{"gene":"IQGAP2","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1996,"finding":"IQGAP2 harbors an N-terminal calponin homology domain that functions as a potential F-actin binding domain, and binds calmodulin via IQ motifs; it binds Cdc42 and Rac1 (but not RhoA) through its C-terminal half in a nucleotide-status-independent manner and inhibits both intrinsic and RhoGAP-stimulated GTP hydrolysis by Cdc42 and Rac1 without acting as a GAP.","method":"Domain analysis, calmodulin-binding assays, GTPase binding assays, GTP hydrolysis assays, truncation mutants","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — multiple in vitro biochemical assays with truncation mutants, replicated across binding and enzymatic measurements","pmids":["8756646"],"is_preprint":false},{"year":1996,"finding":"IQGAP2 (identified as p175 from rabbit liver cytosol) binds preferentially to Cdc42 and Rac1 but not RhoA or Ha-Ras; binding requires both the switch I domain and an insert region unique to Rho GTPases, and is competed by the Cdc42-binding domain of mPAK-3 but not by Cdc42-GAP.","method":"Cytosol pulldown, microsequencing, competition assays with GTPase mutants and chimeras","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with defined mutants and chimeras, replicates findings of PMID:8756646 with orthogonal methods","pmids":["8702968"],"is_preprint":false},{"year":2002,"finding":"In thrombin-activated platelets, IQGAP2 assembles into a cytoplasmic complex with Arp2/3 and actin, an association regulated by GTP-bound Rac1 but not GTP-bound Cdc42; IQGAP2 translocates to the platelet cytoskeleton specifically upon thrombin (not collagen or ADP) activation, and colocalizes with F-actin in lamellipodia and filopodia of transfected COS1 cells.","method":"Immunofluorescence microscopy, co-immunoprecipitation, platelet activation assays, subcellular fractionation","journal":"Blood","confidence":"High","confidence_rationale":"Tier 2 / Moderate — reciprocal co-IP with agonist specificity controls, immunofluorescence localization, multiple orthogonal approaches in one study","pmids":["12515716"],"is_preprint":false},{"year":2007,"finding":"Morpholino knockdown of XIQGAP2 in Xenopus laevis embryos causes loss of actin filaments, beta-catenin, and XIQGAP1 from cell borders in the ectoderm and inhibits Ca2+-induced reaggregation of dissociated embryonic cells, establishing that IQGAP2 is required for cadherin-mediated cell-to-cell adhesion.","method":"Morpholino antisense knockdown, histology, immunofluorescence, Ca2+-induced cell reaggregation assay","journal":"Developmental biology","confidence":"High","confidence_rationale":"Tier 2 / Moderate — loss-of-function with specific adhesion phenotype validated by multiple readouts in a vertebrate model","pmids":["17617398"],"is_preprint":false},{"year":2008,"finding":"Targeted disruption of murine Iqgap2 leads to overexpression of IQGAP1, loss of membrane E-cadherin, cytoplasmic translocation and activation of beta-catenin, and overexpression of cyclin D1; IQGAP2 normally exists in a scaffolding complex with IQGAP1, beta-catenin, and E-cadherin in hepatocytes (no direct IQGAP1–IQGAP2 interaction detected); crossing Iqgap2−/− onto Iqgap1−/− background rescues HCC phenotype, establishing epistatic dependence of the HCC phenotype on IQGAP1.","method":"Gene knockout, genetic epistasis (double KO), co-immunoprecipitation, immunofluorescence, Western blotting","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic epistasis with double knockout rescue, co-IP of endogenous complex, multiple orthogonal readouts","pmids":["18180285"],"is_preprint":false},{"year":2011,"finding":"The IQ-motifs of IQGAP2 show selectivity for calmodulin: IQ motifs 2 and 3 interact with calmodulin in the presence of calcium ions, while IQ motif 1 forms only a transient interaction with calmodulin in the absence of calcium; none of the IQGAP2 IQ motifs interact with S100B.","method":"Synthetic peptide binding assays, native gel electrophoresis, molecular modelling","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — defined biochemical assay but single lab, peptide-based (not full-length protein)","pmids":["21299499"],"is_preprint":false},{"year":2011,"finding":"Iqgap2-deficient mice show selective loss of the facilitated (carrier-assisted) phase of hepatocyte long-chain fatty acid (LCFA) uptake, with preservation of the diffusional component, implicating IQGAP2 in an intracellular signaling pathway required for functional fatty acid uptake.","method":"Iqgap2 knockout mouse, LCFA uptake assays in isolated hepatocytes (facilitated vs. diffusional phases), high-fat diet feeding","journal":"Regulatory peptides","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO model with quantitative uptake assays distinguishing kinetic phases, in vitro and in vivo","pmids":["21968151"],"is_preprint":false},{"year":2015,"finding":"IQGAP2 is required for normal podocyte structure and glomerular filtration; morpholino knockdown of iqgap2 in zebrafish causes foot process effacement and loss of size-selective glomerular filtration, demonstrated by permeability to high-molecular-weight dextrans.","method":"Morpholino knockdown in zebrafish, immunohistochemistry, in situ hybridization, dextran permeability assay","journal":"Kidney international","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — loss-of-function in zebrafish model with functional filtration assay, single lab","pmids":["26154927"],"is_preprint":false},{"year":2015,"finding":"IQGAP2 promotes colonic inflammatory response via TLR4/NF-κB signaling locally in colonic epithelium; Iqgap2−/− mice are resistant to DSS-induced colitis, showing suppressed NF-κB signaling, reduced IL-6, and diminished neutrophil/macrophage production and recruitment.","method":"Iqgap2 knockout mouse, DSS colitis model, NF-κB signaling assays, cytokine measurements, histology","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO with defined pathway (TLR4/NF-κB) and multiple cellular readouts, single lab","pmids":["26047140"],"is_preprint":false},{"year":2016,"finding":"IQGAP2 acts downstream of IFN-α receptor binding, independently of the JAK-STAT pathway, by physically interacting with RelA (NF-κB p65 subunit); both IQGAP2 and RelA are required for IFN-stimulated induction of a subset of antiviral ISGs in hepatoma cells.","method":"siRNA knockdown, co-immunoprecipitation (IQGAP2–RelA), HCV infection assay, NF-κB reporter assays","journal":"Journal of hepatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of endogenous interaction, functional rescue/loss-of-function assays, single lab","pmids":["27401546"],"is_preprint":false},{"year":2018,"finding":"Using all-atom MD simulations validated by site-directed mutagenesis, two Cdc42 molecules can bind simultaneously to IQGAP2: one via the Ex-domain of the GRD (requiring Cdc42's insert loop) and one via the RasGAP site, with the first binding event driving allosteric changes that facilitate the second binding and promote IQGAP2 dimerization; Rac1, due to differences in its insert loop, can only bind the RasGAP site and cannot facilitate IQGAP2 dimerization.","method":"All-atom molecular dynamics simulations, site-directed mutagenesis, Western blotting","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — computational MD validated by mutagenesis, single lab; structure not experimentally solved","pmids":["29358323"],"is_preprint":false},{"year":2020,"finding":"IQGAP2 interacts with SHIP2 (via SHIP2's PRD and SAM domains) in the cytoplasm of gastric cancer cells; this interaction elevates SHIP2 phosphatase activity, thereby inactivating Akt and reducing EMT-driven migration and invasion.","method":"Co-immunoprecipitation, mass spectrometry, domain deletion mutants, SHIP2 phosphatase activity assay, siRNA knockdown, migration/invasion assays","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP with domain mapping, enzymatic activity assay, functional rescue experiments, single lab","pmids":["32183047"],"is_preprint":false},{"year":2021,"finding":"Using limited proteolysis–mass spectrometry (LiP-SMap), IQGAP2 was identified as a direct binding target of isoliquiritigenin (ISO); through this interaction, ISO promotes phosphorylation of CREB, which upregulates SIRT1 expression, defining a novel IQGAP2-CREB-SIRT1 axis that reduces lipid accumulation in NAFLD.","method":"LiP-SMap (limited proteolysis combined with mass spectrometry), siRNA knockdown, phospho-kinase