved questions include the full-length SHIP2 structure integrating all domains, the identity of kinases and phosphatases that regulate Ser132 and activating tyrosine phosphorylation in specific contexts, the mechanistic basis of SHIP2's role in endochondral ossification, and how its catalytic and scaffolding functions are coordinately regulated at individual receptor platforms.
  • No full-length structure available
  • Chondrocyte-specific mechanism unexplored
  • Coordinate regulation of catalytic vs. scaffold activity not modeled

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0016787 hydrolase activity 7 GO:0098772 molecular function regulator activity 4 GO:0008289 lipid binding 2 GO:0060090 molecular adaptor activity 2
Localization
GO:0005886 plasma membrane 6 GO:0005856 cytoskeleton 4 GO:0005634 nucleus 2 GO:0005654 nucleoplasm 2 GO:0031410 cytoplasmic vesicle 2 GO:0005829 cytosol 1
Pathway
R-HSA-162582 Signal Transduction 8 R-HSA-1430728 Metabolism 3 R-HSA-168256 Immune System 3 R-HSA-5653656 Vesicle-mediated transport 3 R-HSA-1474244 Extracellular matrix organization 2
Partners
ENAHEPHA2FLNAIQGAP2ITSN1LPDNMETSHC1
Complex memberships
Filamin-SHIP2-actin-GPIb-IX-V (platelet)LL5β-Filamin-SHIP2Nephrin-SHIP2-Filamin-Lamellipodin

Evidence

Reading pass · 55 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1998 SHIP2 (51C/SHIP2) hydrolyzes phosphatidylinositol 3,4,5-trisphosphate to phosphatidylinositol 3,4-bisphosphate, and undergoes tyrosine phosphorylation in response to EGF, PDGF, NGF, IGF-1, and insulin; it associates with the Shc adapter protein upon 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; a truncated 103-kDa recombinant protein purified from E. coli retains both activities. Recombinant protein expression in E. coli and COS-7 cells; in vitro phosphatase assays with InsP4 and PtdIns(3,4,5)P3 substrates FEBS letters High 9824312
1999 SHIP2 is constitutively tyrosine-phosphorylated and associated with SHC in CML progenitor cells expressing p210(bcr/abl); SHIP2 selectively hydrolyzes PtdIns(3,4,5)P3 but not Ins(1,3,4,5)P4 in vitro (unlike SHIP1); SHIP2 binds the PTB domain of SHC, selectively binds the SH3 domain of ABL (not Src or GRB2 SH3), and does not bind GRB2 SH3 domains. Mass spectrometric identification, in vitro phosphatase assay, GST-pulldown with SH3/PTB domains, co-immunoprecipitation Blood High 10194451
1999 Overexpression of SHIP2 in insulin-receptor-expressing fibroblasts inhibits insulin-induced Akt activation and MAP kinase activation; SHIP2 undergoes insulin-induced tyrosine phosphorylation and competes with Grb2 SH2 domain for Shc phosphotyrosine, reducing Shc-Grb2 association. Stable overexpression in Rat1-HIRc cells; immunoprecipitation, kinase assays, thymidine incorporation Biochemical and biophysical research communications High 10381377
2000 Overexpression of SHIP-2 in glioblastoma cells abolishes PtdIns(3,4,5)P3 levels while leaving PtdIns(3,4)P2 elevated, reduces PKB phosphorylation and activity, decreases membrane-associated PKB, and causes G1 cell cycle arrest with stabilization of p27KIP1; antisense reduction of SHIP-2 increases PKB activity. Overexpression and antisense oligonucleotides in glioblastoma cells; lipid measurements, PKB kinase assay, cell cycle analysis, p27 immunoblot Molecular and cellular biology High 10958682
2000 SHIP1 and SHIP2 are recruited to the phosphorylated FcγRIIB ITIM via their SH2 domains; the Y+2 leucine residue in the FcγRIIB ITIM is the key determinant for SHIP binding (distinct from the Y-2 isoleucine that determines SHP binding). Loss-of-function and gain-of-function ITIM substitutions; in vitro phosphopeptide binding assays; co-immunoprecipitation from mast cells/B cells The Journal of biological chemistry High 11016922
2001 SHIP-2 binds filamin A, B, and C via its C-terminal proline-rich domain; filamin-dependent localization of SHIP-2 to membrane ruffles is required for its regulation of PtdIns(3,4,5)P3 levels and submembraneous actin; SHIP-2 catalytic activity is required for its effect on actin remodeling. Yeast two-hybrid screening, co-immunoprecipitation from COS-7 cells, immunofluorescence in filamin-deficient cells, growth factor stimulation with lipid measurement The Journal of cell biology High 11739414
