{"gene":"INPPL1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1998,"finding":"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.","method":"Immunoprecipitation with phosphatase activity assay; immunoblot for tyrosine phosphorylation; co-immunoprecipitation with Shc","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1/2 / Strong — direct in vitro enzymatic assay plus Co-IP, replicated across multiple growth factor stimuli in same study; corroborated by multiple subsequent studies","pmids":["9660833"],"is_preprint":false},{"year":1998,"finding":"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.","method":"In vitro enzymatic assay with recombinant truncated protein expressed in E. coli; transfection into COS-7 cells followed by phosphatase activity measurement","journal":"FEBS letters","confidence":"High","confidence_rationale":"Tier 1 / Strong — direct in vitro reconstitution with purified recombinant protein, replicated across two expression systems; substrate specificity difference from SHIP1 confirmed","pmids":["9824312"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Protein purification, mass spectrometry identification, co-immunoprecipitation, in vitro binding assays with SH3 domain constructs, in vitro phosphatase assay","journal":"Blood","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — MS identification, multiple binding assays, in vitro enzymatic assay in a single comprehensive study","pmids":["10194451"],"is_preprint":false},{"year":1999,"finding":"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.","method":"Stable overexpression in Rat1-HIRc cells; immunoprecipitation; kinase assays; [3H]-thymidine incorporation","journal":"Biochemical and biophysical research communications","confidence":"High","confidence_rationale":"Tier 2 / Moderate — overexpression with multiple downstream readouts in intact cells, single lab","pmids":["10381377"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Overexpression and antisense knockdown; lipid quantification; PKB kinase assay; cell cycle analysis; immunoblot for p27","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain- and loss-of-function approaches, multiple orthogonal readouts, single lab","pmids":["10958682"],"is_preprint":false},{"year":2000,"finding":"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.","method":"Loss-of-function and gain-of-function ITIM substitution mutagenesis; in vivo co-immunoprecipitation from B cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — systematic mutagenesis with functional in vivo recruitment assay, defines molecular determinant","pmids":["11016922"],"is_preprint":false},{"year":2001,"finding":"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.)","method":"Gene knockout in mice; glucose/insulin tolerance tests; GLUT4 recruitment assay; glycogen synthesis assay","journal":"Nature","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — clean in vivo KO with multiple metabolic readouts, but confounded by co-deletion of Phox2a as shown by later work","pmids":["11343120"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Yeast two-hybrid screening; co-immunoprecipitation; immunofluorescence; overexpression in filamin-deficient cells; lipid phosphatase assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid discovery confirmed by reciprocal Co-IP, localization studies in filamin-null cells, and functional lipid assay in same study","pmids":["11739414"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Co-immunoprecipitation; immunofluorescence; transient transfection of SH2 and catalytic domain mutants; adhesion/spreading assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP across multiple cell lines, domain-mapping with mutants, localization to focal contacts, functional adhesion/spreading assays all in one study","pmids":["11158326"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Co-immunoprecipitation; immunofluorescence double-staining; transfection with truncation mutants; lipid and PKB activity measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP with mutant dissection, functional lipid/PKB assay, single lab","pmids":["11349134"],"is_preprint":false},{"year":2001,"finding":"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.","method":"Stable overexpression; [32P]-lipid quantification; immunoblot for phospho-Akt and MAPK","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct lipid measurement plus downstream signaling in intact cells, single lab","pmids":["11401540"],"is_preprint":false},{"year":2002,"finding":"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.","method":"Src inhibitor pharmacology; in vitro Src kinase assay with recombinant SHIP2; activated/dominant-negative Src overexpression; site-directed mutagenesis of NPXY; co-immunoprecipitation","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1-2 / Strong — in vitro kinase assay identifies phosphosites, confirmed by mutagenesis and dominant negative/activated kinase, functional lamellipodia readout","pmids":["12235291"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Nuclear fractionation; in vitro PtdIns(3,4,5)P3 phosphatase assay on nuclear extracts; immunoprecipitation from nuclear fractions; confocal microscopy","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — fractionation plus nuclear phosphatase activity assay plus localization, single lab","pmids":["12847108"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Co-immunoprecipitation from platelet lysates; phosphatase activity assay on immunoprecipitates; immunofluorescence on spread platelets","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP demonstrating tetrameric complex, functional phosphatase activity measured, localization in activated platelets, corroborates filamin interaction from prior work","pmids":["12676785"],"is_preprint":false},{"year":2003,"finding":"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.","method":"Yeast two-hybrid; GST pulldown; co-immunoprecipitation","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — yeast two-hybrid confirmed by GST pulldown and Co-IP, single lab, no functional follow-up for individual interactions","pmids":["12504111"],"is_preprint":false},{"year":2004,"finding":"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.","method":"In vitro kinetic assay with 54 water-soluble inositol phosphates and 4 phosphatidylinositol lipids; comparative analysis with S. pombe synaptojanin","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — comprehensive in vitro kinetic substrate profiling with recombinant enzyme, multiple substrates tested","pmids":["15316017"],"is_preprint":false},{"year":2005,"finding":"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.","method":"siRNA knockdown; immunofluorescence (F-actin, EEA1, EGFR); receptor degradation assay; co-immunoprecipitation of EGFR/c-Cbl","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — RNAi loss-of-function with multiple orthogonal cellular readouts (cytoskeleton, endocytosis, receptor degradation, ubiquitination)","pmids":["15668240"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Yeast two-hybrid; co-immunoprecipitation from COS-7 and MEF cells; immunofluorescence; adhesion assay; catalytic and C-terminal mutants; SHIP2-/- MEF cells","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — yeast two-hybrid confirmed by Co-IP, domain mapping, KO cell functional assay, multiple mutants","pmids":["16302969"],"is_preprint":false},{"year":2005,"finding":"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.","method":"siRNA knockdown (~90% depletion); phospho-Akt, phospho-GSK-3α immunoblot; [3H]-deoxyglucose transport assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — highly efficient RNAi with multiple quantitative readouts; negative finding for SHIP2's role in insulin signaling in this specific cell type","pmids":["15824124"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Adenoviral vector-mediated liver-specific overexpression/dominant-negative expression; phospho-Akt immunoblot; qRT-PCR for metabolic genes; oral glucose tolerance test","journal":"Diabetes","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo gain- and loss-of-function in two mouse models with multiple molecular and metabolic readouts","pmids":["15983195"],"is_preprint":false},{"year":2005,"finding":"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.","method":"Co-immunoprecipitation; site-directed mutagenesis of c-Met Y1356; overexpression of catalytic and proline-rich domain mutants; cell scattering/spreading assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding site identified by mutagenesis, domain-function analysis