{"gene":"IQGAP1","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":1996,"finding":"IQGAP1 (p195) binds directly to GTP-bound Cdc42 and Rac1 but not to Ras, inhibiting their intrinsic GTPase activity; the C-terminal half containing the GRD mediates this interaction in a GRD-dependent fashion. Calmodulin co-immunoprecipitates with IQGAP1 via its IQ domain. IQGAP1 localizes to lamellipodia and ruffling membranes where it co-localizes with actin.","method":"Affinity chromatography pulldown, Co-IP, GTPase activity assay, yeast functional complementation, immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — multiple orthogonal methods (biochemical pulldown, GTPase assay, Co-IP, yeast genetics, immunofluorescence) in a single foundational study","pmids":["8670801"],"is_preprint":false},{"year":1997,"finding":"Purified native IQGAP1 directly binds F-actin and cross-links actin filaments into bundles with gel-like properties. Exogenous calmodulin (especially Ca2+-free form) partially inhibits IQGAP1 binding to F-actin, acting at the calponin homology domain.","method":"Protein purification from bovine adrenal, F-actin co-sedimentation assay, electron microscopy, immunofluorescence with cytochalasin D","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstituted in vitro with purified proteins, multiple orthogonal assays","pmids":["9199170"],"is_preprint":false},{"year":1999,"finding":"Ca2+/calmodulin dissociates Cdc42 from IQGAP1 and abrogates IQGAP1's inhibition of Cdc42 GTPase activity. Calmodulin binds both the calponin homology domain and IQ motifs of IQGAP1; F-actin competes with Ca2+/calmodulin for the calponin homology domain only. Increasing Ca2+ enhances calmodulin–IQGAP1 association with concomitant decrease in Cdc42–IQGAP1 association.","method":"In vitro binding assays with purified proteins, GTPase activity assay, cell lysate co-immunoprecipitation","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution with purified proteins plus multiple domain-mapping and functional assays","pmids":["9867866"],"is_preprint":false},{"year":1999,"finding":"Calmodulin and E-cadherin compete for binding to IQGAP1 in vitro and in cells. E-cadherin is required for accumulation of IQGAP1 at cell–cell junctions. Calmodulin antagonism increases IQGAP1 at cell–cell contacts and decreases E-cadherin there, impairing homophilic E-cadherin adhesion.","method":"In vitro competition binding assay, immunocytochemistry in MCF-7 and MDA-MB-231 cells, calmodulin antagonist (CGS9343B) treatment, cell adhesion assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal competition assays, cell biology with functional adhesion readout, multiple cell lines","pmids":["10608854"],"is_preprint":false},{"year":2002,"finding":"IQGAP1 interacts with CLIP-170, and activated Rac1/Cdc42 form a tripartite complex with IQGAP1 and CLIP-170 to capture microtubule plus ends at the cell cortex, generating a polarized microtubule array. Expression of a C-terminal IQGAP1 fragment delocalizes CLIP-170 from microtubule tips and alters the microtubule array; an IQGAP1 mutant defective in Rac1/Cdc42 binding induces multiple leading edges.","method":"Co-IP, dominant-negative and mutant construct expression, GFP-CLIP-170 live imaging, immunofluorescence in Vero fibroblasts","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple mutant constructs, Co-IP, live imaging, functional cell polarity readouts","pmids":["12110184"],"is_preprint":false},{"year":2003,"finding":"IQGAP1 overexpression enhances cell migration and invasion in a Cdc42- and Rac1-dependent manner; knockdown of endogenous IQGAP1 by siRNA significantly decreases cell motility and invasion. A dominant-negative construct lacking the GRD (IQGAP1ΔGRD) also inhibits invasion mediated by constitutively active Cdc42.","method":"siRNA knockdown, dominant-negative construct transfection, transwell migration and invasion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — bidirectional manipulation (KD and dominant-negative), multiple functional assays","pmids":["12900413"],"is_preprint":false},{"year":2003,"finding":"IQGAP1 associates with AKAP79, which bridges PKA to the C-terminal domain of IQGAP1, forming an IQGAP1/AKAP79/PKA complex in beta-cells and linking cAMP/PKA signaling to Ca2+/calmodulin and GTPase pathways.","method":"cAMP affinity chromatography, co-immunoprecipitation, in vitro binding with GST fusion