2001 SHIP2 associates with the p130(Cas) adapter protein primarily via the SH2 domain of SHIP2; this interaction is stimulated during cell re-attachment; SHIP2 localizes to focal contacts and lamellipodia; wild-type SHIP2 increases adhesion while a catalytic-domain deletion mutant inhibits cell spreading. Co-immunoprecipitation from multiple cell types, immunofluorescence, transfection of SH2 and catalytic mutants with adhesion/spreading assays Molecular and cellular biology High 11158326
2001 SHIP2 overexpression decreases PtdIns(3,4,5)P3 production and Akt/PKB activation in CHO-IR cells stimulated by insulin, and accounts for PtdIns(3,4,5)P3 5-phosphatase activity recovered in anti-phosphotyrosine immunoprecipitates from insulin-stimulated cells. Overexpression in CHO-IR cells, radiolabeled lipid measurement, Akt phosphorylation assay, immunoprecipitation Biochemical and biophysical research communications Medium 11401540
2001 SHIP2 is recruited to activated EGF receptor via co-immunoprecipitation; SHIP2 is tyrosine-phosphorylated at two sites upon EGF stimulation; SHIP2 overexpression in COS-7 cells decreases PtdIns(3,4,5)P3 and PKB activity upon EGF stimulation; C-terminal truncation (not SH2 domain alone) mediates EGFR association. Co-immunoprecipitation, immunofluorescence double-staining, lipid measurement, PKB activity assay in transfected COS-7 cells The Journal of biological chemistry High 11349134
2001 Loss of SHIP2 in mice leads to increased insulin sensitivity, severe neonatal hypoglycemia, deregulated gluconeogenic gene expression, and increased GLUT4 recruitment and glycogen synthesis in skeletal muscle; SHIP2 functions as a potent negative regulator of insulin signaling in vivo. Gene knockout in mice; glucose tolerance tests, insulin tolerance tests, GLUT4 translocation assay, glycogen synthesis assay Nature High 11343120
2002 SHIP2 tyrosine phosphorylation on its NPXY motif (Tyr986-987) by Src family kinases mediates association with Shc during cell attachment to collagen I; Src-mediated SHIP2 phosphorylation is required for normal lamellipodia formation during spreading on collagen I. Src kinase inhibitors, activated/dominant-negative Src constructs, in vitro Src phosphorylation of SHIP2, NPXY motif mutagenesis, immunofluorescence Journal of cell science High 12235291
2003 SHIP-2 and PTEN are expressed and catalytically active in vascular smooth muscle cell nuclei; SHIP-2 (but not PTEN) colocalizes with the SC35 splicing factor at nuclear speckles, suggesting a distinct nuclear function for SHIP-2 in metabolizing PtdIns(3,4,5)P3 to PtdIns(3,4)P2 within the nucleus. Subcellular fractionation, in vitro PtdIns(3,4,5)P3 phosphatase assay on isolated nuclei, immunoprecipitation from nuclear fractions, confocal microscopy with SC35 co-staining The Journal of biological chemistry High 12847108
2003 SHIP-2 forms a tetrameric complex with filamin, actin, and GPIb-IX-V in platelets; the complex is functionally active for PtdIns(3,4,5)P3 5-phosphatase activity; upon platelet activation, SHIP-2 redistributes to the actin ring, filopodia, and lamellipodia. Immunoprecipitation from Triton-soluble platelet fractions, in vitro phosphatase assay on immunoprecipitates, immunofluorescence on spread platelets Blood High 12676785
2003 SHIP2 associates with the CAP (c-Cbl-associated protein) via the SH3C domain of CAP binding to SHIP2's proline-rich domain, and with c-Cbl; SHIP2 also co-immunoprecipitates with the insulin receptor in CHO-IR cells. Yeast two-hybrid, GST-pulldown, co-immunoprecipitation from COS-7 and CHO-IR cells Biochemical and biophysical research communications Medium 12504111