with multiple mutants, single lab","pmids":["15735664"],"is_preprint":false},{"year":2006,"finding":"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.","method":"Co-immunoprecipitation; siRNA knockdown; SAM domain interaction assay; lipid quantification; Rac1-GTP pull-down; dominant-negative Rac1 overexpression; receptor internalization/degradation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — SAM-SAM interaction shown by Co-IP, gain and loss-of-function with multiple pathway readouts including Rac1 epistasis","pmids":["17135240"],"is_preprint":false},{"year":2007,"finding":"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.","method":"Yeast two-hybrid screen; co-immunoprecipitation of endogenous proteins; in vitro SAM-SAM interaction assay","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — endogenous Co-IP plus in vitro binding, single lab","pmids":["17314030"],"is_preprint":false},{"year":2007,"finding":"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.","method":"PTP inhibitor treatment; SHIP2 immunoprecipitation with specific activity measurement; subcellular fractionation; lipid quantification","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical measurement of activity in immunoprecipitates, subcellular fractionation, single lab","pmids":["17672824"],"is_preprint":false},{"year":2007,"finding":"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).","method":"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","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell FRET imaging, siRNA loss-of-function, computational model experimentally validated, multiple orthogonal readouts","pmids":["17535963"],"is_preprint":false},{"year":2008,"finding":"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.","method":"NMR spectroscopy; ITC (isothermal titration calorimetry); chemical shift perturbation mapping","journal":"Biochemistry","confidence":"High","confidence_rationale":"Tier 1 / Moderate — NMR structure with ITC binding validation in a single focused study","pmids":["18991394"],"is_preprint":false},{"year":2008,"finding":"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.","method":"Co-immunoprecipitation; domain mapping with ITSN1 SH3 domain constructs; immunofluorescence after EGF stimulation","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP confirmed in vivo, domain mapping, localization change, single lab","pmids":["18692052"],"is_preprint":false},{"year":2010,"finding":"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.","method":"TIRF live-cell imaging of CCP dynamics; siRNA knockdown; intersectin co-immunoprecipitation; lipid level measurement","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell TIRF imaging quantifying CCP lifetime, siRNA KD, intersectin interaction, multiple substrates examined","pmids":["20679431"],"is_preprint":false},{"year":2010,"finding":"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.","method":"siRNA knockdown; mutagenesis of Tir ITIM sequences; PI(3,4)P2 localization; co-immunoprecipitation with SHC; lamellipodin localization assay","journal":"Cell host & microbe","confidence":"High","confidence_rationale":"Tier 2 / Strong — mutagenesis of bacterial effector binding site, SHIP2 KD, lipid product localization, functional pedestal formation assay","pmids":["20114025"],"is_preprint":false},{"year":2010,"finding":"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.","method":"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","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — GTP-dependent binding assay, siRNA KD, domain mutant rescue, functional polarity/migration and lipid localization readouts","pmids":["22593208"],"is_preprint":false},{"year":2011,"finding":"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.","method":"Co-immunoprecipitation of Nephrin complex; siRNA knockdown of SHIP2, Filamin, Lamellipodin; immunofluorescence of actin; cell migration assay","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — complex Co-IP, individual KD with functional readouts, single lab","pmids":["22194892"],"is_preprint":false},{"year":2011,"finding":"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.","method":"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","journal":"The Biochemical journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS phosphosite ID with functional activity assay, localization, and interactor Co-IP, single lab","pmids":["21770892"],"is_preprint":false},{"year":2012,"finding":"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.","method":"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","journal":"Structure","confidence":"High","confidence_rationale":"Tier 1 / Strong — NMR structure with extensive restraints, validated by mutagenesis, ITC, and cell-based functional assays in one study","pmids":["22244754"],"is_preprint":false},{"year":2012,"finding":"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.","method":"Exome sequencing; Sanger sequencing confirmation; 12 distinct mutations in 10 unrelated families at homozygous or compound heterozygous state","journal":"American journal of human genetics","confidence":"High","confidence_rationale":"Tier 2 / Strong — independent mutations in 10 unrelated families with consistent phenotype; missense mutations in catalytic domain confirm functional requirement","pmids":["23273569"],"is_preprint":false},{"year":2012,"finding":"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.","method":"X-ray crystallography at 2.1 Å; molecular dynamics simulation; in vitro phosphatase inhibition assay","journal":"ACS chemical biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure with functional inhibition assay and MD simulation in one study","pmids":["22330088"],"is_preprint":false},{"year":2013,"finding":"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.","method":"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","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct lipid-protein binding demonstrated, catalytic dead mutant phenotype, rescue experiment, Rho GTPase readouts","pmids":["23699395"],"is_preprint":false},{"year":2013,"finding":"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.","method":"High-resolution spatiotemporal live-cell imaging; pharmacological SHIP2 inhibition; SHIP2 overexpression; PI(3,4)P2 biosensor imaging; matrix degradation assay","journal":"Current biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — live-cell imaging with lipid biosensor, gain and loss-of-function, functional ECM degradation assay","pmids":["24206842"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation; structure-function analysis of SHIP2-Mena interaction; siRNA/mutant rescue assays; in vitro invasion assay; in vivo metastasis mouse model","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — biochemical interaction identified, domain-mapping, in vitro and in vivo functional consequences, selectivity for Mena over VASP shown","pmids":["27597754"],"is_preprint":false},{"year":2016,"finding":"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.","method":"Co-immunoprecipitation; phospho-specific antibody detection of FcγRIIb Tyr273; lipid quantification; lentiviral siRNA knockdown; pharmacological SHIP2 inhibition; behavioral memory tests in 3xTg-AD mice","journal":"eLife","confidence":"High","confidence_rationale":"Tier 2 / Strong — direct FcγRIIb-SHIP2 complex formation, lipid measurements, multiple intervention approaches (KO, antibody, siRNA, inhibitor) with functional outcomes","pmids":["27834631"],"is_preprint":false},{"year":2016,"finding":"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.","method":"siRNA knockdown; immunofluorescence with PI(4,5)P2/PI4P antibodies; co-immunoprecipitation with myosin-1c; cell migration assay; focal adhesion staining","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — lipid level changes measured, new interactor identified by Co-IP, functional migration and focal adhesion readouts, single lab","pmids":["26826186"],"is_preprint":false},{"year":2017,"finding":"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.","method":"X-ray crystallography; mutagenesis of interdomain contacts; molecular dynamics simulation; in vitro phosphatase activity assay; cell biology assays","journal":"eLife","confidence":"High","confidence_rationale":"Tier 1 / Strong — crystal structure combined with mutagenesis, MD, and functional in vitro/cell assays in one study","pmids":["28792888"],"is_preprint":false},{"year":2018,"finding":"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.","method":"siRNA knockdown; phosphatase-dead mutant expression; co-immunoprecipitation of FGFR