array, Western blotting","journal":"Phytotherapy research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct target identification by LiP-SMap, pathway validated by siRNA rescue, single lab","pmids":["33860590"],"is_preprint":false},{"year":2021,"finding":"IQGAP2 suppresses IQGAP1-mediated ERK activation; pull-down assay confirmed direct IQGAP1–IQGAP2 interaction, and IQGAP2 overexpression rescued IQGAP1-driven ERK phosphorylation, suggesting IQGAP1 sequestration as a mechanism; IQGAP2 also enhances apoptosis via ROS–P38–p53 pathway and reduces EMT via MEK-ERK inhibition.","method":"Pull-down assay, Western blotting, siRNA/overexpression, tumor xenograft model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct pulldown plus functional rescue experiments, single lab, multiple pathways assessed","pmids":["33846302"],"is_preprint":false},{"year":2023,"finding":"IQGAP2 immunoprecipitation from mouse liver revealed interaction with glycogen synthase kinase 3 (GSK3) and glycogen synthase (GYS); IQGAP2 knockout mice in the fed state showed decreased phosphorylated GSK3α and total GYS protein, reduced periportal glycogen, and impaired AKT and FOXO3 phosphorylation downstream of insulin signaling.","method":"Immunoprecipitation, knockout mouse model, Western blotting, glycogen staining, in vitro siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — co-IP of endogenous proteins plus KO phenotype validated in vivo and in vitro, single lab","pmids":["37805137"],"is_preprint":false},{"year":2023,"finding":"EBV transcription factor Rta binds directly to an Rta-responsive element (RRE) in the IQGAP2 promoter to upregulate IQGAP2 expression; Rta and IQGAP2 physically interact and co-localize in the nucleus; IQGAP2 is required for Rta-mediated activation of the Rta promoter and influences E-cadherin expression and cell clumping morphology in lymphoblastoid cells.","method":"ChIP/promoter binding assay, co-immunoprecipitation, co-localization (immunofluorescence), siRNA knockdown, luciferase reporter assay","journal":"Journal of virology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein–protein interaction confirmed by co-IP, promoter binding by direct assay, functional knockdown, single lab","pmids":["37504571"],"is_preprint":false},{"year":2023,"finding":"IQGAP2 knockdown in HaCaT and HEK293 cells increases phosphorylation of AKT and S6K, activating the mTOR pathway and increasing cell proliferation; AKT and mTOR inhibitors partially rescue the proliferation phenotype caused by IQGAP2 deficiency.","method":"siRNA knockdown, multi-omics (transcriptome, proteome, phosphoproteome), inhibitor rescue experiments","journal":"Human cell","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-omics with pharmacological rescue, single lab","pmids":["37154877"],"is_preprint":false},{"year":2024,"finding":"IQGAP2 colocalizes and directly interacts with the human colonic thiamin pyrophosphate transporter (hcTPPT) at the apical membrane of colonocytes; IQGAP2 overexpression enhances TPP uptake and hcTPPT protein stability, while IQGAP2 knockdown reduces TPP uptake.","method":"Yeast two-hybrid screen, co-immunoprecipitation, fluorescence microscopy co-localization, siRNA knockdown, overexpression in NCM460 cells and colonoid monolayers, TPP uptake assay","journal":"American journal of physiology. Cell physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Y2H confirmed by co-IP and functional uptake assays in two cell models, single lab","pmids":["39401425"],"is_preprint":false},{"year":2024,"finding":"In clear cell renal cell carcinoma, ALDH9A1 sequesters NPM1 in the cytoplasm, which in turn allows NPM1 to support IQGAP2 transcription; loss of ALDH9A1 releases NPM1 from the cytoplasm, suppresses IQGAP2 expression, and activates AKT-mTOR signaling to promote tumor progression.","method":"RNA sequencing, mass spectrometry, immunoprecipitation, luciferase reporter assay, mutational studies, immunofluorescence, in vitro and in vivo functional assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multi-method mechanistic chain (IP, reporter, mutants), single lab","pmids":["39039052"],"is_preprint":false},{"year":2025,"finding":"Loss of Iqgap2 in mice and zebrafish increases infiltration of peripheral leukocytes into the CNS under homeostatic and inflammatory conditions; brain endothelial cells from Iqgap2-knockout mice show extensive upregulation of adhesion receptors and antigen-processing machinery, establishing IQGAP2 as a regulator of blood-brain barrier immune privilege.","method":"Iqgap2 knockout mice, zebrafish knockdown, single-cell RNA sequencing, immunohistology, leukocyte infiltration quantification","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two vertebrate loss-of-function models with scRNA-seq and histological validation, single lab","pmids":["40071147"],"is_preprint":false}],"current_model":"IQGAP2 is a multidomain scaffold protein that binds Cdc42 and Rac1 (but not RhoA) through its GRD domain—inhibiting their GTP hydrolysis rather than acting as a GAP—and binds calmodulin via IQ motifs and F-actin via its calponin homology domain; in platelets it assembles a GTP-Rac1-dependent IQGAP2/Arp2/3/actin complex downstream of thrombin, in hepatocytes it forms a complex with E-cadherin and beta-catenin to suppress Wnt/beta-catenin and IQGAP1-driven oncogenesis, it interacts with RelA/NF-κB to mediate interferon antiviral ISG induction, binds and activates SHIP2 phosphatase to restrain Akt-driven EMT, interacts with GSK3 and glycogen synthase to support fed-state glycogen synthesis, and suppresses mTOR/AKT-driven cell proliferation; it also directly interacts with IQGAP1 to sequester it and blunt ERK activation, regulates BBB immune privilege by suppressing adhesion receptor expression in brain endothelial cells, and acts as a transcriptional target and binding partner of EBV Rta to promote lytic cycle progression."},"narrative":{"mechanistic_narrative":"IQGAP2 is a multidomain cytoplasmic scaffold protein that integrates Rho-family GTPase signaling, cytoskeletal organization, and cell adhesion to constrain proliferative and inflammatory programs [PMID:8756646, PMID:18180285]. It binds Cdc42 and Rac1, but not RhoA or Ras, through its C-terminal GAP-related domain in a nucleotide-independent manner, and rather than catalyzing GTP hydrolysis it inhibits both intrinsic and GAP-stimulated hydrolysis, effectively stabilizing the GTP-bound state of these GTPases [PMID:8756646, PMID:8702968]; structurally, two Cdc42 molecules can engage IQGAP2 cooperatively—one at an extra GRD site requiring the Cdc42 insert loop and one at the RasGAP site—an arrangement that drives IQGAP2 dimerization, whereas Rac1 occupies only the RasGAP site [PMID:29358323]. Through an N-terminal calponin-homology domain it binds F-actin, and via its IQ motifs it binds calmodulin in a calcium- and motif-selective fashion [PMID:8756646, PMID:21299499]. These activities support cytoskeletal remodeling and adhesion: in thrombin-activated platelets IQGAP2 assembles a Rac1-GTP-dependent complex with Arp2/3 and actin and translocates to the cytoskeleton [PMID:12515716], and it is required for cadherin-mediated cell-cell adhesion, maintaining E-cadherin, beta-catenin, and actin at cell borders [PMID:17617398, PMID:18180285]. In hepatocytes IQGAP2 forms a scaffolding complex with IQGAP1, beta-catenin, and E-cadherin, and its loss causes IQGAP1 overexpression, beta-catenin activation, and cyclin D1 induction, with the resulting hepatocellular carcinoma phenotype genetically dependent on IQGAP1 [PMID:18180285]; IQGAP2 directly binds and sequesters IQGAP1 to suppress ERK activation, acting broadly as a tumor suppressor that also restrains AKT/mTOR-driven proliferation and EMT [PMID:33846302, PMID:37154877]. It limits oncogenic AKT signaling by binding SHIP2 and elevating its phosphatase activity [PMID:32183047], and supports antiviral and metabolic programs by interacting with RelA/NF-kB to induce a subset of interferon-stimulated genes [PMID:27401546] and with GSK3 and glycogen synthase to sustain fed-state hepatic glycogen synthesis downstream of insulin [PMID:37805137]. IQGAP2 additionally functions in epithelial transport and barrier homeostasis, stabilizing solute transporters at the apical colonocyte membrane [PMID:39401425] and maintaining blood-brain barrier immune privilege by suppressing endothelial adhesion-receptor and antigen-processing expression [PMID:40071147].","teleology":[{"year":1996,"claim":"Established IQGAP2 as a Cdc42/Rac1-selective effector that, unexpectedly, inhibits rather than stimulates GTP hydrolysis, defining it as a non-catalytic GTPase scaffold rather than a true GAP.","evidence":"Domain analysis, calmodulin- and GTPase-binding assays, and GTP hydrolysis assays with truncation mutants; cytosol pulldown with microsequencing and competition assays using GTPase chimeras","pmids":["8756646","8702968"],"confidence":"High","gaps":["No structural basis for the hydrolysis inhibition","Functional consequence of stabilizing GTP-bound Cdc42/Rac1 in cells not defined","F-actin binding by the CH domain inferred, not directly demonstrated"]},{"year":2002,"claim":"Showed that IQGAP2 functions as an agonist-specific cytoskeletal effector, linking Rac1-GTP to actin polymerization machinery in activated platelets.","evidence":"Reciprocal co-IP, immunofluorescence, subcellular fractionation, and platelet activation assays with agonist specificity controls","pmids":["12515716"],"confidence":"High","gaps":["Direct vs. indirect association with Arp2/3 not resolved","Mechanism of thrombin-specific recruitment unknown"]},{"year":2007,"claim":"Demonstrated an in vivo requirement for IQGAP2 in cadherin-mediated cell-cell adhesion, connecting its cytoskeletal role to junction assembly.","evidence":"Morpholino knockdown in Xenopus embryos with histology, immunofluorescence, and Ca2+-induced reaggregation assays","pmids":["17617398"],"confidence":"High","gaps":["Molecular partner at the junction not identified in this system","Morpholino off-target effects not excluded"]},{"year":2008,"claim":"Defined IQGAP2 as a tumor suppressor that restrains IQGAP1, with the hepatocellular carcinoma phenotype of its loss genetically dependent on IQGAP1.","evidence":"Iqgap2 knockout and Iqgap1/Iqgap2 double-knockout epistasis, co-IP of endogenous E-cadherin/beta-catenin/IQGAP1 complex, immunofluorescence and Western blotting","pmids":["18180285"],"confidence":"High","gaps":["Direct IQGAP1-IQGAP2 interaction not detected here (later reconciled)","How IQGAP2 loss elevates IQGAP1 unresolved"]},{"year":2011,"claim":"Refined the calmodulin-binding code of IQGAP2 and extended its role to hepatic fatty-acid handling, broadening its metabolic functions.","evidence":"Synthetic IQ-motif peptide binding assays with native gels and modelling; Iqgap2 knockout mouse LCFA uptake assays distinguishing facilitated vs. diffusional phases","pmids":["21299499","21968151"],"confidence":"Medium","gaps":["Peptide assays do not reflect full-length protein","Molecular link between IQGAP2 and the fatty-acid transport apparatus undefined"]},{"year":2015,"claim":"Extended IQGAP2's adhesion/cytoskeletal function to organ physiology (podocyte filtration) and uncovered a pro-inflammatory role via TLR4/NF-kB in colonic epithelium.","evidence":"Zebrafish morpholino knockdown with dextran permeability assays; Iqgap2 knockout mouse DSS colitis model with NF-kB and cytokine readouts","pmids":["26154927","26047140"],"confidence":"Medium","gaps":["Direct molecular targets in podocytes and colonocytes not identified","Whether the inflammatory role is cell-autonomous in epithelium unresolved"]},{"year":2016,"claim":"Identified a JAK-STAT-independent antiviral signaling role in which IQGAP2 physically partners with RelA to drive a subset of interferon-stimulated genes.","evidence":"siRNA knockdown, IQGAP2-RelA co-IP, NF-kB reporter assays, and HCV infection assay in hepatoma cells","pmids":["27401546"],"confidence":"Medium","gaps":["Structural basis of IQGAP2-RelA interaction unknown","Which ISG subset and promoter logic not fully defined"]},{"year":2018,"claim":"Provided a structural-dynamic model explaining differential Cdc42 vs. Rac1 engagement and IQGAP2 dimerization, linking GTPase insert-loop differences to oligomerization.","evidence":"All-atom molecular dynamics simulations validated by site-directed mutagenesis and Western blotting","pmids":["29358323"],"confidence":"Medium","gaps":["No experimentally solved structure","Functional role of IQGAP2 dimerization in cells untested"]},{"year":2020,"claim":"Established a mechanism for IQGAP2 tumor suppression through activation of SHIP2 phosphatase to inactivate Akt and reduce EMT.","evidence":"Co-IP with mass spectrometry, SHIP2 domain-deletion mapping, phosphatase activity assays, and migration/invasion assays in gastric cancer cells","pmids":["32183047"],"confidence":"Medium","gaps":["How IQGAP2 binding elevates SHIP2 catalytic activity mechanistically unclear","Single cancer-cell context"]},{"year":2021,"claim":"Resolved the long-standing question of direct IQGAP1-IQGAP2 contact and tied it to ERK suppression, plus identified IQGAP2 as a small-molecule (isoliquiritigenin) target in a CREB-SIRT1 metabolic axis.","evidence":"Pull-down assay with overexpression rescue and xenograft model; LiP-SMap target identification with siRNA rescue and phospho-kinase arrays","pmids":["33846302","33860590"],"confidence":"Medium","gaps":["Sequestration model not quantified stoichiometrically","How ISO binding alters IQGAP2 function mechanistically undefined"]},{"year":2023,"claim":"Expanded IQGAP2's interactome and roles to insulin-dependent glycogen synthesis (GSK3/GYS), mTOR/AKT proliferation control, and an EBV Rta-driven lytic-cycle program in which IQGAP2 is both a transcriptional target and a nuclear binding partner.","evidence":"Co-IP from mouse liver with knockout phenotyping; siRNA with multi-omics and inhibitor rescue; ChIP/promoter binding, co-IP, nuclear co-localization and luciferase reporters","pmids":["37805137","37154877","37504571"],"confidence":"Medium","gaps":["Whether GSK3/GYS binding is direct vs. complex-mediated unclear","Nuclear pool of IQGAP2 and its function poorly defined","Reconciliation of cytoplasmic scaffold vs. nuclear Rta partner not addressed"]},{"year":2024,"claim":"Connected IQGAP2 to apical solute-transporter stabilization (hcTPPT) and to a transcriptional regulatory circuit (ALDH9A1-NPM1) that gates AKT-mTOR signaling in renal carcinoma.","evidence":"Yeast two-hybrid, co-IP, co-localization, knockdown/overexpression with TPP uptake assays; RNA-seq, IP, luciferase reporters and in vivo functional assays in ccRCC","pmids":["39401425","39039052"],"confidence":"Medium","gaps":["Generality of transporter-stabilization role beyond hcTPPT unknown","Direct vs. indirect control of IQGAP2 transcription by NPM1 not fully resolved"]},{"year":2025,"claim":"Established IQGAP2 as a regulator of blood-brain barrier immune privilege, suppressing endothelial adhesion-receptor and antigen-processing expression to limit CNS leukocyte infiltration.","evidence":"Iqgap2 knockout mice and zebrafish knockdown with single-cell RNA-seq, immunohistology, and leukocyte infiltration quantification","pmids":["40071147"],"confidence":"Medium","gaps":["Endothelial molecular targets downstream of IQGAP2 not pinned to a single pathway","Cell-autonomous mechanism in brain endothelium not fully dissected"]},{"year":null,"claim":"How IQGAP2's diverse molecular activities—GTPase scaffolding, actin/calmodulin binding, IQGAP1 sequestration, and multiple signaling partnerships—are coordinated within and across cell types to produce its context-specific tumor-suppressive, metabolic, and barrier functions remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No experimentally solved full-length structure","No unifying model linking cytoplasmic scaffold and nuclear roles","Whether GTPase regulation underlies the tumor-suppressive and metabolic phenotypes is untested"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,10]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[2,4,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,2]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[3,4]}],"localization":[{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[2,11]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[2]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[3,17]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,11,16]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[3,4]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[8,9,19]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[6,14]}],"complexes":["IQGAP2/Arp2/3/actin complex","IQGAP1/IQGAP2/beta-catenin/E-cadherin scaffold"],"partners":["CDC42","RAC1","IQGAP1","CTNNB1","CDH1","RELA","INPPL1","GSK3"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q13576","full_name":"Ras