2004 Detailed kinetic analysis reveals SHIP2 substrate rank order: Ins(1,2,3,4,5)P5 > Ins(1,3,4,5)P4 > PtdIns(3,4,5)P3 ≈ PtdIns(3,5)P2 > other inositol phosphates; SHIP2 has broader substrate specificity than previously appreciated, dephosphorylating multiple phosphoinositide species at the 5-position. In vitro enzymatic assays with 54 water-soluble inositol phosphates and four phosphatidylinositol lipid substrates; comparative kinetics with SPsynaptojanin The Journal of biological chemistry High 15316017
2005 SHIP2 deletion mice targeted to the ATG start codon (null for INPPL1 mRNA and protein) are viable with normal glucose and insulin levels but are highly resistant to diet-induced obesity; the original SHIP2 KO phenotype was confounded by co-deletion of Phox2a. Gene targeting at ATG, metabolic phenotyping (glucose tolerance, insulin tolerance), high-fat diet challenge Nature medicine High 15654325
2005 SHIP2 interacts with the cytoskeletal protein Vinexin via SHIP2's C-terminal proline-rich domain; the interaction promotes SHIP2 localization at the cell periphery; cell adhesion to collagen I is enhanced by SHIP2 and requires both SHIP2 catalytic activity and its C-terminus, and is reduced in SHIP2-/- MEFs. Yeast two-hybrid, co-immunoprecipitation from COS-7 and MEF cells, immunofluorescence co-localization, cell adhesion assay with catalytic/C-terminal mutants, SHIP2-/- MEFs The FEBS journal High 16302969
2005 SHIP2 silencing in HeLa cells causes severe F-actin deformities, cell-spreading defects, altered early endosome distribution, enhanced EGFR ubiquitination and degradation, and increased EGFR-c-Cbl association, demonstrating roles for SHIP2 in actin cytoskeleton maintenance and EGFR endocytic trafficking. RNAi knockdown, immunofluorescence for actin/focal contacts/endosomes, EGFR ubiquitination assay, co-immunoprecipitation of EGFR with c-Cbl The Journal of biological chemistry High 15668240
2005 Hepatic overexpression of SHIP2 impairs insulin-induced Akt phosphorylation in liver and increases gluconeogenic gene expression (G6Pase, PEPCK) while decreasing SREBP-1; dominant-negative SHIP2 in db/db mice reverses these effects; SHIP2 action is liver-specific with no effect on muscle or fat insulin signaling. Adenoviral hepatic expression in db/db and db/+m mice; Akt phosphorylation, gluconeogenic gene mRNA quantification, glucose tolerance test Diabetes High 15983195
2006 SHIP2 is recruited to activated EphA2 receptor via a heterotypic SAM-SAM domain interaction; SHIP2 overexpression inhibits EphA2 endocytosis while SHIP2 siRNA knockdown promotes EphA2 internalization and degradation; SHIP2 regulates EphA2 endocytosis via PI3K-dependent Rac1 activation. SAM domain interaction assay, SHIP2 overexpression and siRNA knockdown, EphA2 internalization assay, PI3K inhibitor treatment, dominant-negative Rac1, PIP3 measurement The Journal of biological chemistry High 17135240
2006 Phosphatidylserine vesicles specifically stimulate SHIP2 PtdIns(3,4,5)P3 5-phosphatase activity (but not InsP4 or SKIP activity), and this effect depends on the fatty acid composition of the PtdIns(3,4,5)P3 substrate; both the catalytic domain alone and full-length SHIP2 respond to phosphatidylserine. In vitro phosphatase assays with lipid vesicles of defined composition; comparative study with PTEN and SKIP Cellular signalling High 16824732
2007 SHIP2 directly binds the HGF receptor c-Met via phosphotyrosine 1356; SHIP2 phosphatase activity is required for HGF-induced cell scattering and spreading but not for lamellipodium number; the SHIP2 proline-rich C-terminal domain is required for lamellipodium formation; SHIP2 colocalizes with actin at the leading edge. Co-immunoprecipitation with c-Met, phosphopeptide pulldown, catalytic and proline-rich domain mutants, HGF-induced scattering/spreading assays, immunofluorescence Oncogene High 15735664
2007 SHIP2 depletion in NGF-stimulated PC12 cells markedly potentiates PIP3 accumulation and Rac1/Cdc42 activation, increases neurite number and length; FRET imaging and kinetic modeling indicate SHIP2 creates a negative feedback loop on PIP3 that coordinates with PI3K-positive feedback for proper neurite formation. siRNA knockdown combined with FRET imaging of PIP3 and Rac1/Cdc42 activity, neurite quantification, computational kinetic modeling validated experimentally The Journal of cell biology High 17535963