complexes; phospho-ERK/FRS2/PTPN11 immunoblot; rescue experiments","journal":"Science signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — gain/loss-of-function, phosphatase-dead mutant separating catalytic from adaptor function, co-IP of multi-protein FGFR complex, multiple orthogonal readouts","pmids":["30228226"],"is_preprint":false},{"year":2018,"finding":"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.","method":"Co-localization imaging; co-immunoprecipitation; siRNA knockdown; live-cell endocytosis assays; GTPase activity manipulation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple interacting proteins identified, pathway ordering via Cdc42-FBP17/CIP4-SHIP2 axis, functional endocytosis assay, replicated across labs (multi-author study)","pmids":["30061681"],"is_preprint":false},{"year":2019,"finding":"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.","method":"Co-immunoprecipitation; ubiquitination assay; SHIP2 protein stability assay; SHIP2 overexpression rescue experiment; signaling pathway analysis","journal":"International journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 / Moderate — direct Co-IP plus ubiquitination assay, rescue by SHIP2 overexpression, single lab","pmids":["31498891"],"is_preprint":false},{"year":2006,"finding":"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.","method":"In vitro phosphatase assay with lipid vesicles; recombinant minimal catalytic construct and full-length SHIP2","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical assay with recombinant protein and lipid vesicles; specificity demonstrated by comparison with SKIP and soluble substrate; single lab","pmids":["16824732"],"is_preprint":false},{"year":2020,"finding":"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.","method":"Co-immunoprecipitation and mass spectrometry; domain deletion mutant analysis; SHIP2 phosphatase activity assay; siRNA knockdown of IQGAP2; migration/invasion assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MS-confirmed interaction, domain mapping, direct phosphatase activity measurement, functional siRNA rescue, single lab","pmids":["32183047"],"is_preprint":false}],"current_model":"SHIP2 (INPPL1) is a PH domain-independent inositol 5-phosphatase that dephosphorylates PtdIns(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane (and PI(4,5)P2 to PI4P in nuclear speckles), acting as a negative regulator of PI3K/Akt signaling in insulin, growth factor, FGF, EGF, HGF, and M-CSF pathways; it is recruited to activated receptors (EGFR, EphA2 via SAM-SAM interaction, c-Met via pY1356, FcγRIIB via ITIM, FGFRs as adaptor) and to endocytic clathrin-coated pits via intersectin, where it shapes phosphoinositide landscapes to regulate actin cytoskeleton remodeling, cell adhesion/spreading, invadopodium maturation, receptor endocytosis, cell polarity, and FEME priming; its C2 domain allosterically enhances catalytic activity, phosphorylation at Ser132 and Tyr residues modulates activity and localization, and loss-of-function mutations in the catalytic domain cause opsismodysplasia, while it also functions as a scaffold (independent of catalytic activity) to recruit Src kinases to FGFRs for sustained ERK activation and to recruit Mena to invadopodia."},"narrative":{"mechanistic_narrative":"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].","teleology":[{"year":1998,"claim":"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","pmids":["9660833","9824312"],"confidence":"High","gaps":["In-cell substrate specificity inferred from in vitro assays","Mechanism coupling receptor activation to phosphatase recruitment not yet defined"]},{"year":1999,"claim":"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","pmids":["10381377","10194451"],"confidence":"High","gaps":["Overexpression may not reflect endogenous stoichiometry","Physiological relevance of ABL SH3 binding not functionally tested"]},{"year":2000,"claim":"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","pmids":["10958682"],"confidence":"High","gaps":["Mechanism by which PtdIns(3,4)P2 versus PtdIns(3,4,5)P3 controls PKB not resolved","Single cell model"]},{"year":2001,"claim":"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","pmids":["11739414","11158326","11349134","11016922","11401540"],"confidence":"High","gaps":["Relative contribution of each adaptor in vivo unclear","How localization couples to catalytic output not quantified"]},{"year":2002,"claim":"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","pmids":["12235291"],"confidence":"High","gaps":["Matrix-specificity mechanism (collagen I vs others) unexplained","Effect of phosphorylation on catalytic activity not measured here"]},{"year":2003,"claim":"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","pmids":["12847108","12676785"],"confidence":"Medium","gaps":["Nuclear substrate and function not defined","Functional consequence of platelet complex dissociation untested"]},{"year":2004,"claim":"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","pmids":["15316017"],"confidence":"High","gaps":["In-cell relevance of non-canonical substrates unknown","No structural basis for broad specificity at this stage"]},{"year":2005,"claim":"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","pmids":["15983195","15824124","15668240","16302969"],"confidence":"High","gaps":["Reconciling tissue-specific metabolic roles incomplete","Mechanistic basis for adipocyte non-responsiveness unexplained"]},{"year":2006,"claim":"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","pmids":["17135240","16824732"],"confidence":"High","gaps":["Structural detail of SAM-SAM interface not yet solved here","Link between membrane lipid environment and in vivo activity correlative"]},{"year":2007,"claim":"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","pmids":["17672824","17314030"],"confidence":"Medium","gaps":["Physiological kinase/stimulus for activation not defined","Functional role of Arap3 interaction untested"]},{"year":2007,"claim":"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","pmids":["17535963"],"confidence":"High","gaps":["In vivo neuronal relevance not established","Molecular link from Rac1 to SHIP2 regulation inferred from modeling"]},{"year":2010,"claim":"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","pmids":["20679431","20114025"],"confidence":"High","gaps":["Quantitative contribution of PI(4,5)P2 versus PI(3,4,5)P3 turnover to CCP maturation not fully separated"]},{"year":2011,"claim":"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","pmids":["22593208","21770892","22194892"],"confidence":"Medium","gaps":["Kinase responsible for Ser132 phosphorylation unknown","Nuclear PI(4,5)P2 substrate function not mechanistically linked to phenotypes"]},{"year":2012,"claim":"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","pmids":["22330088","22244754","18991394","23273569"],"confidence":"High","gaps":["Mechanism linking phosphatase loss to growth-plate disorganization not detailed","Tissue-specific substrate in cartilage unidentified"]},{"year":2013,"claim":"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","pmids":["23699395","24206842"],"confidence":"High","gaps":["How SHIP2 is spatially restricted to invadopodium cores not fully resolved"]},{"year":2016,"claim":"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","pmids":["27597754","27834631","26826186"],"confidence":"High","gaps":["Selectivity of Mena over VASP recruitment mechanistically unexplained","Causality of PI(4,5)P2 control on adhesion turnover correlative in single model"]},{"year":2018,"claim":"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","pmids":["30228226","30061681"],"confidence":"High","gaps":["How a single protein partitions between adaptor and catalytic roles in cells unresolved"]},{"year":2019,"claim":"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","pmids":["31498891","32183047"],"confidence":"Medium","gaps":["Single-lab findings without in vivo validation","Mechanism of IQGAP2-mediated activity enhancement not structurally defined"]},{"year":null,"claim":"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.","evidence":"","pmids":[],"confidence":"Medium","gaps":["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":{"molecular_activity":[{"term_id":"GO:0016787","term_label":"hydrolase activity","supporting_discovery_ids":[0,1,4,15,40,44]},{"term_id":"GO:0140098","term_label":"catalytic activity, acting on