GTPase-activating-like protein IQGAP2","aliases":[],"length_aa":1575,"mass_kda":180.6,"function":"Binds to activated CDC42 and RAC1 but does not seem to stimulate their GTPase activity. Associates with calmodulin","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/Q13576/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IQGAP2","classification":"Not Classified","n_dependent_lines":0,"n_total_lines":1208,"dependency_fraction":0.0},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CDC42","stoichiometry":0.2},{"gene":"RAC1","stoichiometry":0.2},{"gene":"RAC3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IQGAP2","total_profiled":1310},"omim":[{"mim_id":"621092","title":"IQ MOTIF-CONTAINING GTPase-ACTIVATING PROTEIN 3; IQGAP3","url":"https://www.omim.org/entry/621092"},{"mim_id":"612976","title":"AGE-RELATED HEARING IMPAIRMENT 2; ARHI2","url":"https://www.omim.org/entry/612976"},{"mim_id":"610528","title":"CHROMODOMAIN HELICASE DNA-BINDING PROTEIN 8; CHD8","url":"https://www.omim.org/entry/610528"},{"mim_id":"605401","title":"IQ MOTIF-CONTAINING GTPase-ACTIVATING PROTEIN 2; IQGAP2","url":"https://www.omim.org/entry/605401"},{"mim_id":"603379","title":"IQ MOTIF-CONTAINING GTPase-ACTIVATING PROTEIN 1; IQGAP1","url":"https://www.omim.org/entry/603379"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Vesicles","reliability":"Approved"},{"location":"Plasma membrane","reliability":"Approved"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in many","driving_tissues":[{"tissue":"liver","ntpm":105.8}],"url":"https://www.proteinatlas.org/search/IQGAP2"},"hgnc":{"alias_symbol":[],"prev_symbol":[]},"alphafold":{"accession":"Q13576","domains":[{"cath_id":"1.10.418.10","chopping":"26-208","consensus_level":"high","plddt":82.2915,"start":26,"end":208},{"cath_id":"-","chopping":"209-276_283-293","consensus_level":"medium","plddt":79.4661,"start":209,"end":293},{"cath_id":"-","chopping":"446-523","consensus_level":"medium","plddt":85.5023,"start":446,"end":523},{"cath_id":"-","chopping":"531-655","consensus_level":"medium","plddt":79.4938,"start":531,"end":655},{"cath_id":"-","chopping":"784-813_1290-1347_1355-1432","consensus_level":"high","plddt":78.5003,"start":784,"end":1432},{"cath_id":"1.10.506.10","chopping":"952-1199","consensus_level":"medium","plddt":86.387,"start":952,"end":1199},{"cath_id":"-","chopping":"1480-1574","consensus_level":"high","plddt":80.5841,"start":1480,"end":1574}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13576","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q13576-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q13576-F1-predicted_aligned_error_v6.png","plddt_mean":77.88},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IQGAP2","jax_strain_url":"https://www.jax.org/strain/search?query=IQGAP2"},"sequence":{"accession":"Q13576","fasta_url":"https://rest.uniprot.org/uniprotkb/Q13576.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q13576/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q13576"}},"corpus_meta":[{"pmid":"8756646","id":"PMC_8756646","title":"The Ras GTPase-activating-protein-related human protein IQGAP2 harbors a potential actin binding domain and interacts with calmodulin and Rho family GTPases.","date":"1996","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/8756646","citation_count":233,"is_preprint":false},{"pmid":"8702968","id":"PMC_8702968","title":"Identification of a putative effector for Cdc42Hs with high sequence similarity to the RasGAP-related protein IQGAP1 and a Cdc42Hs binding partner with similarity to IQGAP2.","date":"1996","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/8702968","citation_count":132,"is_preprint":false},{"pmid":"18180285","id":"PMC_18180285","title":"Development of hepatocellular carcinoma in Iqgap2-deficient mice is IQGAP1 dependent.","date":"2008","source":"Molecular and cellular biology","url":"https://pubmed.ncbi.nlm.nih.gov/18180285","citation_count":109,"is_preprint":false},{"pmid":"20977743","id":"PMC_20977743","title":"IQGAP1 and IQGAP2 are reciprocally altered in hepatocellular carcinoma.","date":"2010","source":"BMC gastroenterology","url":"https://pubmed.ncbi.nlm.nih.gov/20977743","citation_count":63,"is_preprint":false},{"pmid":"22406297","id":"PMC_22406297","title":"IQGAP2, A candidate tumour suppressor of prostate tumorigenesis.","date":"2012","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/22406297","citation_count":50,"is_preprint":false},{"pmid":"17957782","id":"PMC_17957782","title":"IQGAP2 inactivation through aberrant promoter methylation and promotion of invasion in gastric cancer cells.","date":"2008","source":"International journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/17957782","citation_count":48,"is_preprint":false},{"pmid":"12515716","id":"PMC_12515716","title":"IQGAP2 functions as a GTP-dependent effector protein in thrombin-induced platelet cytoskeletal reorganization.","date":"2002","source":"Blood","url":"https://pubmed.ncbi.nlm.nih.gov/12515716","citation_count":47,"is_preprint":false},{"pmid":"33846302","id":"PMC_33846302","title":"Reduced IQGAP2 expression promotes EMT and inhibits apoptosis by modulating the MEK-ERK and p38 signaling in breast cancer irrespective of ER status.","date":"2021","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/33846302","citation_count":41,"is_preprint":false},{"pmid":"27903427","id":"PMC_27903427","title":"Anti-inflammatory effect of miltirone on inflammatory bowel disease via TLR4/NF-κB/IQGAP2 signaling pathway.","date":"2016","source":"Biomedicine & pharmacotherapy = Biomedecine & pharmacotherapie","url":"https://pubmed.ncbi.nlm.nih.gov/27903427","citation_count":41,"is_preprint":false},{"pmid":"29358323","id":"PMC_29358323","title":"Unraveling the molecular mechanism of interactions of the Rho GTPases Cdc42 and Rac1 with the scaffolding protein IQGAP2.","date":"2018","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/29358323","citation_count":39,"is_preprint":false},{"pmid":"26549344","id":"PMC_26549344","title":"Epigenetic regulation of IQGAP2 promotes ovarian cancer progression via activating Wnt/β-catenin signaling.","date":"2015","source":"International journal of oncology","url":"https://pubmed.ncbi.nlm.nih.gov/26549344","citation_count":36,"is_preprint":false},{"pmid":"32250392","id":"PMC_32250392","title":"Circular RNA sequencing indicates circ-IQGAP2 and circ-ZC3H6 as noninvasive biomarkers of primary Sjögren's syndrome.","date":"2020","source":"Rheumatology (Oxford, England)","url":"https://pubmed.ncbi.nlm.nih.gov/32250392","citation_count":35,"is_preprint":false},{"pmid":"21299499","id":"PMC_21299499","title":"IQ-motif selectivity in human IQGAP2 and IQGAP3: binding of calmodulin and myosin essential light chain.","date":"2011","source":"Bioscience reports","url":"https://pubmed.ncbi.nlm.nih.gov/21299499","citation_count":28,"is_preprint":false},{"pmid":"33860590","id":"PMC_33860590","title":"Administration of isoliquiritigenin prevents nonalcoholic fatty liver disease through a novel IQGAP2-CREB-SIRT1 axis.","date":"2021","source":"Phytotherapy research : PTR","url":"https://pubmed.ncbi.nlm.nih.gov/33860590","citation_count":28,"is_preprint":false},{"pmid":"33248413","id":"PMC_33248413","title":"LncRNA PDCD4-AS1 alleviates triple negative breast cancer by increasing expression of IQGAP2 via miR-10b-5p.","date":"2020","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/33248413","citation_count":25,"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":"23951254","id":"PMC_23951254","title":"Transcript profiling identifies iqgap2(-/-) mouse as a model for advanced human hepatocellular carcinoma.","date":"2013","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/23951254","citation_count":22,"is_preprint":false},{"pmid":"27401546","id":"PMC_27401546","title":"IQGAP2 is a novel interferon-alpha antiviral effector gene acting non-conventionally through the NF-κB pathway.","date":"2016","source":"Journal of hepatology","url":"https://pubmed.ncbi.nlm.nih.gov/27401546","citation_count":21,"is_preprint":false},{"pmid":"26047140","id":"PMC_26047140","title":"IQ Motif-Containing GTPase-Activating Protein 2 (IQGAP2) Is a Novel Regulator of Colonic Inflammation in Mice.