proteins","journal":"Journal of cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — Co-IP and pulldown but single lab, single study","pmids":["12938160"],"is_preprint":false},{"year":2004,"finding":"ERK2 binds directly to IQGAP1 in vitro; endogenous ERK2 co-immunoprecipitates with IQGAP1 in cells. Manipulation of IQGAP1 levels significantly reduces EGF- and IGF-I-stimulated ERK1/2 activity; an IQGAP1 construct lacking the ERK2-binding region does not affect EGF-stimulated ERK activation.","method":"In vitro binding with purified proteins, Co-IP, IQGAP1 overexpression/knockdown, ERK kinase activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro binding, Co-IP, loss- and gain-of-function with domain-mapping mutants","pmids":["14970219"],"is_preprint":false},{"year":2005,"finding":"Both MEK1 and MEK2 bind directly to IQGAP1 in vitro and co-immunoprecipitate with it; ERK2 enhances MEK2–IQGAP1 interaction fourfold in vitro. EGF differentially regulates binding: enhancing MEK1 and reducing MEK2 interaction. Both knockdown and overexpression of IQGAP1 reduce EGF-stimulated MEK and ERK activation, establishing IQGAP1 as a scaffold for the Ras/MAPK cascade.","method":"In vitro binding, Co-IP, siRNA knockdown, EGF stimulation assays, selective mutant constructs","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding reconstitution, Co-IP, bidirectional manipulation, functional pathway assays","pmids":["16135787"],"is_preprint":false},{"year":2005,"finding":"IQGAP1 self-associates, forming monomers, dimers, and larger oligomers; the self-association region maps to amino acids 763–863. Self-association is required for IQGAP1 to maintain active Cdc42 levels in cells; deletion of this region or competing peptide abolishes Cdc42 activation.","method":"Co-IP in cells, in vitro binding, gel filtration, competing peptide assay, active Cdc42 pulldown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — biochemical domain mapping, in vitro and in-cell assays, functional Cdc42 activation readout","pmids":["16105843"],"is_preprint":false},{"year":2005,"finding":"IQGAP1 is phosphorylated at Ser-1443 (and Ser-1441) by protein kinase Cε in vitro; Ser-1443 is the major site phosphorylated in intact cells after PMA stimulation. A non-phosphorylatable IQGAP1 S1441A/S1443A fails to promote neurite outgrowth, whereas the phosphomimetic S1441E/S1443D markedly enhances it, demonstrating phosphorylation-dependent regulation of IQGAP1 cytoskeletal function.","method":"Mass spectrometry phosphosite identification, in vitro kinase assay with purified PKCε, phosphomimetic and non-phosphorylatable mutant constructs, neurite outgrowth assay in N1E-115 cells","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro kinase reconstitution, MS identification, mutagenesis with functional readout","pmids":["15695813"],"is_preprint":false},{"year":2006,"finding":"IQGAP1 stimulates Arp2/3-dependent actin assembly by activating N-WASP through its C-terminal half (interacting with the BR-CRIB domain of N-WASP in a Cdc42-like manner); the N-terminal half of IQGAP1 antagonizes this activation via intramolecular binding. Signal-induced relief of autoinhibition is proposed to allow N-WASP activation.","method":"Pulldown, Co-IP, kinetic actin polymerization assays with purified proteins and Arp2/3 complex, quantitative co-localization analysis, IQGAP1 siRNA knockdown","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of actin polymerization with purified components plus domain-mapping and cellular validation","pmids":["17085436"],"is_preprint":false},{"year":2007,"finding":"IQGAP1 interacts with the Diaphanous-related formin Dia1 through a region within the Diaphanous inhibitory domain after RhoA-mediated release of Dia1 autoinhibition; this interaction is required for Dia1 subcellular localization, phagocytic cup formation, and phagocytosis in macrophages.","method":"Co-IP, pulldown, immunofluorescence co-localization, siRNA knockdown, phagocytosis assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, pulldown, functional KD phenotype with phagocytosis readout, domain mapping","pmids":["17620407"],"is_preprint":false},{"year":2007,"finding":"IQGAP1 binds directly to the cytoplasmic tail of FGFR1 and to N-WASP; FGF2 stimulation promotes association of IQGAP1 with FGFR1, N-WASP, and Arp2/3 complex in lamellipodia. IQGAP1 stimulates branched actin filament nucleation