2007 The PI3K effector Arap3 interacts with SHIP2 via a heterotypic SAM-SAM domain interaction; this interaction is mediated by endogenous proteins and recruits SHIP2 into the PI3K effector complex. Yeast two-hybrid, co-immunoprecipitation of endogenous proteins, in vitro SAM-SAM binding assay Cellular signalling Medium 17314030
2007 Tyrosine phosphorylation of SHIP2 by protein tyrosine phosphatase inhibitor (vanadate) treatment or EGF increases SHIP2 specific activity 5-10-fold and promotes SHIP2 translocation from cytosol to Triton-insoluble fraction, switching PI3K signal output from PtdIns(3,4,5)P3 to PtdIns(3,4)P2. PTP inhibitor treatment, SHIP2 immunoprecipitation with in vitro phosphatase assay, subcellular fractionation, lipid measurements in 1321N1 and HeLa cells The Biochemical journal High 17672824
2008 SHIP2 SAM domain adopts a five-helix bundle and forms a heterodimeric complex with EphA2 SAM domain; a minimal peptide within SHIP2 SAM retains binding affinity for EphA2 SAM, identified by NMR and ITC. NMR spectroscopy, isothermal titration calorimetry (ITC), structure determination of SHIP2 SAM domain Biochemistry High 18991394
2008 SHIP2 associates with intersectin-1 (ITSN1) via SH3 domains D, A, C, and E of ITSN1; upon EGF stimulation, SHIP2 recruits intersectin-1 short form to the cell membrane. Co-immunoprecipitation, SH3 domain mapping, immunofluorescence after EGF treatment FEBS letters Medium 18692052
2008 SHIP2 associates with the adaptor protein APS in adipocytes; SHIP2 negatively regulates APS insulin-induced tyrosine phosphorylation and APS-c-Cbl association; APS increases SHIP2 PtdIns(3,4,5)P3 5-phosphatase activity; co-expression of APS and SHIP2 further suppresses insulin-induced Akt phosphorylation. Co-immunoprecipitation from 3T3-L1 adipocytes and CHO-IR cells, immunofluorescence, in vitro phosphatase assay, Akt phosphorylation assay Journal of cellular physiology Medium 17620296
2009 SHIP2 SAM domain uses the same binding surface (mid-loop/end-helix mode) to interact with both EphA2-SAM and Arap3-SAM; the NMR solution structure of Arap3-SAM was determined and its interaction with SHIP2-SAM characterized by NMR, ITC, mutagenesis, and molecular modeling. NMR structure determination, ITC, mutagenesis of binding interface, molecular modeling BMC structural biology High 19765305
2010 SHIP2 is concentrated at endocytic clathrin-coated pits (CCPs) via interaction with the scaffold protein intersectin; SHIP2 is recruited early at CCPs and dissociates before fission; SHIP2 negatively regulates PI(4,5)P2 levels (in addition to PI(3,4,5)P3); SHIP2 knockdown shortens CCP lifetime by enhancing pit maturation rate. Live-cell imaging, SHIP2 knockdown, intersectin binding assay, PI(4,5)P2 measurement, CCP lifetime analysis The Journal of cell biology High 20679431
2010 Enteropathogenic E. coli recruits SHIP2 to bacterial actin pedestals via tandem ITIM-like sequences (Y483, Y511) in the bacterial effector Tir; SHIP2 generates a PI(3,4)P2-enriched lipid platform recruiting lamellipodin, and engages the adaptor SHC to control F-actin pedestal formation. Mutagenesis of Tir ITIM-like tyrosines, co-immunoprecipitation, PI(3,4)P2 measurement, lamellipodin recruitment assay, bacterial infection assays Cell host & microbe High 20114025
2010 miR-205 targets SHIP2 mRNA in epithelial cells to suppress SHIP2 protein levels and Akt signaling; miR-184 antagonizes miR-205 to maintain SHIP2 levels; SHIP2 silencing or miR-205 overexpression impairs keratinocyte migration via RhoA-ROCK-cofilin inactivation and reduced filamentous actin. Antagomirs, ectopic miRNA expression, siRNA knockdown of SHIP2, scratch wound migration assay, Rho-ROCK activity assay, cofilin phosphorylation, F-actin staining FASEB journal High 20530248