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26047140","citation_count":21,"is_preprint":false},{"pmid":"17617398","id":"PMC_17617398","title":"IQGAP2 is required for the cadherin-mediated cell-to-cell adhesion in Xenopus laevis embryos.","date":"2007","source":"Developmental biology","url":"https://pubmed.ncbi.nlm.nih.gov/17617398","citation_count":21,"is_preprint":false},{"pmid":"30428404","id":"PMC_30428404","title":"Downregulation of IQGAP2 Correlates with Prostate Cancer Recurrence and Metastasis.","date":"2018","source":"Translational oncology","url":"https://pubmed.ncbi.nlm.nih.gov/30428404","citation_count":19,"is_preprint":false},{"pmid":"25254002","id":"PMC_25254002","title":"Role of the tumor suppressor IQGAP2 in metabolic homeostasis: Possible link between diabetes and cancer.","date":"2014","source":"Metabolomics : Official journal of the Metabolomic Society","url":"https://pubmed.ncbi.nlm.nih.gov/25254002","citation_count":19,"is_preprint":false},{"pmid":"36831467","id":"PMC_36831467","title":"The Antithetic Roles of IQGAP2 and IQGAP3 in Cancers.","date":"2023","source":"Cancers","url":"https://pubmed.ncbi.nlm.nih.gov/36831467","citation_count":18,"is_preprint":false},{"pmid":"36362301","id":"PMC_36362301","title":"Reduced IQGAP2 Promotes Bladder Cancer through Regulation of MAPK/ERK Pathway and Cytokines.","date":"2022","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/36362301","citation_count":18,"is_preprint":false},{"pmid":"21968151","id":"PMC_21968151","title":"Ablation of Iqgap2 protects from diet-induced hepatic steatosis due to impaired fatty acid uptake.","date":"2011","source":"Regulatory peptides","url":"https://pubmed.ncbi.nlm.nih.gov/21968151","citation_count":17,"is_preprint":false},{"pmid":"26154927","id":"PMC_26154927","title":"The Rho-GTPase binding protein IQGAP2 is required for the glomerular filtration barrier.","date":"2015","source":"Kidney international","url":"https://pubmed.ncbi.nlm.nih.gov/26154927","citation_count":16,"is_preprint":false},{"pmid":"28179424","id":"PMC_28179424","title":"Altered methylation of specific DNA loci in the liver of Bhmt-null mice results in repression of Iqgap2 and F2rl2 and is associated with development of preneoplastic foci.","date":"2017","source":"FASEB journal : official publication of the Federation of American Societies for Experimental Biology","url":"https://pubmed.ncbi.nlm.nih.gov/28179424","citation_count":16,"is_preprint":false},{"pmid":"34935307","id":"PMC_34935307","title":"Long non-coding ribonucleic acid ATP2B1-AS1 modulates endothelial permeability through regulating the miR-4729-IQGAP2 axis in diabetic retinopathy.","date":"2022","source":"Journal of diabetes investigation","url":"https://pubmed.ncbi.nlm.nih.gov/34935307","citation_count":10,"is_preprint":false},{"pmid":"26865277","id":"PMC_26865277","title":"Integrated genomic profiling identifies microRNA-92a regulation of IQGAP2 in locally advanced rectal cancer.","date":"2016","source":"Genes, chromosomes & cancer","url":"https://pubmed.ncbi.nlm.nih.gov/26865277","citation_count":9,"is_preprint":false},{"pmid":"15621655","id":"PMC_15621655","title":"Cloning and characterization of a novel transcript variant of IQGAP2 in human testis.","date":"2004","source":"DNA sequence : the journal of DNA sequencing and mapping","url":"https://pubmed.ncbi.nlm.nih.gov/15621655","citation_count":8,"is_preprint":false},{"pmid":"39039052","id":"PMC_39039052","title":"N6-methyladenosine-modified ALDH9A1 modulates lipid accumulation and tumor progression in clear cell renal cell carcinoma through the NPM1/IQGAP2/AKT signaling pathway.","date":"2024","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/39039052","citation_count":7,"is_preprint":false},{"pmid":"37805137","id":"PMC_37805137","title":"Depletion of IQ motif-containing GTPase activating protein 2 (IQGAP2) reduces hepatic glycogen and impairs insulin signaling.","date":"2023","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/37805137","citation_count":6,"is_preprint":false},{"pmid":"40071147","id":"PMC_40071147","title":"IQGAP2 regulates blood-brain barrier immune dynamics.","date":"2025","source":"iScience","url":"https://pubmed.ncbi.nlm.nih.gov/40071147","citation_count":6,"is_preprint":false},{"pmid":"37504571","id":"PMC_37504571","title":"Upregulation of IQGAP2 by EBV transactivator Rta and its influence on EBV life cycle.","date":"2023","source":"Journal of virology","url":"https://pubmed.ncbi.nlm.nih.gov/37504571","citation_count":4,"is_preprint":false},{"pmid":"26187738","id":"PMC_26187738","title":"The European GWAS-identified risk SNP rs457717 within IQGAP2 is not associated with age-related hearing impairment in Han male Chinese population.","date":"2015","source":"European archives of oto-rhino-laryngology : official journal of the European Federation of Oto-Rhino-Laryngological Societies (EUFOS) : affiliated with the German Society for Oto-Rhino-Laryngology - Head and Neck Surgery","url":"https://pubmed.ncbi.nlm.nih.gov/26187738","citation_count":4,"is_preprint":false},{"pmid":"39682792","id":"PMC_39682792","title":"Polymorphisms Within the IQGAP2 and CRTAC1 Genes of Gannan Yaks and Their Association with Milk Quality Characteristics.","date":"2024","source":"Foods (Basel, Switzerland)","url":"https://pubmed.ncbi.nlm.nih.gov/39682792","citation_count":3,"is_preprint":false},{"pmid":"39401425","id":"PMC_39401425","title":"IQGAP-2: a novel interacting partner with the human colonic thiamin pyrophosphate transporter.","date":"2024","source":"American journal of physiology. Cell physiology","url":"https://pubmed.ncbi.nlm.nih.gov/39401425","citation_count":1,"is_preprint":false},{"pmid":"38645082","id":"PMC_38645082","title":"IQGAP2 regulates blood-brain barrier immune dynamics.","date":"2024","source":"bioRxiv : the preprint server for biology","url":"https://pubmed.ncbi.nlm.nih.gov/38645082","citation_count":0,"is_preprint":false},{"pmid":"37154877","id":"PMC_37154877","title":"Multi-omics data integration reveals the molecular network of dysregulation IQGAP2-mTOR promotes cell proliferation.","date":"2023","source":"Human cell","url":"https://pubmed.ncbi.nlm.nih.gov/37154877","citation_count":0,"is_preprint":false},{"pmid":"36380106","id":"PMC_36380106","title":"Transcriptome analysis of PBMCs isolated from piglets treated with a miR-124 sponge construct identified miR124/IQGAP2/Rho GTPase as a target pathway support Salmonella Typhimurium infection.","date":"2022","source":"Molecular genetics and genomics : MGG","url":"https://pubmed.ncbi.nlm.nih.gov/36380106","citation_count":0,"is_preprint":false},{"pmid":"40640432","id":"PMC_40640432","title":"Unveiling the therapeutic potential of senescence-related IQGAP2 in pancreatic Cancer through post-GWAS genomic and scRNA-seq analyses.","date":"2025","source":"Discover oncology","url":"https://pubmed.ncbi.nlm.nih.gov/40640432","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":23900,"output_tokens":5140,"usd":0.0744,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":13349,"output_tokens":5171,"usd":0.09801,"stage2_stop_reason":"end_turn"},"total_usd":0.17241,"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\": 1996,\n      \"finding\": \"IQGAP2 harbors an N-terminal calponin homology domain that functions as a potential F-actin binding domain, and binds calmodulin via IQ motifs; it binds Cdc42 and Rac1 (but not RhoA) through its C-terminal half in a nucleotide-status-independent manner and inhibits both intrinsic and RhoGAP-stimulated GTP hydrolysis by Cdc42 and Rac1 without acting as a GAP.\",\n      \"method\": \"Domain analysis, calmodulin-binding assays, GTPase binding assays, GTP hydrolysis assays, truncation mutants\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — multiple in vitro biochemical assays with truncation mutants, replicated across binding and enzymatic measurements\",\n      \"pmids\": [\"8756646\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"IQGAP2 (identified as p175 from rabbit liver cytosol) binds preferentially to Cdc42 and Rac1 but not RhoA or Ha-Ras; binding requires both the switch I domain and an insert region unique to Rho GTPases, and is competed by the Cdc42-binding domain of mPAK-3 but not by Cdc42-GAP.\",\n      \"method\": \"Cytosol pulldown, microsequencing, competition assays with GTPase mutants and chimeras\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with defined mutants and chimeras, replicates findings of PMID:8756646 with orthogonal methods\",\n      \"pmids\": [\"8702968\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"In thrombin-activated platelets, IQGAP2 assembles into a cytoplasmic complex with Arp2/3 and actin, an association regulated by GTP-bound Rac1 but not GTP-bound Cdc42; IQGAP2 translocates to the platelet cytoskeleton specifically upon thrombin (not collagen or ADP) activation, and colocalizes with F-actin in lamellipodia and filopodia of transfected COS1 cells.