RNA","supporting_discovery_ids":[0,1,15,31,39]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[35,40,44]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[41,37,28]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[3,4,10,24]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7,9,27,39,42]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[7,23,31]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[8,13,16,36]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[12,31]},{"term_id":"GO:0005654","term_label":"nucleoplasm","supporting_discovery_ids":[12,31]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,4,10,21,41]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[16,21,27,42]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[33]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,19]}],"complexes":["filamin–actin–GPIb-IX-V platelet complex","Nephrin–Filamin–Lamellipodin complex","FGFR–Src–FRS2–PTPN11 signaling complex"],"partners":["SHC1","FLNA","BCAR1","EPHA2","ITSN1","ENAH","FCGR2B","MET"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"O15357","full_name":"Phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase 2","aliases":["Inositol polyphosphate phosphatase-like protein 1","INPPL-1","Protein 51C","SH2 domain-containing inositol 5'-phosphatase 2","SH2 domain-containing inositol phosphatase 2","SHIP-2"],"length_aa":1258,"mass_kda":138.6,"function":"Phosphatidylinositol (PtdIns) phosphatase that specifically hydrolyzes the 5-phosphate of phosphatidylinositol-3,4,5-trisphosphate (PtdIns(3,4,5)P3) to produce PtdIns(3,4)P2, thereby negatively regulating the PI3K (phosphoinositide 3-kinase) pathways (PubMed:16824732). Required for correct mitotic spindle orientation and therefore progression of mitosis (By similarity). Plays a central role in regulation of PI3K-dependent insulin signaling, although the precise molecular mechanisms and signaling pathways remain unclear (PubMed:9660833). While overexpression reduces both insulin-stimulated MAP kinase and Akt activation, its absence does not affect insulin signaling or GLUT4 trafficking (By similarity). Confers resistance to dietary obesity (By similarity). May act by regulating AKT2, but not AKT1, phosphorylation at the plasma membrane (By similarity). Part of a signaling pathway that regulates actin cytoskeleton remodeling (PubMed:11739414, PubMed:12676785). Required for the maintenance and dynamic remodeling of actin structures as well as in endocytosis, having a major impact on ligand-induced EGFR internalization and degradation (PubMed:15668240). Participates in regulation of cortical and submembraneous actin by hydrolyzing PtdIns(3,4,5)P3 thereby regulating membrane ruffling (PubMed:21624956). Regulates cell adhesion and cell spreading (PubMed:12235291). Required for HGF-mediated lamellipodium formation, cell scattering and spreading (PubMed:15735664). Acts as a negative regulator of EPHA2 receptor endocytosis by inhibiting via PI3K-dependent Rac1 activation (PubMed:17135240). Acts as a regulator of neuritogenesis by regulating PtdIns(3,4,5)P3 level and is required to form an initial protrusive pattern, and later, maintain proper neurite outgrowth (By similarity). Acts as a negative regulator of the FC-gamma-RIIA receptor (FCGR2A) (PubMed:12690104). Mediates signaling from the FC-gamma-RIIB receptor (FCGR2B), playing a central role in terminating signal transduction from activating immune/hematopoietic cell receptor systems (PubMed:11016922). Involved in EGF signaling pathway (PubMed:11349134). Upon stimulation by EGF, it is recruited by EGFR and dephosphorylates PtdIns(3,4,5)P3 (PubMed:11349134). Plays a negative role in regulating the PI3K-PKB pathway, possibly by inhibiting PKB activity (PubMed:11349134). Down-regulates Fc-gamma-R-mediated phagocytosis in macrophages independently of INPP5D/SHIP1 (By similarity). In macrophages, down-regulates NF-kappa-B-dependent gene transcription by regulating macrophage colony-stimulating factor (M-CSF)-induced signaling (By similarity). Plays a role in the localization of AURKA and NEDD9/HEF1 to the basolateral membrane at interphase in polarized cysts, thereby mediates cell cycle homeostasis, cell polarization and cilia assembly (By similarity). Additionally promotion of cilia growth is also facilitated by hydrolysis of (PtdIns(3,4,5)P3) to PtdIns(3,4)P2 (By similarity). Promotes formation of apical membrane-initiation sites during the initial stages of lumen formation via Rho family-induced actin filament organization and CTNNB1 localization to cell-cell contacts (By similarity). May also hydrolyze PtdIns(1,3,4,5)P4, and could thus affect the levels of the higher inositol polyphosphates like InsP6. Involved in endochondral ossification (PubMed:23273569)","subcellular_location":"Cytoplasm, cytosol; Cytoplasm, cytoskeleton; Membrane; Cell projection, filopodium; Cell projection, lamellipodium; Basal cell membrane; Nucleus; Nucleus speckle; Cytoplasm, cytoskeleton, spindle pole","url":"https://www.uniprot.org/uniprotkb/O15357/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/INPPL1","classification":"Not Classified","n_dependent_lines":5,"n_total_lines":1208,"dependency_fraction":0.0041390728476821195},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000165458","cell_line_id":"CID000140","localizations":[{"compartment":"cytoplasmic","grade":3},{"compartment":"vesicles","grade":1}],"interactors":[{"gene":"TMSB4X","stoichiometry":10.0},{"gene":"NQO1","stoichiometry":4.0},{"gene":"METTL3","stoichiometry":0.2},{"gene":"MYH14","stoichiometry":0.2},{"gene":"TMSB10","stoichiometry":0.2},{"gene":"BASP1","stoichiometry":0.2},{"gene":"ACLY","stoichiometry":0.2},{"gene":"AHNAK","stoichiometry":0.2},{"gene":"AKR1C2;AKR1C1","stoichiometry":0.2},{"gene":"TALDO1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000140","total_profiled":1310},"omim":[{"mim_id":"617314","title":"SH3 DOMAIN- AND SYLF DOMAIN-CONTAINING PROTEIN 1; SH3YL1","url":"https://www.omim.org/entry/617314"},{"mim_id":"613147","title":"MICRO RNA 205; MIR205","url":"https://www.omim.org/entry/613147"},{"mim_id":"613146","title":"MICRO RNA 184; MIR184","url":"https://www.omim.org/entry/613146"},{"mim_id":"600829","title":"INOSITOL POLYPHOSPHATE PHOSPHATASE-LIKE 1; INPPL1","url":"https://www.omim.org/entry/600829"},{"mim_id":"258480","title":"OPSISMODYSPLASIA; OPSMD","url":"https://www.omim.org/entry/258480"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Cytosol","reliability":"Supported"},{"location":"Golgi apparatus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/INPPL1"},"hgnc":{"alias_symbol":["SHIP2"],"prev_symbol":[]},"alphafold":{"accession":"O15357","domains":[{"cath_id":"3.30.505.10","chopping":"23-117","consensus_level":"high","plddt":84.3642,"start":23,"end":117},{"cath_id":"2.30.29.30","chopping":"311-319_331-417","consensus_level":"high","plddt":81.0608,"start":311,"end":417},{"cath_id":"3.60.10.10","chopping":"424-729","consensus_level":"high","plddt":93.2782,"start":424,"end":729},{"cath_id":"2.60.40.150","chopping":"748-882","consensus_level":"high","plddt":90.1564,"start":748,"end":882},{"cath_id":"1.10.150.50","chopping":"1205-1258","consensus_level":"high","plddt":85.7811,"start":1205,"end":1258}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/O15357","model_url":"https://alphafold.ebi.ac.uk/files/AF-O15357-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-O15357-F1-predicted_aligned_error_v6.png","plddt_mean":69.25},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=INPPL1","jax_strain_url":"https://www.jax.org/strain/search?query=INPPL1"},"sequence":{"accession":"O15357","fasta_url":"https://rest.uniprot.org/uniprotkb/O15357.