2010 LL5β recruits filamin A and SHIP2 to sites of PtdIns(3,4,5)P3 accumulation at the plasma membrane; SHIP2 recruited to these sites dephosphorylates PtdIns(3,4,5)P3 locally; this mechanism promotes efficient lamellipodium formation in response to EGF. Co-immunoprecipitation, depletion of LL5β/filamin A, overexpression of F-actin crosslinking mutants, EGF-stimulated lamellipodium assay, PtdIns(3,4,5)P3 measurement The Journal of biological chemistry High 20236936
2010 SHIP2 is recruited to the plasma membrane after M-CSF stimulation of macrophages and associates with the M-CSF receptor; membrane localization requires the proline-rich domain (not SH2 domain) and involves filamin; wild-type SHIP2 reduces Akt activation and NF-κB transcription while catalytically deficient SHIP2 enhances Akt; SHIP2 KO macrophages show enhanced Akt activation. Co-immunoprecipitation of SHIP2 with M-CSF receptor, subcellular fractionation, wild-type/mutant SHIP2 expression, Akt phosphorylation, NF-κB reporter assay, SHIP2 KO fetal liver macrophages Journal of immunology High 15557176
2011 SHIP2 is phosphorylated on Ser132 (identified by MS); phospho-Ser132-SHIP2 localizes to nucleus and nuclear speckles in a cell-cycle-dependent manner and has PtdIns(4,5)P2 phosphatase activity; SHIP2 S132A mutant is more resistant to calpain-mediated C-terminal degradation; nuclear lamin A/C is identified as a SHIP2 interactor. Mass spectrometry identification of phosphosites, phospho-specific immunostaining, in vitro phosphatase assay with phospho-SHIP2, calpain digestion assay, co-immunoprecipitation with lamin A/C The Biochemical journal High 21770892
2011 Nephrin activation recruits a complex containing SHIP2, Filamin, and Lamellipodin to regulate lamellipodia formation in podocytes; knockdown of SHIP2, Filamin, or Lamellipodin individually disrupts actin tail architecture and reduces lamellipodia formation and cell migration. CD16-Nephrin clustering system, co-immunoprecipitation, yeast two-hybrid (SHIP2-CD2AP), siRNA knockdown of complex components, immunofluorescence, migration assay PloS one High 22194892
2011 SHIP2 localizes to vaccinia virus actin tails in a phosphotyrosine-, Abl/Src kinase-, and N-WASP-dependent manner (not requiring Arp2/3 or actin); SHIP2-deficient cells release more virus; the viral protein A34 inhibits virus release by recruiting SHIP2 to tails. Immunofluorescence in infected cells, SHIP2 KO cells, kinase inhibitors, viral plaque assay for release, A34-mutant virus Journal of virology High 21543482
2012 NMR structure of EphA2-SHIP2 SAM:SAM heterodimeric complex reveals specific contacts differing from previous models; EphA family (EphA1) but not EphB members bind SHIP2-SAM; an EphB2 SAM variant engineered to bind SHIP2 was created; mutant EphA2 defective in SHIP2 binding reveals SHIP2 suppresses ligand-induced EphA2 activation and promotes EphA2-coordinated chemotactic cell migration. NMR structure determination with NOE, chemical shift perturbation, and RDC restraints; molecular dynamics; mutagenesis of binding interface; functional EphA2 signaling and migration assays Structure High 22244754
2012 SHIP2 is an effector of GTP-loaded RhoA (interacts in a GTP-dependent manner); the SHIP2-RhoA association is observed in spreading/migrating glioma cells; SHIP2 depletion attenuates cell polarization and migration, which is rescued by wild-type SHIP2 but not by a RhoA-binding-defective mutant; RhoA-SHIP2 interaction is required for proper PtdIns(3,4,5)P3 localization. GTPγS-pulldown and co-immunoprecipitation in U251 glioma cells, siRNA knockdown, rescue with wild-type vs. RhoA-binding mutant SHIP2, PIP3 localization by fluorescence Molecular biology of the cell High 22593208
2012 A 2.1 Å crystal structure of the SHIP2 phosphatase domain bound to a synthetic polyphosphoinositide headgroup surrogate (BiPh(2,3',4,5',6)P5) reveals active site architecture; molecular dynamics suggests a flexible loop closes over the ligand upon binding. X-ray crystallography at 2.1 Å, molecular dynamics simulation, enzymatic inhibition assay ACS chemical biology High 22330088