\",\n      \"method\": \"Immunofluorescence microscopy, co-immunoprecipitation, platelet activation assays, subcellular fractionation\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal co-IP with agonist specificity controls, immunofluorescence localization, multiple orthogonal approaches in one study\",\n      \"pmids\": [\"12515716\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Morpholino knockdown of XIQGAP2 in Xenopus laevis embryos causes loss of actin filaments, beta-catenin, and XIQGAP1 from cell borders in the ectoderm and inhibits Ca2+-induced reaggregation of dissociated embryonic cells, establishing that IQGAP2 is required for cadherin-mediated cell-to-cell adhesion.\",\n      \"method\": \"Morpholino antisense knockdown, histology, immunofluorescence, Ca2+-induced cell reaggregation assay\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function with specific adhesion phenotype validated by multiple readouts in a vertebrate model\",\n      \"pmids\": [\"17617398\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Targeted disruption of murine Iqgap2 leads to overexpression of IQGAP1, loss of membrane E-cadherin, cytoplasmic translocation and activation of beta-catenin, and overexpression of cyclin D1; IQGAP2 normally exists in a scaffolding complex with IQGAP1, beta-catenin, and E-cadherin in hepatocytes (no direct IQGAP1–IQGAP2 interaction detected); crossing Iqgap2−/− onto Iqgap1−/− background rescues HCC phenotype, establishing epistatic dependence of the HCC phenotype on IQGAP1.\",\n      \"method\": \"Gene knockout, genetic epistasis (double KO), co-immunoprecipitation, immunofluorescence, Western blotting\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic epistasis with double knockout rescue, co-IP of endogenous complex, multiple orthogonal readouts\",\n      \"pmids\": [\"18180285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"The IQ-motifs of IQGAP2 show selectivity for calmodulin: IQ motifs 2 and 3 interact with calmodulin in the presence of calcium ions, while IQ motif 1 forms only a transient interaction with calmodulin in the absence of calcium; none of the IQGAP2 IQ motifs interact with S100B.\",\n      \"method\": \"Synthetic peptide binding assays, native gel electrophoresis, molecular modelling\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — defined biochemical assay but single lab, peptide-based (not full-length protein)\",\n      \"pmids\": [\"21299499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Iqgap2-deficient mice show selective loss of the facilitated (carrier-assisted) phase of hepatocyte long-chain fatty acid (LCFA) uptake, with preservation of the diffusional component, implicating IQGAP2 in an intracellular signaling pathway required for functional fatty acid uptake.\",\n      \"method\": \"Iqgap2 knockout mouse, LCFA uptake assays in isolated hepatocytes (facilitated vs. diffusional phases), high-fat diet feeding\",\n      \"journal\": \"Regulatory peptides\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO model with quantitative uptake assays distinguishing kinetic phases, in vitro and in vivo\",\n      \"pmids\": [\"21968151\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP2 is required for normal podocyte structure and glomerular filtration; morpholino knockdown of iqgap2 in zebrafish causes foot process effacement and loss of size-selective glomerular filtration, demonstrated by permeability to high-molecular-weight dextrans.\",\n      \"method\": \"Morpholino knockdown in zebrafish, immunohistochemistry, in situ hybridization, dextran permeability assay\",\n      \"journal\": \"Kidney international\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — loss-of-function in zebrafish model with functional filtration assay, single lab\",\n      \"pmids\": [\"26154927\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP2 promotes colonic inflammatory response via TLR4/NF-κB signaling locally in colonic epithelium; Iqgap2−/− mice are resistant to DSS-induced colitis, showing suppressed NF-κB signaling, reduced IL-6, and diminished neutrophil/macrophage production and recruitment.\",\n      \"method\": \"Iqgap2 knockout mouse, DSS colitis model, NF-κB signaling assays, cytokine measurements, histology\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO with defined pathway (TLR4/NF-κB) and multiple cellular readouts, single lab\",\n      \"pmids\": [\"26047140\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IQGAP2 acts downstream of IFN-α receptor binding, independently of the JAK-STAT pathway, by physically interacting with RelA (NF-κB p65 subunit); both IQGAP2 and RelA are required for IFN-stimulated induction of a subset of antiviral ISGs in hepatoma cells.\",\n      \"method\": \"siRNA knockdown, co-immunoprecipitation (IQGAP2–RelA), HCV infection assay, NF-κB reporter assays\",\n      \"journal\": \"Journal of hepatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of endogenous interaction, functional rescue/loss-of-function assays, single lab\",\n      \"pmids\": [\"27401546\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"Using all-atom MD simulations validated by site-directed mutagenesis, two Cdc42 molecules can bind simultaneously to IQGAP2: one via the Ex-domain of the GRD (requiring Cdc42's insert loop) and one via the RasGAP site, with the first binding event driving allosteric changes that facilitate the second binding and promote IQGAP2 dimerization; Rac1, due to differences in its insert loop, can only bind the RasGAP site and cannot facilitate IQGAP2 dimerization.\",\n      \"method\": \"All-atom molecular dynamics simulations, site-directed mutagenesis, Western blotting\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — computational MD validated by mutagenesis, single lab; structure not experimentally solved\",\n      \"pmids\": [\"29358323\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IQGAP2 interacts with SHIP2 (via SHIP2's PRD and SAM domains) in the cytoplasm of gastric cancer cells; this interaction elevates SHIP2 phosphatase activity, thereby inactivating Akt and reducing EMT-driven migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, domain deletion mutants, SHIP2 phosphatase activity assay, siRNA knockdown, migration/invasion assays\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP with domain mapping, enzymatic activity assay, functional rescue experiments, single lab\",\n      \"pmids\": [\"32183047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Using limited proteolysis–mass spectrometry (LiP-SMap), IQGAP2 was identified as a direct binding target of isoliquiritigenin (ISO); through this interaction, ISO promotes phosphorylation of CREB, which upregulates SIRT1 expression, defining a novel IQGAP2-CREB-SIRT1 axis that reduces lipid accumulation in NAFLD.\",\n      \"method\": \"LiP-SMap (limited proteolysis combined with mass spectrometry), siRNA knockdown, phospho-kinase array, Western blotting\",\n      \"journal\": \"Phytotherapy research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct target identification by LiP-SMap, pathway validated by siRNA rescue, single lab\",\n      \"pmids\": [\"33860590\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IQGAP2 suppresses IQGAP1-mediated ERK activation; pull-down assay confirmed direct IQGAP1–IQGAP2 interaction, and IQGAP2 overexpression rescued IQGAP1-driven ERK phosphorylation, suggesting IQGAP1 sequestration as a mechanism; IQGAP2 also enhances apoptosis via ROS–P38–p53 pathway and reduces EMT via MEK-ERK inhibition.\",\n      \"method\": \"Pull-down assay, Western blotting, siRNA/overexpression, tumor xenograft model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct pulldown plus functional rescue experiments, single lab, multiple pathways assessed\",\n      \"pmids\": [\"33846302\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IQGAP2 immunoprecipitation from mouse liver revealed interaction with glycogen synthase kinase 3 (GSK3) and glycogen synthase (GYS); IQGAP2 knockout mice in the fed state showed decreased phosphorylated GSK3α and total GYS protein, reduced periportal glycogen, and impaired AKT and FOXO3 phosphorylation downstream of insulin signaling.