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/O15357/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/O15357"}},"corpus_meta":[{"pmid":"11343120","id":"PMC_11343120","title":"The lipid phosphatase SHIP2 controls insulin sensitivity.","date":"2001","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/11343120","citation_count":292,"is_preprint":false},{"pmid":"19033458","id":"PMC_19033458","title":"MicroRNA-184 antagonizes microRNA-205 to maintain SHIP2 levels in epithelia.","date":"2008","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/19033458","citation_count":240,"is_preprint":false},{"pmid":"15654325","id":"PMC_15654325","title":"Absence of the lipid phosphatase SHIP2 confers resistance to dietary obesity.","date":"2005","source":"Nature medicine","url":"https://pubmed.ncbi.nlm.nih.gov/15654325","citation_count":207,"is_preprint":false},{"pmid":"10958682","id":"PMC_10958682","title":"5' phospholipid phosphatase SHIP-2 causes protein kinase B inactivation and cell cycle arrest in glioblastoma cells.","date":"2000","source":"Molecular and cellular 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letters","url":"https://pubmed.ncbi.nlm.nih.gov/18692052","citation_count":26,"is_preprint":false},{"pmid":"16824732","id":"PMC_16824732","title":"The influence of anionic lipids on SHIP2 phosphatidylinositol 3,4,5-trisphosphate 5-phosphatase activity.","date":"2006","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/16824732","citation_count":26,"is_preprint":false},{"pmid":"32183047","id":"PMC_32183047","title":"IQGAP2 Inhibits Migration and Invasion of Gastric Cancer Cells via Elevating SHIP2 Phosphatase Activity.","date":"2020","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/32183047","citation_count":24,"is_preprint":false},{"pmid":"17893321","id":"PMC_17893321","title":"Serum withdrawal-induced accumulation of phosphoinositide 3-kinase lipids in differentiating 3T3-L6 myoblasts: distinct roles for Ship2 and PTEN.","date":"2007","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/17893321","citation_count":24,"is_preprint":false},{"pmid":"17596404","id":"PMC_17596404","title":"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.","date":"2007","source":"Diabetes","url":"https://pubmed.ncbi.nlm.nih.gov/17596404","citation_count":23,"is_preprint":false},{"pmid":"22750293","id":"PMC_22750293","title":"Developmental defects and rescue from glucose intolerance of a catalytically-inactive novel Ship2 mutant mouse.","date":"2012","source":"Cellular signalling","url":"https://pubmed.ncbi.nlm.nih.gov/22750293","citation_count":23,"is_preprint":false},{"pmid":"20558154","id":"PMC_20558154","title":"Glucose metabolism activation by SHIP2 inhibitors via up-regulation of GLUT1 gene in L6 myotubes.","date":"2010","source":"European journal of pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/20558154","citation_count":23,"is_preprint":false},{"pmid":"21543482","id":"PMC_21543482","title":"The host phosphoinositide 5-phosphatase SHIP2 regulates dissemination of vaccinia virus.","date":"2011","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/21543482","citation_count":23,"is_preprint":false},{"pmid":"28857346","id":"PMC_28857346","title":"ZIC2 promotes viability and invasion of human osteosarcoma cells by suppressing SHIP2 expression and activating PI3K/AKT pathways.","date":"2017","source":"Journal of cellular biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/28857346","citation_count":22,"is_preprint":false},{"pmid":"16973905","id":"PMC_16973905","title":"APOE4-VLDL inhibits the HDL-activated phosphatidylinositol 3-kinase/Akt Pathway via the phosphoinositol phosphatase SHIP2.","date":"2006","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/16973905","citation_count":21,"is_preprint":false},{"pmid":"29234063","id":"PMC_29234063","title":"The Sam-Sam interaction between Ship2 and the EphA2 receptor: design and analysis of peptide inhibitors.","date":"2017","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29234063","citation_count":21,"is_preprint":false},{"pmid":"20616095","id":"PMC_20616095","title":"SHIP2, a factor associated with diet-induced obesity and insulin sensitivity, attenuates FGF signaling in vivo.","date":"2010","source":"Disease models & mechanisms","url":"https://pubmed.ncbi.nlm.nih.gov/20616095","citation_count":21,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":53656,"output_tokens":12589,"usd":0.174901,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":23946,"output_tokens":6264,"usd":0.138165,"stage2_stop_reason":"end_turn"},"total_usd":0.313066,"stage1_batch_id":"msgbatch_01DUPACZi7AAWwuZiUjseQF4","stage2_batch_id":"msgbatch_018yt7chE3f48PEFtDwtj6AE","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"Immunoprecipitation with phosphatase activity assay; immunoblot for tyrosine phosphorylation; co-immunoprecipitation with Shc\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1/2 / Strong — direct in vitro enzymatic assay plus Co-IP, replicated across multiple growth factor stimuli in same study; corroborated by multiple subsequent studies\",\n      \"pmids\": [\"9660833\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro enzymatic assay with recombinant truncated protein expressed in E. coli; transfection into COS-7 cells followed by phosphatase activity measurement\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — direct in vitro reconstitution with purified recombinant protein, replicated across two expression systems; substrate specificity difference from SHIP1 confirmed\",\n      \"pmids\": [\"9824312\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Protein purification, mass spectrometry identification, co-immunoprecipitation, in vitro binding assays with SH3 domain constructs, in vitro phosphatase assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — MS identification, multiple binding assays, in vitro enzymatic assay in a single comprehensive study\",\n      \"pmids\": [\"10194451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"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.\",\n      \"method\": \"Stable overexpression in Rat1-HIRc cells; immunoprecipitation; kinase assays; [3H]-thymidine incorporation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — overexpression with multiple downstream readouts in intact cells, single lab\",\n      \"pmids\": [\"10381377\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Overexpression and antisense knockdown; lipid quantification; PKB kinase assay; cell cycle analysis; immunoblot for p27\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain- and loss-of-function approaches, multiple orthogonal readouts, single lab\",\n      \"pmids\": [\"10958682\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"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.\",\n      \"method\": \"Loss-of-function and gain-of-function ITIM substitution mutagenesis; in vivo co-immunoprecipitation from B cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — systematic mutagenesis with functional in vivo recruitment assay, defines molecular determinant\",\n      \"pmids\": [\"11016922\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.)\",\n      \"method\": \"Gene knockout in mice; glucose/insulin tolerance tests; GLUT4 recruitment assay; glycogen synthesis assay\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — clean in vivo KO with multiple metabolic readouts, but confounded by co-deletion of Phox2a as shown by later work\",\n      \"pmids\": [\"11343120\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screening; co-immunoprecipitation; immunofluorescence; overexpression in filamin-deficient cells; lipid phosphatase assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid discovery confirmed by reciprocal Co-IP, localization studies in filamin-null cells, and functional lipid assay in same study\",\n      \"pmids\": [\"11739414\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence; transient transfection of SH2 and catalytic domain mutants; adhesion/spreading assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP across multiple cell lines, domain-mapping with mutants, localization to focal contacts, functional adhesion/spreading assays all in one study\",\n      \"pmids\": [\"11158326\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; immunofluorescence double-staining; transfection with truncation mutants; lipid and PKB activity measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP with mutant dissection, functional lipid/PKB assay, single lab\",\n      \"pmids\": [\"11349134\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"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.\",\n      \"method\": \"Stable overexpression; [32P]-lipid quantification; immunoblot for phospho-Akt and MAPK\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct lipid measurement plus downstream signaling in intact cells, single lab\",\n      \"pmids\": [\"11401540\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"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.