2012 Catalytically inactive SHIP2 knock-in mice show defects in somatic growth, muscle, adipose tissue, and female genital tract development, and altered lipid metabolism, but normal glucose tolerance and insulin sensitivity, indicating that SHIP2's non-catalytic (scaffolding) functions contribute importantly to its in vivo phenotypes. Germline catalytically-inactive SHIP2 knock-in mice; metabolic phenotyping, tissue morphology, genetic epistasis with p110α kinase-dead mice Cellular signalling High 22750293
2012 INPPL1 (SHIP2) loss-of-function mutations (premature stop codons, splice site, and missense mutations in the 5-phosphatase catalytic domain) cause opsismodysplasia, a severe chondrodysplasia; this establishes SHIP2 phosphatase activity as essential for endochondral ossification. Exome sequencing of 16 opsismodysplasia cases, Sanger sequencing confirmation, compound heterozygous and homozygous mutations in catalytic domain American journal of human genetics High 23273569
2013 SHIP2 localizes at invadopodium cores and generates PI(3,4)P2 locally; SHIP2 inhibition reduces mature invadopodia and matrix degradation while SHIP2 overexpression increases degradation; SHIP2 arrival at the invadopodium precursor coincides with PI(3,4)P2 accumulation; SHIP2 does not affect precursor initiation. High-resolution live-cell imaging of invadopodium dynamics, SHIP2 inhibition, SHIP2 overexpression, PI(3,4)P2 and PI(3,4,5)P3 biosensors, gelatin degradation assay Current biology High 24206842
2013 SHIP2 generates PtdIns(3,4)P2 at the basolateral membrane of polarized epithelial cells; PtdIns(3,4)P2 binds Dlg1 (a polarity protein); SHIP2 silencing or catalytic-dead SHIP2 disrupts apicobasal polarity similar to HCV core protein; SHIP2 expression rescues polarity and RhoA activation in HCV core-expressing cells. siRNA knockdown, catalytic-dead SHIP2 expression, immunofluorescence for polarity markers, RhoA/Rac1 activity assays, PtdIns(3,4)P2-Dlg1 binding assay in MDCK and Huh7 cells Molecular biology of the cell High 23699395
2016 The FcγRIIb-SHIP2 axis links Aβ neurotoxicity to tau hyperphosphorylation: Aβ1-42 induces FcγRIIb phosphorylation at Tyr273 which recruits SHIP2, increasing PtdIns(3,4)P2 levels and mediating tau hyperphosphorylation; SHIP2 siRNA or pharmacological inhibition rescues tau pathology and memory in 3xTg-AD mice. FcγRIIb Tyr273 phosphorylation assay, SHIP2 co-immunoprecipitation with FcγRIIb, PtdIns(3,4)P2 measurement, lentiviral SHIP2 siRNA in AD mice, behavioral testing, tau phosphorylation assay eLife High 27834631
2016 SHIP2 controls PI(4,5)P2 levels (in addition to PI(3,4,5)P3) at the plasma membrane; SHIP2 depletion in glioblastoma 1321 N1 cells increases PI(4,5)P2 and decreases PI4P; SHIP2 inhibits cell migration via regulation of PI(4,5)P2 and focal adhesion organization; myosin-1c is identified as a novel SHIP2 interactor. SHIP2 knockdown, PI(4,5)P2 and PI4P immunostaining and quantification, co-immunoprecipitation with myosin-1c, migration assay, focal adhesion imaging Journal of cell science High 26826186
2016 SHIP2 scaffolds Mena (an Ena/VASP actin regulatory protein) to invadopodia via a direct SHIP2-Mena interaction; disruption of SHIP2-Mena interaction attenuates invadopodium-mediated ECM degradation, invasion in vitro, and metastasis in vivo. Biochemical co-immunoprecipitation and GST-pulldown for SHIP2-Mena interaction, structure-function mutagenesis, gelatin degradation assay, transwell invasion, xenograft metastasis model The Journal of cell biology High 27597754
2017 Crystal structures of SHIP2 containing both the 5-phosphatase domain and an adjacent C2 domain reveal an extensive interdomain interface that induces structural changes in the phosphatase domain; the C2 domain and phosphatase domain both bind phosphatidylserine lipids; the C2 domain greatly enhances catalytic turnover via two allosteric signaling pathways (hydrophobic and polar) affecting lipid chain and headgroup moieties of PI(3,4,5)P3 respectively. X-ray crystallography, molecular dynamics simulation, mutagenesis of interdomain interface, in vitro phosphatase activity assays, cell biology with mutants eLife High 28792888