\",\n      \"method\": \"Immunoprecipitation, knockout mouse model, Western blotting, glycogen staining, in vitro siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — co-IP of endogenous proteins plus KO phenotype validated in vivo and in vitro, single lab\",\n      \"pmids\": [\"37805137\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"EBV transcription factor Rta binds directly to an Rta-responsive element (RRE) in the IQGAP2 promoter to upregulate IQGAP2 expression; Rta and IQGAP2 physically interact and co-localize in the nucleus; IQGAP2 is required for Rta-mediated activation of the Rta promoter and influences E-cadherin expression and cell clumping morphology in lymphoblastoid cells.\",\n      \"method\": \"ChIP/promoter binding assay, co-immunoprecipitation, co-localization (immunofluorescence), siRNA knockdown, luciferase reporter assay\",\n      \"journal\": \"Journal of virology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein–protein interaction confirmed by co-IP, promoter binding by direct assay, functional knockdown, single lab\",\n      \"pmids\": [\"37504571\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"IQGAP2 knockdown in HaCaT and HEK293 cells increases phosphorylation of AKT and S6K, activating the mTOR pathway and increasing cell proliferation; AKT and mTOR inhibitors partially rescue the proliferation phenotype caused by IQGAP2 deficiency.\",\n      \"method\": \"siRNA knockdown, multi-omics (transcriptome, proteome, phosphoproteome), inhibitor rescue experiments\",\n      \"journal\": \"Human cell\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-omics with pharmacological rescue, single lab\",\n      \"pmids\": [\"37154877\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IQGAP2 colocalizes and directly interacts with the human colonic thiamin pyrophosphate transporter (hcTPPT) at the apical membrane of colonocytes; IQGAP2 overexpression enhances TPP uptake and hcTPPT protein stability, while IQGAP2 knockdown reduces TPP uptake.\",\n      \"method\": \"Yeast two-hybrid screen, co-immunoprecipitation, fluorescence microscopy co-localization, siRNA knockdown, overexpression in NCM460 cells and colonoid monolayers, TPP uptake assay\",\n      \"journal\": \"American journal of physiology. Cell physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Y2H confirmed by co-IP and functional uptake assays in two cell models, single lab\",\n      \"pmids\": [\"39401425\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"In clear cell renal cell carcinoma, ALDH9A1 sequesters NPM1 in the cytoplasm, which in turn allows NPM1 to support IQGAP2 transcription; loss of ALDH9A1 releases NPM1 from the cytoplasm, suppresses IQGAP2 expression, and activates AKT-mTOR signaling to promote tumor progression.\",\n      \"method\": \"RNA sequencing, mass spectrometry, immunoprecipitation, luciferase reporter assay, mutational studies, immunofluorescence, in vitro and in vivo functional assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multi-method mechanistic chain (IP, reporter, mutants), single lab\",\n      \"pmids\": [\"39039052\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Loss of Iqgap2 in mice and zebrafish increases infiltration of peripheral leukocytes into the CNS under homeostatic and inflammatory conditions; brain endothelial cells from Iqgap2-knockout mice show extensive upregulation of adhesion receptors and antigen-processing machinery, establishing IQGAP2 as a regulator of blood-brain barrier immune privilege.\",\n      \"method\": \"Iqgap2 knockout mice, zebrafish knockdown, single-cell RNA sequencing, immunohistology, leukocyte infiltration quantification\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two vertebrate loss-of-function models with scRNA-seq and histological validation, single lab\",\n      \"pmids\": [\"40071147\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IQGAP2 is a multidomain scaffold protein that binds Cdc42 and Rac1 (but not RhoA) through its GRD domain—inhibiting their GTP hydrolysis rather than acting as a GAP—and binds calmodulin via IQ motifs and F-actin via its calponin homology domain; in platelets it assembles a GTP-Rac1-dependent IQGAP2/Arp2/3/actin complex downstream of thrombin, in hepatocytes it forms a complex with E-cadherin and beta-catenin to suppress Wnt/beta-catenin and IQGAP1-driven oncogenesis, it interacts with RelA/NF-κB to mediate interferon antiviral ISG induction, binds and activates SHIP2 phosphatase to restrain Akt-driven EMT, interacts with GSK3 and glycogen synthase to support fed-state glycogen synthesis, and suppresses mTOR/AKT-driven cell proliferation; it also directly interacts with IQGAP1 to sequester it and blunt ERK activation, regulates BBB immune privilege by suppressing adhesion receptor expression in brain endothelial cells, and acts as a transcriptional target and binding partner of EBV Rta to promote lytic cycle progression.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IQGAP2 is a multidomain cytoplasmic scaffold protein that integrates Rho-family GTPase signaling, cytoskeletal organization, and cell adhesion to constrain proliferative and inflammatory programs [#0, #4]. It binds Cdc42 and Rac1, but not RhoA or Ras, through its C-terminal GAP-related domain in a nucleotide-independent manner, and rather than catalyzing GTP hydrolysis it inhibits both intrinsic and GAP-stimulated hydrolysis, effectively stabilizing the GTP-bound state of these GTPases [#0, #1]; structurally, two Cdc42 molecules can engage IQGAP2 cooperatively—one at an extra GRD site requiring the Cdc42 insert loop and one at the RasGAP site—an arrangement that drives IQGAP2 dimerization, whereas Rac1 occupies only the RasGAP site [#10]. Through an N-terminal calponin-homology domain it binds F-actin, and via its IQ motifs it binds calmodulin in a calcium- and motif-selective fashion [#0, #5]. These activities support cytoskeletal remodeling and adhesion: in thrombin-activated platelets IQGAP2 assembles a Rac1-GTP-dependent complex with Arp2/3 and actin and translocates to the cytoskeleton [#2], and it is required for cadherin-mediated cell-cell adhesion, maintaining E-cadherin, beta-catenin, and actin at cell borders [#3, #4]. In hepatocytes IQGAP2 forms a scaffolding complex with IQGAP1, beta-catenin, and E-cadherin, and its loss causes IQGAP1 overexpression, beta-catenin activation, and cyclin D1 induction, with the resulting hepatocellular carcinoma phenotype genetically dependent on IQGAP1 [#4]; IQGAP2 directly binds and sequesters IQGAP1 to suppress ERK activation, acting broadly as a tumor suppressor that also restrains AKT/mTOR-driven proliferation and EMT [#13, #16]. It limits oncogenic AKT signaling by binding SHIP2 and elevating its phosphatase activity [#11], and supports antiviral and metabolic programs by interacting with RelA/NF-kB to induce a subset of interferon-stimulated genes [#9] and with GSK3 and glycogen synthase to sustain fed-state hepatic glycogen synthesis downstream of insulin [#14]. IQGAP2 additionally functions in epithelial transport and barrier homeostasis, stabilizing solute transporters at the apical colonocyte membrane [#17] and maintaining blood-brain barrier immune privilege by suppressing endothelial adhesion-receptor and antigen-processing expression [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established IQGAP2 as a Cdc42/Rac1-selective effector that, unexpectedly, inhibits rather than stimulates GTP hydrolysis, defining it as a non-catalytic GTPase scaffold rather than a true GAP.\",\n      \"evidence\": \"Domain analysis, calmodulin- and GTPase-binding assays, and GTP hydrolysis assays with truncation mutants; cytosol pulldown with microsequencing and competition assays using GTPase chimeras\",\n      \"pmids\": [\"8756646\", \"8702968\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"No structural basis for the hydrolysis inhibition\", \"Functional consequence of stabilizing GTP-bound Cdc42/Rac1 in cells not defined\", \"F-actin binding by the CH domain inferred, not directly demonstrated\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Showed that IQGAP2 functions as an agonist-specific cytoskeletal effector, linking Rac1-GTP to actin polymerization machinery in activated platelets.