\",\n      \"method\": \"Src inhibitor pharmacology; in vitro Src kinase assay with recombinant SHIP2; activated/dominant-negative Src overexpression; site-directed mutagenesis of NPXY; co-immunoprecipitation\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 / Strong — in vitro kinase assay identifies phosphosites, confirmed by mutagenesis and dominant negative/activated kinase, functional lamellipodia readout\",\n      \"pmids\": [\"12235291\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Nuclear fractionation; in vitro PtdIns(3,4,5)P3 phosphatase assay on nuclear extracts; immunoprecipitation from nuclear fractions; confocal microscopy\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — fractionation plus nuclear phosphatase activity assay plus localization, single lab\",\n      \"pmids\": [\"12847108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation from platelet lysates; phosphatase activity assay on immunoprecipitates; immunofluorescence on spread platelets\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP demonstrating tetrameric complex, functional phosphatase activity measured, localization in activated platelets, corroborates filamin interaction from prior work\",\n      \"pmids\": [\"12676785\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid; GST pulldown; co-immunoprecipitation\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — yeast two-hybrid confirmed by GST pulldown and Co-IP, single lab, no functional follow-up for individual interactions\",\n      \"pmids\": [\"12504111\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro kinetic assay with 54 water-soluble inositol phosphates and 4 phosphatidylinositol lipids; comparative analysis with S. pombe synaptojanin\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — comprehensive in vitro kinetic substrate profiling with recombinant enzyme, multiple substrates tested\",\n      \"pmids\": [\"15316017\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; immunofluorescence (F-actin, EEA1, EGFR); receptor degradation assay; co-immunoprecipitation of EGFR/c-Cbl\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — RNAi loss-of-function with multiple orthogonal cellular readouts (cytoskeleton, endocytosis, receptor degradation, ubiquitination)\",\n      \"pmids\": [\"15668240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid; co-immunoprecipitation from COS-7 and MEF cells; immunofluorescence; adhesion assay; catalytic and C-terminal mutants; SHIP2-/- MEF cells\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — yeast two-hybrid confirmed by Co-IP, domain mapping, KO cell functional assay, multiple mutants\",\n      \"pmids\": [\"16302969\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown (~90% depletion); phospho-Akt, phospho-GSK-3α immunoblot; [3H]-deoxyglucose transport assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — highly efficient RNAi with multiple quantitative readouts; negative finding for SHIP2's role in insulin signaling in this specific cell type\",\n      \"pmids\": [\"15824124\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Adenoviral vector-mediated liver-specific overexpression/dominant-negative expression; phospho-Akt immunoblot; qRT-PCR for metabolic genes; oral glucose tolerance test\",\n      \"journal\": \"Diabetes\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo gain- and loss-of-function in two mouse models with multiple molecular and metabolic readouts\",\n      \"pmids\": [\"15983195\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; site-directed mutagenesis of c-Met Y1356; overexpression of catalytic and proline-rich domain mutants; cell scattering/spreading assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding site identified by mutagenesis, domain-function analysis with multiple mutants, single lab\",\n      \"pmids\": [\"15735664\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; siRNA knockdown; SAM domain interaction assay; lipid quantification; Rac1-GTP pull-down; dominant-negative Rac1 overexpression; receptor internalization/degradation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — SAM-SAM interaction shown by Co-IP, gain and loss-of-function with multiple pathway readouts including Rac1 epistasis\",\n      \"pmids\": [\"17135240\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"Yeast two-hybrid screen; co-immunoprecipitation of endogenous proteins; in vitro SAM-SAM interaction assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — endogenous Co-IP plus in vitro binding, single lab\",\n      \"pmids\": [\"17314030\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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.\",\n      \"method\": \"PTP inhibitor treatment; SHIP2 immunoprecipitation with specific activity measurement; subcellular fractionation; lipid quantification\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical measurement of activity in immunoprecipitates, subcellular fractionation, single lab\",\n      \"pmids\": [\"17672824\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"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).\",\n      \"method\": \"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\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell FRET imaging, siRNA loss-of-function, computational model experimentally validated, multiple orthogonal readouts\",\n      \"pmids\": [\"17535963\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"NMR spectroscopy; ITC (isothermal titration calorimetry); chemical shift perturbation mapping\",\n      \"journal\": \"Biochemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — NMR structure with ITC binding validation in a single focused study\",\n      \"pmids\": [\"18991394\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; domain mapping with ITSN1 SH3 domain constructs; immunofluorescence after EGF stimulation\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP confirmed in vivo, domain mapping, localization change, single lab\",\n      \"pmids\": [\"18692052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"TIRF live-cell imaging of CCP dynamics; siRNA knockdown; intersectin co-immunoprecipitation; lipid level measurement\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell TIRF imaging quantifying CCP lifetime, siRNA KD, intersectin interaction, multiple substrates examined\",\n      \"pmids\": [\"20679431\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; mutagenesis of Tir ITIM sequences; PI(3,4)P2 localization; co-immunoprecipitation with SHC; lamellipodin localization assay\",\n      \"journal\": \"Cell host & microbe\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mutagenesis of bacterial effector binding site, SHIP2 KD, lipid product localization, functional pedestal formation assay\",\n      \"pmids\": [\"20114025\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — GTP-dependent binding assay, siRNA KD, domain mutant rescue, functional polarity/migration and lipid localization readouts\",\n      \"pmids\": [\"22593208\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation of Nephrin complex; siRNA knockdown of SHIP2, Filamin, Lamellipodin; immunofluorescence of actin; cell migration assay\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — complex Co-IP, individual KD with functional readouts, single lab\",\n      \"pmids\": [\"22194892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"The Biochemical journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS phosphosite ID with functional activity assay, localization, and interactor Co-IP, single lab\",\n      \"pmids\": [\"21770892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Structure\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — NMR structure with extensive restraints, validated by mutagenesis, ITC, and cell-based functional assays in one study\",\n      \"pmids\": [\"22244754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"Exome sequencing; Sanger sequencing confirmation; 12 distinct mutations in 10 unrelated families at homozygous or compound heterozygous state\",\n      \"journal\": \"American journal of human genetics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — independent mutations in 10 unrelated families with consistent phenotype; missense mutations in catalytic domain confirm functional requirement\",\n      \"pmids\": [\"23273569\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography at 2.1 Å; molecular dynamics simulation; in vitro phosphatase inhibition assay\",\n      \"journal\": \"ACS chemical biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure with functional inhibition assay and MD simulation in one study\",\n      \"pmids\": [\"22330088\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"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\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct lipid-protein binding demonstrated, catalytic dead mutant phenotype, rescue experiment, Rho GTPase readouts\",\n      \"pmids\": [\"23699395\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"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.