in vitro in the presence of N-WASP and Arp2/3, linking FGF2 receptor signaling to actin assembly.","method":"In vitro binding with purified proteins, Co-IP, immunofluorescence, actin polymerization assay, siRNA knockdown, cell migration assay","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro reconstitution plus cellular Co-IP and functional migration readout","pmids":["17264147"],"is_preprint":false},{"year":2007,"finding":"IQGAP1 binds directly to Rap1; GTP-loading of Rap1 augments this interaction. Calmodulin (with or without Ca2+) eliminates Rap1–IQGAP1 binding, mapped to the IQ region of IQGAP1. Overexpression of IQGAP1 reduces adhesion- and cAMP-mediated Rap1 activation, while IQGAP1 loss enhances it.","method":"In vitro binding with purified proteins, Co-IP, confocal microscopy, gain- and loss-of-function manipulation, Rap1 activation assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding reconstitution, domain mapping, bidirectional functional assays","pmids":["17517894"],"is_preprint":false},{"year":2007,"finding":"Actin binding (via the calponin homology domain) is essential for IQGAP1 to stimulate cell migration; elimination of Ca2+/calmodulin binding augments IQGAP1-stimulated migration. Both Cdc42 and Rac1 contribute to IQGAP1-stimulated migration.","method":"IQGAP1 point mutant constructs, calmodulin inhibitor peptide, wound-healing and transwell migration assays, immunofluorescence","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mutant constructs with functional readouts, single lab","pmids":["17544257"],"is_preprint":false},{"year":2007,"finding":"Rac1 and Cdc42 use distinct switch-region residues to bind IQGAP1: switch I residues 32 and 36 are important for both; switch II mutations at Asp-63, Arg-68, or Leu-70 abrogate Rac1 binding but do not affect Cdc42 binding. The Rho insert loop does not contribute to IQGAP1 binding. Binding sites for IQGAP1 and RhoGAP on Rac1/Cdc42 only partially overlap.","method":"Site-directed mutagenesis of Rac1/Cdc42, affinity measurements, thermodynamic analysis, competition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — systematic mutagenesis with quantitative binding measurements and thermodynamic analysis","pmids":["17984089"],"is_preprint":false},{"year":2008,"finding":"Ca2+ directly promotes IQGAP1 binding to B-Raf in vitro; calmodulin inhibits this interaction in a Ca2+-regulated manner. Chelation of intracellular Ca2+ enhances EGF-stimulated B-Raf activity in an IQGAP1-dependent manner; EGF promotes B-Raf–IQGAP1 association in cells; Ca2+ ionophores reduce this co-immunoprecipitation.","method":"In vitro binding with purified proteins, Co-IP, calmodulin competition, Ca2+ ionophore and chelator treatment, B-Raf kinase activity assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding reconstitution, mechanistic Ca2+ regulation, multiple orthogonal approaches","pmids":["18567582"],"is_preprint":false},{"year":2008,"finding":"IQGAP1 is required for VEGFR2-mediated signaling: c-Src phosphorylates IQGAP1 on tyrosine and acts as an adaptor bridging IQGAP1 to VEGFR2; IQGAP1 then activates b-Raf and mediates endothelial cell proliferation and angiogenesis.","method":"Co-IP (SH2 domain pulldown), siRNA knockdown of IQGAP1 and b-Raf, in vivo CAM angiogenesis assay, kinase assays","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional knockdown, in vivo assay; single lab","pmids":["19050761"],"is_preprint":false},{"year":2008,"finding":"Cdc42 acts upstream of IQGAP1 in mouse oocytes: Toxin B inhibition of Cdc42 relocates IQGAP1, inhibits polar body emission, and abolishes cortical actin without affecting meiotic spindle migration. IQGAP1 concentrates in the contractile ring during cytokinesis.","method":"Toxin B treatment, immunofluorescence, confocal microscopy in mouse oocytes and embryos","journal":"Developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via pharmacological inhibition with clear localization and functional readouts; single lab","pmids":["18662680"],"is_preprint":false},{"year":2009,"finding":"IQGAP1 interacts with mTOR through its N-terminus; this interaction is required for IQGAP1-mediated cell proliferation. The N-terminus increases cell size while the C-terminus reduces it, suggesting IQGAP1 is a phosphorylation-sensitive conformational switch coupling cell growth and division via a CDC42–mTOR pathway.","method":"Domain-specific