\",\n      \"evidence\": \"Reciprocal co-IP, immunofluorescence, subcellular fractionation, and platelet activation assays with agonist specificity controls\",\n      \"pmids\": [\"12515716\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct vs. indirect association with Arp2/3 not resolved\", \"Mechanism of thrombin-specific recruitment unknown\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Demonstrated an in vivo requirement for IQGAP2 in cadherin-mediated cell-cell adhesion, connecting its cytoskeletal role to junction assembly.\",\n      \"evidence\": \"Morpholino knockdown in Xenopus embryos with histology, immunofluorescence, and Ca2+-induced reaggregation assays\",\n      \"pmids\": [\"17617398\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular partner at the junction not identified in this system\", \"Morpholino off-target effects not excluded\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Defined IQGAP2 as a tumor suppressor that restrains IQGAP1, with the hepatocellular carcinoma phenotype of its loss genetically dependent on IQGAP1.\",\n      \"evidence\": \"Iqgap2 knockout and Iqgap1/Iqgap2 double-knockout epistasis, co-IP of endogenous E-cadherin/beta-catenin/IQGAP1 complex, immunofluorescence and Western blotting\",\n      \"pmids\": [\"18180285\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct IQGAP1-IQGAP2 interaction not detected here (later reconciled)\", \"How IQGAP2 loss elevates IQGAP1 unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Refined the calmodulin-binding code of IQGAP2 and extended its role to hepatic fatty-acid handling, broadening its metabolic functions.\",\n      \"evidence\": \"Synthetic IQ-motif peptide binding assays with native gels and modelling; Iqgap2 knockout mouse LCFA uptake assays distinguishing facilitated vs. diffusional phases\",\n      \"pmids\": [\"21299499\", \"21968151\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide assays do not reflect full-length protein\", \"Molecular link between IQGAP2 and the fatty-acid transport apparatus undefined\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Extended IQGAP2's adhesion/cytoskeletal function to organ physiology (podocyte filtration) and uncovered a pro-inflammatory role via TLR4/NF-kB in colonic epithelium.\",\n      \"evidence\": \"Zebrafish morpholino knockdown with dextran permeability assays; Iqgap2 knockout mouse DSS colitis model with NF-kB and cytokine readouts\",\n      \"pmids\": [\"26154927\", \"26047140\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular targets in podocytes and colonocytes not identified\", \"Whether the inflammatory role is cell-autonomous in epithelium unresolved\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Identified a JAK-STAT-independent antiviral signaling role in which IQGAP2 physically partners with RelA to drive a subset of interferon-stimulated genes.\",\n      \"evidence\": \"siRNA knockdown, IQGAP2-RelA co-IP, NF-kB reporter assays, and HCV infection assay in hepatoma cells\",\n      \"pmids\": [\"27401546\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural basis of IQGAP2-RelA interaction unknown\", \"Which ISG subset and promoter logic not fully defined\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Provided a structural-dynamic model explaining differential Cdc42 vs. Rac1 engagement and IQGAP2 dimerization, linking GTPase insert-loop differences to oligomerization.\",\n      \"evidence\": \"All-atom molecular dynamics simulations validated by site-directed mutagenesis and Western blotting\",\n      \"pmids\": [\"29358323\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimentally solved structure\", \"Functional role of IQGAP2 dimerization in cells untested\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Established a mechanism for IQGAP2 tumor suppression through activation of SHIP2 phosphatase to inactivate Akt and reduce EMT.\",\n      \"evidence\": \"Co-IP with mass spectrometry, SHIP2 domain-deletion mapping, phosphatase activity assays, and migration/invasion assays in gastric cancer cells\",\n      \"pmids\": [\"32183047\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How IQGAP2 binding elevates SHIP2 catalytic activity mechanistically unclear\", \"Single cancer-cell context\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Resolved the long-standing question of direct IQGAP1-IQGAP2 contact and tied it to ERK suppression, plus identified IQGAP2 as a small-molecule (isoliquiritigenin) target in a CREB-SIRT1 metabolic axis.\",\n      \"evidence\": \"Pull-down assay with overexpression rescue and xenograft model; LiP-SMap target identification with siRNA rescue and phospho-kinase arrays\",\n      \"pmids\": [\"33846302\", \"33860590\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Sequestration model not quantified stoichiometrically\", \"How ISO binding alters IQGAP2 function mechanistically undefined\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Expanded IQGAP2's interactome and roles to insulin-dependent glycogen synthesis (GSK3/GYS), mTOR/AKT proliferation control, and an EBV Rta-driven lytic-cycle program in which IQGAP2 is both a transcriptional target and a nuclear binding partner.\",\n      \"evidence\": \"Co-IP from mouse liver with knockout phenotyping; siRNA with multi-omics and inhibitor rescue; ChIP/promoter binding, co-IP, nuclear co-localization and luciferase reporters\",\n      \"pmids\": [\"37805137\", \"37154877\", \"37504571\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether GSK3/GYS binding is direct vs. complex-mediated unclear\", \"Nuclear pool of IQGAP2 and its function poorly defined\", \"Reconciliation of cytoplasmic scaffold vs. nuclear Rta partner not addressed\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Connected IQGAP2 to apical solute-transporter stabilization (hcTPPT) and to a transcriptional regulatory circuit (ALDH9A1-NPM1) that gates AKT-mTOR signaling in renal carcinoma.\",\n      \"evidence\": \"Yeast two-hybrid, co-IP, co-localization, knockdown/overexpression with TPP uptake assays; RNA-seq, IP, luciferase reporters and in vivo functional assays in ccRCC\",\n      \"pmids\": [\"39401425\", \"39039052\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Generality of transporter-stabilization role beyond hcTPPT unknown\", \"Direct vs. indirect control of IQGAP2 transcription by NPM1 not fully resolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Established IQGAP2 as a regulator of blood-brain barrier immune privilege, suppressing endothelial adhesion-receptor and antigen-processing expression to limit CNS leukocyte infiltration.\",\n      \"evidence\": \"Iqgap2 knockout mice and zebrafish knockdown with single-cell RNA-seq, immunohistology, and leukocyte infiltration quantification\",\n      \"pmids\": [\"40071147\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Endothelial molecular targets downstream of IQGAP2 not pinned to a single pathway\", \"Cell-autonomous mechanism in brain endothelium not fully dissected\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IQGAP2's diverse molecular activities—GTPase scaffolding, actin/calmodulin binding, IQGAP1 sequestration, and multiple signaling partnerships—are coordinated within and across cell types to produce its context-specific tumor-suppressive, metabolic, and barrier functions remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No experimentally solved full-length structure\", \"No unifying model linking cytoplasmic scaffold and nuclear roles\", \"Whether GTPase regulation underlies the tumor-suppressive and metabolic phenotypes is untested\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 10]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [2, 4, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 2]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [3, 4]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [2, 11]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [2]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [3, 17]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 11, 16]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [3, 4]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [8, 9, 19]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [6, 14]}\n    ],\n    \"complexes\": [\n      \"IQGAP2/Arp2/3/actin complex\",\n      \"IQGAP1/IQGAP2/beta-catenin/E-cadherin scaffold\"\n    ],\n    \"partners\": [\n      \"CDC42\",\n      \"RAC1\",\n      \"IQGAP1\",\n      \"CTNNB1\",\n      \"CDH1\",\n      \"RELA\",\n      \"INPPL1\",\n      \"GSK3\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}