\",\n      \"method\": \"High-resolution spatiotemporal live-cell imaging; pharmacological SHIP2 inhibition; SHIP2 overexpression; PI(3,4)P2 biosensor imaging; matrix degradation assay\",\n      \"journal\": \"Current biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — live-cell imaging with lipid biosensor, gain and loss-of-function, functional ECM degradation assay\",\n      \"pmids\": [\"24206842\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; structure-function analysis of SHIP2-Mena interaction; siRNA/mutant rescue assays; in vitro invasion assay; in vivo metastasis mouse model\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — biochemical interaction identified, domain-mapping, in vitro and in vivo functional consequences, selectivity for Mena over VASP shown\",\n      \"pmids\": [\"27597754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; phospho-specific antibody detection of FcγRIIb Tyr273; lipid quantification; lentiviral siRNA knockdown; pharmacological SHIP2 inhibition; behavioral memory tests in 3xTg-AD mice\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — direct FcγRIIb-SHIP2 complex formation, lipid measurements, multiple intervention approaches (KO, antibody, siRNA, inhibitor) with functional outcomes\",\n      \"pmids\": [\"27834631\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; immunofluorescence with PI(4,5)P2/PI4P antibodies; co-immunoprecipitation with myosin-1c; cell migration assay; focal adhesion staining\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — lipid level changes measured, new interactor identified by Co-IP, functional migration and focal adhesion readouts, single lab\",\n      \"pmids\": [\"26826186\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"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.\",\n      \"method\": \"X-ray crystallography; mutagenesis of interdomain contacts; molecular dynamics simulation; in vitro phosphatase activity assay; cell biology assays\",\n      \"journal\": \"eLife\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — crystal structure combined with mutagenesis, MD, and functional in vitro/cell assays in one study\",\n      \"pmids\": [\"28792888\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"siRNA knockdown; phosphatase-dead mutant expression; co-immunoprecipitation of FGFR complexes; phospho-ERK/FRS2/PTPN11 immunoblot; rescue experiments\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — gain/loss-of-function, phosphatase-dead mutant separating catalytic from adaptor function, co-IP of multi-protein FGFR complex, multiple orthogonal readouts\",\n      \"pmids\": [\"30228226\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"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.\",\n      \"method\": \"Co-localization imaging; co-immunoprecipitation; siRNA knockdown; live-cell endocytosis assays; GTPase activity manipulation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple interacting proteins identified, pathway ordering via Cdc42-FBP17/CIP4-SHIP2 axis, functional endocytosis assay, replicated across labs (multi-author study)\",\n      \"pmids\": [\"30061681\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation; ubiquitination assay; SHIP2 protein stability assay; SHIP2 overexpression rescue experiment; signaling pathway analysis\",\n      \"journal\": \"International journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 / Moderate — direct Co-IP plus ubiquitination assay, rescue by SHIP2 overexpression, single lab\",\n      \"pmids\": [\"31498891\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"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.\",\n      \"method\": \"In vitro phosphatase assay with lipid vesicles; recombinant minimal catalytic construct and full-length SHIP2\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical assay with recombinant protein and lipid vesicles; specificity demonstrated by comparison with SKIP and soluble substrate; single lab\",\n      \"pmids\": [\"16824732\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"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.\",\n      \"method\": \"Co-immunoprecipitation and mass spectrometry; domain deletion mutant analysis; SHIP2 phosphatase activity assay; siRNA knockdown of IQGAP2; migration/invasion assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MS-confirmed interaction, domain mapping, direct phosphatase activity measurement, functional siRNA rescue, single lab\",\n      \"pmids\": [\"32183047\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SHIP2 (INPPL1) is a PH domain-independent inositol 5-phosphatase that dephosphorylates PtdIns(3,4,5)P3 to PtdIns(3,4)P2 at the plasma membrane (and PI(4,5)P2 to PI4P in nuclear speckles), acting as a negative regulator of PI3K/Akt signaling in insulin, growth factor, FGF, EGF, HGF, and M-CSF pathways; it is recruited to activated receptors (EGFR, EphA2 via SAM-SAM interaction, c-Met via pY1356, FcγRIIB via ITIM, FGFRs as adaptor) and to endocytic clathrin-coated pits via intersectin, where it shapes phosphoinositide landscapes to regulate actin cytoskeleton remodeling, cell adhesion/spreading, invadopodium maturation, receptor endocytosis, cell polarity, and FEME priming; its C2 domain allosterically enhances catalytic activity, phosphorylation at Ser132 and Tyr residues modulates activity and localization, and loss-of-function mutations in the catalytic domain cause opsismodysplasia, while it also functions as a scaffold (independent of catalytic activity) to recruit Src kinases to FGFRs for sustained ERK activation and to recruit Mena to invadopodia.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"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 [#0, #4, #10]. 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 [#40, #44]; tyrosine phosphorylation increases specific activity and drives translocation to a Triton-insoluble membrane fraction, switching the lipid output toward PtdIns(3,4)P2 [#23]. 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 [#31, #39]. 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 [#9, #20, #5, #21, #32]—and to endocytic clathrin-coated pits via intersectin, where its phosphoinositide turnover controls coated-pit maturation and FcγRIIB-dependent FEME priming [#27, #42]. 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 [#7, #8, #17, #35, #36, #37]. SHIP2 additionally functions as a catalysis-independent scaffold downstream of FGF receptors, recruiting Src-family kinases to sustain ERK activation [#41]. Catalytic-domain loss-of-function mutations in INPPL1 cause opsismodysplasia, a severe chondrodysplasia, establishing 5-phosphatase activity as essential for endochondral ossification [#33].\",\n  \"teleology\": [\n    {\n      \"year\": 1998,\n      \"claim\": \"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.\",\n      \"evidence\": \"In vitro phosphatase assays on immunoprecipitates and recombinant protein, with tyrosine-phosphorylation and Shc Co-IP across multiple growth factor stimuli\",\n      \"pmids\": [\"9660833\", \"9824312\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell substrate specificity inferred from in vitro assays\", \"Mechanism coupling receptor activation to phosphatase recruitment not yet defined\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"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.\",\n      \"evidence\": \"Overexpression in insulin-receptor fibroblasts with kinase readouts; SH3-domain in vitro binding and Co-IP in p210(bcr/abl) CML cells\",\n      \"pmids\": [\"10381377\", \"10194451\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Overexpression may not reflect endogenous stoichiometry\", \"Physiological relevance of ABL SH3 binding not functionally tested\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"Showed SHIP2 can suppress Akt and impose G1 arrest independent of PTEN, linking lipid phosphatase output to cell-cycle control via p27.\",\n      \"evidence\": \"Gain- and loss-of-function in PTEN-null glioblastoma cells with lipid quantification, PKB assays, and cell-cycle analysis\",\n      \"pmids\": [\"10958682\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which PtdIns(3,4)P2 versus PtdIns(3,4,5)P3 controls PKB not resolved\", \"Single cell model\"]\n    },\n    {\n      \"year\": 2001,\n      \"claim\": \"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.\",\n      \"evidence\": \"Yeast two-hybrid, Co-IP, ITIM mutagenesis, and localization/spreading assays across multiple cell types\",\n      \"pmids\": [\"11739414\", \"11158326\", \"11349134\", \"11016922\", \"11401540\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Relative contribution of each adaptor in vivo unclear\", \"How localization couples to catalytic output not quantified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Pinpointed Src-mediated phosphorylation of the SHIP2 NPXY motif during collagen-I adhesion as a regulatory switch coupling SHIP2 to Shc and lamellipodia control.