2017 Endothelial-specific catalytic inactivation of one SHIP2 allele (ECSHIP2Δ/+) leads to increased basal PI3K/Akt/eNOS activation, impaired incremental insulin- and shear stress-induced signaling, elevated Nox2-dependent superoxide production, impaired vasodilation, and systemic insulin resistance; SHIP2 silencing in human ECs phenocopies these findings. Endothelial-specific knock-in mice, hyperinsulinemic clamp, ex vivo vasodilation, ROS measurement with PI3K/Nox2 inhibitors, siRNA in human ECs Diabetes High 28830894
2018 SHIP2 enables sustained (not transient) ERK activation downstream of FGFRs by acting as a scaffold (not via its phosphatase activity) to recruit Src family kinases to FGFRs; SHIP2 is phosphorylated by FGFRs and promotes phosphorylation of FRS2 and recruitment of PTPN11; loss of SHIP2 converts sustained FGFR-ERK signaling to transient. SHIP2 KO/KD, phosphatase-dead SHIP2 rescue, SHIP2-FGFR co-immunoprecipitation, FRS2 phosphorylation, PTPN11 recruitment, Src kinase co-immunoprecipitation, ERK activation kinetics Science signaling High 30228226
2018 FBP17 and CIP4 recruit SHIP2 (together with lamellipodin) to plasma membrane patches primed for fast endophilin-mediated endocytosis (FEME); SHIP2 locally produces PI(3,4)P2 enabling endophilin pre-enrichment; membrane-bound GTP-Cdc42 recruits FBP17/CIP4 upstream of SHIP2. Co-localization imaging of BAR domain proteins with endophilin, co-immunoprecipitation of SHIP2 with FBP17/CIP4, PI(3,4)P2 measurement, endocytosis assays in SHIP2-depleted cells, Cdc42 manipulation Nature cell biology High 30061681
2019 PLEK2 directly interacts with SHIP2 and targets it for ubiquitin-dependent proteasomal degradation in NSCLC cells, thereby activating TGF-β/PI3K/AKT signaling to promote EMT and migration. Co-immunoprecipitation of PLEK2 with SHIP2, ubiquitination assay, proteasome inhibitor rescue, SHIP2 overexpression rescue of PLEK2 effects, EMT and migration assays International journal of cancer Medium 31498891
2020 IQGAP2 physically associates with SHIP2 via SHIP2's PRD and SAM domains; IQGAP2 binding increases SHIP2 phosphatase activity; knockdown of either partner promotes gastric cancer cell migration and invasion by reducing SHIP2 activity and activating Akt-EMT signaling. Co-immunoprecipitation, mass spectrometry, SHIP2 domain deletion mapping, in vitro phosphatase activity assay, siRNA knockdown, invasion/migration assays International journal of molecular sciences High 32183047
2022 LINC01468 binds SHIP2 and promotes its CUL4A-mediated ubiquitin-proteasomal degradation, thereby activating PI3K/AKT/mTOR signaling and de novo lipogenesis in HCC. RNA pulldown and co-immunoprecipitation of LINC01468 with SHIP2 and CUL4A, ubiquitination assay, SHIP2 half-life measurement, PI3K/AKT pathway readouts in gain/loss-of-function models Cell death discovery Medium 36344496

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 150 10958682
2013 Tks5 and SHIP2 regulate invadopodium maturation, but not initiation, in breast carcinoma cells. Current biology : CB 132 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 132 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 99 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.) 94 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
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
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 82 12847108
2002 PTEN, but not SHIP and SHIP2, suppresses the PI3K/Akt pathway and induces growth inhibition and apoptosis of myeloma cells. Oncogene 82 12149650
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
2018 FBP17 and CIP4 recruit SHIP2 and lamellipodin to prime the plasma membrane for fast endophilin-mediated endocytosis. Nature cell biology 77 30061681