fragment expression, Co-IP, cell size measurements, proliferation and transformation assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and domain constructs with functional readouts; single lab","pmids":["19454477"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 binds directly to EGFR through its IQ domain (and the EGFR kinase domain); calmodulin disrupts this interaction. EGF induces IQGAP1 Ser-1443 phosphorylation via PKCα downstream of EGFR. In IQGAP1-null cells, EGF-stimulated EGFR autophosphorylation is severely attenuated and restored by reconstituting wild-type IQGAP1; the S1443D phosphomimetic enhances it.","method":"Co-IP, in vitro binding domain mapping, MS-based phosphorylation assay, IQGAP1-null cell reconstitution with WT and S1443D mutant","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro binding, null-cell reconstitution, MS-based phosphosite, multiple orthogonal approaches","pmids":["21349850"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 binds directly to HER2; knockdown of IQGAP1 decreases HER2 expression, phosphorylation, and signaling; these effects are reversed by IQGAP1 reconstitution. IQGAP1 is overexpressed in trastuzumab-resistant breast cells, and reducing IQGAP1 restores trastuzumab sensitivity.","method":"In vitro binding with purified proteins, siRNA knockdown, reconstitution, immunoprecipitation, cell proliferation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding, reconstitution, bidirectional manipulation, functional drug-sensitivity readout","pmids":["21724847"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 binds c-Raf, MEK1/2, ERK1/2, and AKT in the heart (pulldown). IQGAP1-null mice show impaired MEK1/2–ERK1/2 and AKT phosphorylation at 4 days (but not 10 min) after aortic banding, leading to accelerated adverse cardiac remodeling including impaired cardiomyocyte hypertrophy and increased apoptosis.","method":"Pulldown, IQGAP1-null mouse model, pressure overload (aortic banding), phosphorylation analysis, cardiac histology","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mouse model, pulldown with multiple components, in vivo functional cardiac phenotype","pmids":["21493702"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 is required for MTOC polarization to the NK immune synapse and for perigranular F-actin network formation; IQGAP1 silencing abolishes YTS NK cell cytotoxic activity without preventing conjugate formation.","method":"siRNA silencing, immunofluorescence, confocal microscopy, cytotoxicity assay in YTS and primary NK cells","journal":"European journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA KD with defined cellular phenotypes (MTOC, F-actin, cytotoxicity); single lab","pmids":["21681737"],"is_preprint":false},{"year":2011,"finding":"IQGAP1-deficient CD8+ T cells are hyperresponsive, showing increased IL-2/IFN-γ production, heightened LCK activation, augmented global phosphorylation after TCR ligation, increased F-actin assembly, and amplified F-actin velocities during spreading. Discrete IQGAP1 regions regulate activation and F-actin accumulation via distinct mechanisms.","method":"IQGAP1-null and siRNA-knockdown T cells, IQGAP1 domain constructs, cytokine ELISA, phospho-flow cytometry, live-cell F-actin imaging","journal":"Journal of immunology","confidence":"High","confidence_rationale":"Tier 2 / Strong — null and KD cells, domain constructs, multiple orthogonal functional readouts","pmids":["22573807"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 and CLIP-170 cooperate to regulate dendritic arbor morphology; mTOR kinase interacts with CLIP-170 and is needed for efficient CLIP-170–IQGAP1 complex formation. Dynamic microtubules, CLIP-170, and IQGAP1 regulate dendritic arbor growth via actin cytoskeleton regulation.","method":"Co-IP, siRNA knockdown of CLIP-170 and IQGAP1 in rat neurons, confocal morphometry, mTOR inhibitor treatment","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and siRNA KD with morphological readouts; single lab","pmids":["21430156"],"is_preprint":false},{"year":2012,"finding":"IQGAP1 interacts directly with GTP-bound, prenylated RhoA and RhoC but not RhoB, acting both upstream (stabilizing Rho-GTP) and downstream of RhoA/C to mediate proliferation and migration in breast cancer cells, respectively.","method":"Proteomics screen, Co-IP, siRNA knockdown, active Rho pulldown, adenoviral constitutively