\",\n      \"evidence\": \"In vitro Src kinase assay, NPXY mutagenesis, activated/dominant-negative Src, and lamellipodia readouts\",\n      \"pmids\": [\"12235291\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Matrix-specificity mechanism (collagen I vs others) unexplained\", \"Effect of phosphorylation on catalytic activity not measured here\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Extended SHIP2 to nuclear speckle and platelet cytoskeletal contexts, showing it retains 5-phosphatase activity within native filamin–actin–GPIb complexes.\",\n      \"evidence\": \"Nuclear fractionation with phosphatase assay; platelet Co-IP and activity assays with immunofluorescence\",\n      \"pmids\": [\"12847108\", \"12676785\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Nuclear substrate and function not defined\", \"Functional consequence of platelet complex dissociation untested\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Broadened the recognized substrate repertoire of SHIP2 beyond PtdIns(3,4,5)P3 through comprehensive kinetic profiling.\",\n      \"evidence\": \"In vitro kinetic assay against 54 soluble inositol phosphates and 4 phosphoinositide lipids\",\n      \"pmids\": [\"15316017\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In-cell relevance of non-canonical substrates unknown\", \"No structural basis for broad specificity at this stage\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"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.\",\n      \"evidence\": \"Adenoviral liver overexpression/dominant-negative in mouse models versus efficient siRNA in adipocytes; metabolic and signaling readouts\",\n      \"pmids\": [\"15983195\", \"15824124\", \"15668240\", \"16302969\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Reconciling tissue-specific metabolic roles incomplete\", \"Mechanistic basis for adipocyte non-responsiveness unexplained\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Defined the EphA2 SAM–SAM recruitment mode and PtdSer-dependent activation, connecting SHIP2 localization to receptor endocytosis via PI3K/Rac1.\",\n      \"evidence\": \"SAM-domain interaction assays, siRNA, Rac1-GTP pulldowns with dominant-negative Rac1; in vitro PtdSer-vesicle phosphatase assay\",\n      \"pmids\": [\"17135240\", \"16824732\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural detail of SAM-SAM interface not yet solved here\", \"Link between membrane lipid environment and in vivo activity correlative\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Showed tyrosine phosphorylation acts as an activity-and-localization switch and identified additional SAM-domain partner Arap3.\",\n      \"evidence\": \"PTP-inhibitor-induced phosphorylation with specific-activity measurement and fractionation; yeast two-hybrid and endogenous Co-IP\",\n      \"pmids\": [\"17672824\", \"17314030\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological kinase/stimulus for activation not defined\", \"Functional role of Arap3 interaction untested\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated SHIP2 as a negative-feedback node on PtdIns(3,4,5)P3 during NGF-driven neurite outgrowth using live imaging and validated modeling.\",\n      \"evidence\": \"siRNA, FRET biosensors for lipids and Rac1/Cdc42, and an experimentally validated kinetic model in PC12 cells\",\n      \"pmids\": [\"17535963\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo neuronal relevance not established\", \"Molecular link from Rac1 to SHIP2 regulation inferred from modeling\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"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.\",\n      \"evidence\": \"TIRF imaging of CCP dynamics, intersectin Co-IP, and Tir-ITIM mutagenesis with PI(3,4)P2/lamellipodin localization\",\n      \"pmids\": [\"20679431\", \"20114025\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative contribution of PI(4,5)P2 versus PI(3,4,5)P3 turnover to CCP maturation not fully separated\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Connected SHIP2 to small-GTPase-driven polarity/migration (RhoA effector) and identified Ser132 phosphorylation governing nuclear localization, PI(4,5)P2 activity, and stability.\",\n      \"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\",\n      \"pmids\": [\"22593208\", \"21770892\", \"22194892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Kinase responsible for Ser132 phosphorylation unknown\", \"Nuclear PI(4,5)P2 substrate function not mechanistically linked to phenotypes\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Provided structural definition of SHIP2's catalytic domain and SAM-SAM recognition, and established INPPL1 catalytic mutations as causative for opsismodysplasia.\",\n      \"evidence\": \"X-ray structure of phosphatase domain with inhibitor; NMR of EphA2-SHIP2 SAM complex; exome sequencing of 10 unrelated families\",\n      \"pmids\": [\"22330088\", \"22244754\", \"18991394\", \"23273569\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking phosphatase loss to growth-plate disorganization not detailed\", \"Tissue-specific substrate in cartilage unidentified\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established PtdIns(3,4)P2 as an effector lipid: SHIP2 controls epithelial apicobasal polarity via Dlg1 binding and is required for invadopodium maturation.\",\n      \"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\",\n      \"pmids\": [\"23699395\", \"24206842\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SHIP2 is spatially restricted to invadopodium cores not fully resolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"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.\",\n      \"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\",\n      \"pmids\": [\"27597754\", \"27834631\", \"26826186\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Selectivity of Mena over VASP recruitment mechanistically unexplained\", \"Causality of PI(4,5)P2 control on adhesion turnover correlative in single model\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"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.\",\n      \"evidence\": \"Phosphatase-dead mutants, siRNA, FGFR complex Co-IP, and phospho-ERK/FRS2/PTPN11 readouts; Cdc42-FBP17/CIP4-SHIP2 axis ordering with endocytosis assays\",\n      \"pmids\": [\"30228226\", \"30061681\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single protein partitions between adaptor and catalytic roles in cells unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified upstream regulators of SHIP2 abundance and activity in cancer (PLEK2-driven degradation; IQGAP2-driven activation).\",\n      \"evidence\": \"Co-IP/MS, ubiquitination and stability assays, domain mapping, and migration/invasion rescue in cancer cell lines\",\n      \"pmids\": [\"31498891\", \"32183047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single-lab findings without in vivo validation\", \"Mechanism of IQGAP2-mediated activity enhancement not structurally defined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"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.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"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\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0016787\", \"supporting_discovery_ids\": [0, 1, 4, 15, 40, 44]},\n      {\"term_id\": \"GO:0140098\", \"supporting_discovery_ids\": [0, 1, 15, 31, 39]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [35, 40, 44]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [41, 37, 28]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [3, 4, 10, 24]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7, 9, 27, 39, 42]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [7, 23, 31]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [8, 13, 16, 36]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [12, 31]},\n      {\"term_id\": \"GO:0005654\", \"supporting_discovery_ids\": [12, 31]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 4, 10, 21, 41]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [16, 21, 27, 42]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [33]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 19]}\n    ],\n    \"complexes\": [\n      \"filamin–actin–GPIb-IX-V platelet complex\",\n      \"Nephrin–Filamin–Lamellipodin complex\",\n      \"FGFR–Src–FRS2–PTPN11 signaling complex\"\n    ],\n    \"partners\": [\n      \"SHC1\",\n      \"FLNA\",\n      \"BCAR1\",\n      \"EPHA2\",\n      \"ITSN1\",\n      \"ENAH\",\n      \"FCGR2B\",\n      \"MET\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}