2009 Discovery and functional characterization of a novel small molecule inhibitor of the intracellular phosphatase, SHIP2. British journal of pharmacology 75 19694723
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 68 11016922
2004 Polymorphisms in type II SH2 domain-containing inositol 5-phosphatase (INPPL1, SHIP2) are associated with physiological abnormalities of the metabolic syndrome. Diabetes 66 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
2005 SHIP2 interaction with the cytoskeletal protein Vinexin. The FEBS journal 53 16302969
2010 Enteropathogenic Escherichia coli recruits the cellular inositol phosphatase SHIP2 to regulate actin-pedestal formation. Cell host & microbe 52 20114025
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
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
2016 FcγRIIb-SHIP2 axis links Aβ to tau pathology by disrupting phosphoinositide metabolism in Alzheimer's disease model. eLife 48 27834631
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
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 48 15735664
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
2017 SHIP2: Structure, Function and Inhibition. Chembiochem : a European journal of chemical biology 40 27907247
2015 Suppression of SHIP2 contributes to tumorigenesis and proliferation of gastric cancer cells via activation of Akt. Journal of gastroenterology 40 26201869
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
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
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
2011 Evidence of SHIP2 Ser132 phosphorylation, its nuclear localization and stability. The Biochemical journal 36 21770892
2006 Regulation of protein kinase B activity by PTEN and SHIP2 in human prostate-derived cell lines. Cellular signalling 36 16842970
2017 Structural basis for interdomain communication in SHIP2 providing high phosphatase activity. eLife 35 28792888
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
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
2010 The inositol phosphatase SHIP2 negatively regulates insulin/IGF-I actions implicated in neuroprotection and memory function in mouse brain. Molecular endocrinology (Baltimore, Md.) 34 20829391
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
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
2009 Inhibitors of the lipid phosphatase SHIP2 discovered by high-throughput affinity selection-mass spectrometry screening of combinatorial libraries. Combinatorial chemistry & high throughput screening 32 19531013
2005 Phosphatidylinositol 3,4,5-trisphosphate modulation in SHIP2-deficient mouse embryonic fibroblasts. The FEBS journal 32 15885100
2022 LINC01468 drives NAFLD-HCC progression through CUL4A-linked degradation of SHIP2. Cell death discovery 31 36344496
2021 Targeting SHIP1 and SHIP2 in Cancer. Cancers 31 33672717
2013 SHIP2 signaling in normal and pathological situations: Its impact on cell proliferation. Advances in biological regulation 30 24091101
2020 Small molecule targeting of SHIP1 and SHIP2. Biochemical Society transactions 29 32049315
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 25 16824732
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
2020 IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity. International journal of molecular sciences 23 32183047
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
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
2010 Glucose metabolism activation by SHIP2 inhibitors via up-regulation of GLUT1 gene in L6 myotubes. European journal of pharmacology 21 20558154
2010 SHIP2, a factor associated with diet-induced obesity and insulin sensitivity, attenuates FGF signaling in vivo. Disease models & mechanisms 21 20616095
2008 The association between the SH2-containing inositol polyphosphate 5-Phosphatase 2 (SHIP2) and the adaptor protein APS has an impact on biochemical properties of both partners. Journal of cellular physiology 21 17620296
2006 APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2. Circulation research 21 16973905