active RhoA, DNA synthesis assay, migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — proteomics identification, Co-IP, multiple functional assays, epistasis established by constitutively active constructs plus KD","pmids":["22992742"],"is_preprint":false},{"year":2013,"finding":"IQGAP1 binds TβRII and suppresses TGF-β signaling in hepatic stellate cells by targeting the E3 ligase SMURF1 to the plasma membrane, promoting TβRII ubiquitination and degradation; IQGAP1 knockdown stabilizes TβRII, potentiating TGF-β1-induced myofibroblastic transdifferentiation.","method":"Co-IP, siRNA knockdown, ubiquitination assay, SMURF1 membrane targeting assay, in vivo tumor implantation in Iqgap1-deficient mice","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP, ubiquitination assay, in vivo model, mechanistic pathway with multiple components","pmids":["23454766"],"is_preprint":false},{"year":2013,"finding":"IQGAP1 WW domain peptide disrupts IQGAP1–ERK1/2 interactions and inhibits RAS- and RAF-driven tumorigenesis; disruption of IQGAP1 scaffold function bypasses acquired resistance to vemurafenib (BRAF inhibitor) and extends lifespan of tumor-bearing mice after systemic delivery.","method":"WW domain peptide competition, IQGAP1-null mouse tumorigenesis model, human tissue validation, in vivo survival studies","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — mechanistic peptide disruption, null mouse model, in vivo therapeutic efficacy","pmids":["23603816"],"is_preprint":false},{"year":2013,"finding":"FOXO1 phosphorylated by AKT at Ser-319 binds IQGAP1 in the cytoplasm and impedes IQGAP1-dependent ERK1/2 phosphorylation, acting as a cytoplasmic tumor suppressor; this interaction is abolished by a non-phosphorylatable FOXO1 mutant.","method":"Co-IP, phospho-FOXO1 binding assays, siRNA, phosphomimetic/mutant FOXO1 constructs, pERK1/2 measurement in cells and patient specimens, in vivo peptide inhibitor studies","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP with phospho-specific conditions, mutant constructs, in vivo validation","pmids":["28279977"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 is identified as an LGR4-interacting protein that mediates RSPO-LGR4 interaction with the Wnt signalosome; RSPO stimulation enhances IQGAP1–DVL interaction, and IQGAP1 potentiates both canonical (via MEK1/2-mediated LRP5/6 phosphorylation) and non-canonical Wnt signaling through actin dynamics.","method":"Co-IP, pulldown, siRNA knockdown, Wnt reporter assay, LRP5/6 phosphorylation measurement","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, siRNA KD, functional signaling readouts; single lab","pmids":["24639526"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 binds directly to ERα and ERβ; the IQ domain of IQGAP1 and the hinge region of ERα mediate this interaction. Association is modulated by estradiol in cells. IQGAP1 knockdown attenuates estradiol-induced transcription of estrogen-responsive genes (pS2, progesterone receptor, cyclin D1).","method":"In vitro binding with purified proteins, Co-IP, domain-mapping constructs, siRNA knockdown, transcription reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding reconstitution, Co-IP, functional transcription assay, domain mapping","pmids":["24550401"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 interacts directly with PTPmu; amino acids 765–958 of PTPmu (juxtamembrane plus first phosphatase domain) mediate binding to IQGAP1. Constitutively active Cdc42 (and to a lesser extent Rac1) enhances this interaction. A peptide competing IQGAP1 binding to Rho GTPases blocks PTPmu-mediated neurite outgrowth.","method":"GST-fusion pulldown, direct binding assay, constitutively active Cdc42/Rac1 co-expression, competing peptide, neurite outgrowth assay","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding, domain mapping, functional neurite outgrowth readout; single lab","pmids":["16380380"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 silencing abolishes HGF-induced endothelial barrier enhancement; IQGAP1 forms a complex with EB1 and cortactin in a Rac1-dependent manner, linking MT growth to peripheral cortactin and actin remodeling. IQGAP1ΔC (lacking C-terminal domain) attenuates cortactin–EB1 association.","method":"siRNA knockdown, Co-IP, confocal microscopy, transendothelial electrical resistance measurement, dominant-negative construct","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, KD with functional barrier readout, domain construct; single lab","pmids":["25022754"],"is_preprint":false},{"year":2013,"finding":"IQGAP1 regulates β-catenin nuclear localization through importin-β5; depletion of IQGAP1 or importin-β5 in Xenopus embryos reduces Wnt-induced nuclear accumulation of β-catenin and expression of Wnt target genes. Ran GTPase contributes to IQGAP1/importin-β5-dependent β-catenin nuclear import.","method":"Morpholino knockdown in Xenopus embryos, nuclear fractionation, Wnt target gene expression assay, Co-IP","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo knockdown in Xenopus with functional readout, Co-IP; single lab","pmids":["24196961"],"is_preprint":false},{"year":2015,"finding":"IQGAP1 binds YAP directly via the IQ domain of IQGAP1 and the TEAD-binding domain of YAP; IQGAP1 knockout increases nuclear YAP-TEAD complex formation and YAP-TEAD-mediated transcription, establishing IQGAP1 as a negative regulator of Hippo/YAP transcriptional output.","method":"Co-IP in cells, in vitro binding with purified proteins, domain-mapping constructs, IQGAP1-null MEFs and CRISPR/Cas9 KD cells, TEAD transcription reporter assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding reconstitution, null cells, CRISPR KD, functional transcription assay, domain mapping","pmids":["27440047"],"is_preprint":false},{"year":2015,"finding":"IQGAP1 promotes CXCR4 expression and trafficking by regulating EEA-1+ endosome positioning relative to the MTOC; IQGAP1 depletion disrupts CXCR4 recycling, reduces SDF-1-induced ERK activation and cell migration. SDF-1 induces IQGAP1 binding to α-tubulin and localization to CXCR4-containing endosomes.","method":"siRNA knockdown, immunofluorescence, Co-IP, endosome positioning analysis, CXCR4 recycling assay, ERK activation assay, migration assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with mechanistic imaging, Co-IP, multiple functional readouts; single lab","pmids":["26195666"],"is_preprint":false},{"year":2015,"finding":"IQGAP1 forms dimers that stably bind actin filament sides and transiently cap barbed ends, organizing filaments into thin bundles, suppressing barbed end growth, and inhibiting filament disassembly. Different activities depend on distinct combinations of IQGAP1 domains and/or dimerization.","method":"Single-molecule and single-filament TIRF microscopy with purified full-length human IQGAP1, domain construct analysis","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — single-molecule in vitro reconstitution with purified protein, domain dissection","pmids":["34731043"],"is_preprint":false},{"year":2015,"finding":"IQGAP1 controls tight junction formation through differential regulation of claudin recruitment (reducing claudin-2 expression and TJ recruitment while increasing claudin-4 recruitment); and through CDC42-JNK pathway: IQGAP1 KD increases CDC42 effector JNK activity, and dominant-negative CDC42 prevents the TER increase caused by IQGAP1 silencing.","method":"siRNA knockdown, TER measurement, quantitative confocal microscopy, biochemical claudin analysis, JNK activity assay, dominant-negative CDC42","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — KD with functional TJ readout, epistasis via dominant-negative, multiple molecular mechanisms identified","pmids":["25588839"],"is_preprint":false},{"year":2017,"finding":"The E3 ubiquitin ligase HECTD1 interacts with IQGAP1 and regulates its degradation through ubiquitination; loss of HECTD1 increases IQGAP1 levels, accelerates cell spreading and migration but impairs directionality. IQGAP1 overexpression phenocopies Hectd1-mutant cells; IQGAP1 knockdown rescues the migration defect.","method":"Hectd1 mutant MEFs, Co-IP, ubiquitination assay, siRNA, IQGAP1 overexpression rescue, cell migration and spreading assays","journal":"Cell communication and signaling","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic model (Hectd1 KO), ubiquitination assay, bidirectional rescue experiments, functional readouts","pmids":["28073378"],"is_preprint":false},{"year":2017,"finding":"IQGAP1 is SUMOylated by SUMO1 at K1445; this modification stabilizes IQGAP1 by reducing ubiquitination. IQGAP1 SUMOylation activates ERK, MEK, and AKT phosphorylation; the K1445R mutation abolishes these effects and reduces proliferation, migration, and tumor growth in vivo.","method":"SUMO1 co-expression, mutagenesis (K1445R), ubiquitination assay, kinase phosphorylation analysis, xenograft tumor model","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — site mutagenesis, functional assays, in vivo model; single lab","pmids":["28987385"],"is_preprint":false},{"year":2017,"finding":"IQGAP1 associates with IR (insulin receptor) via its IQ region binding the intracellular domain of IR, and with IRS-1 via the phosphotyrosine-binding domain of IRS-1 and the C-terminal tail of IQGAP1. In IQGAP1-null cells and mice, insulin-stimulated AKT and ERK phosphorylation, PI3K-IRS-1 association, and glucose homeostasis are significantly impaired.","method":"In vitro binding with purified proteins, Co-IP, IQGAP1-null mice, insulin signaling assays, glucose tolerance tests","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct in vitro binding, domain mapping, null mouse in vivo phenotype, multiple signaling readouts","pmids":["28082684"],"is_preprint":false},{"year":2019,"finding":"The kinase GLK/MAP4K3 directly phosphorylates IQGAP1 at Ser-480 via interaction through GLK proline-rich regions and the IQGAP1 WW domain, enhancing Cdc42 activation and cell migration; GLK-induced lung cancer metastasis is abolished by IQGAP1 depletion.","method":"Co-IP, in vitro kinase assay with purified proteins, phosphomimetic/phosphodeficient IQGAP1 constructs, Cdc42 activation assay, siRNA, GLK transgenic mice, lung metastasis model","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro kinase reconstitution, phosphosite identification, domain mapping, in vivo metastasis model","pmids":["31431460"],"is_preprint":false},{"year":2020,"finding":"Ubiquitination of IQGAP1 at Lys-1155 and Lys-1230 in the GRD reduces its binding to CDC42 and RAC1; the non-ubiquitinatable GRD-2K mutant binds significantly more CDC42/RAC1, increases active CDC42 levels, and enhances cell migration compared to WT IQGAP1.","method":"MS-based ubiquitination site identification, K→R mutagenesis, GTPase pulldown, IQGAP1-null cell reconstitution, active CDC42/RAC1 assay, migration assay","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — MS site identification, mutagenesis, null-cell reconstitution, functional GTPase activation and migration readouts","pmids":["32094223"],"is_preprint":false},{"year":2020,"finding":"IQGAP1 sustains VEGFR2-mediated Rac1 activation in choroidal endothelial cells: IQGAP1-mediated Src activation initiates Rac1 activation; IQGAP1 binding to Rac1-GTP maintains sustained Rac1 activity necessary for endothelial cell migration and choroidal neovascularization. Iqgap1−/− mice have reduced laser-induced CNV volumes and decreased Rac1GTP and p-VEGFR2 in CNV lesions.","method":"Iqgap1-null mice, IQGAP1 Rac1-binding-deficient construct, siRNA, Rac1-GTP pulldown, p-VEGFR2 measurement, cell migration/tube formation assay","journal":"Angiogenesis","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mouse model, binding-deficient construct, multiple mechanistic assays","pmids":["32783108"],"is_preprint":false},{"year":2020,"finding":"IQGAP1 scaffolds AMPK by binding directly to the AMPK α1 subunit and to CaMKK2 (via the IQ domain); both associate with IQGAP1 in cells. IQGAP1 deletion reduces metformin- and Ca2+-stimulated AMPK activation; Ca2+-stimulated AMPK phosphorylation is rescued by IQGAP1 re-expression. IQGAP1-null mice show impaired transcriptional regulation of gluconeogenesis and fatty acid synthesis genes during fasting.","method":"In vitro binding with fusion proteins, Co-IP, siRNA KD, IQGAP1-null mice, reconstitution, AMPK kinase activity assay, gene expression analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — direct binding reconstitution, null mouse model, rescue experiments, multiple orthogonal approaches","pmids":["33191271"],"is_preprint":false},{"year":2021,"finding":"IQGAP1 scaffolds the Hippo pathway core kinases MST2 and LATS1, suppressing their kinase activity and YAP1-dependent transcription; IQGAP1 is a negative regulator of the non-canonical pro-apoptotic Hippo pathway. Bile acids regulate the IQGAP1–MST2–LATS1 module in hepatocellular carcinoma cells.","method":"Co-IP, kinase activity assays, YAP transcription reporter, IQGAP1 knockdown/overexpression, bile acid treatment","journal":"Cells","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, functional kinase and transcription assays; single lab","pmids":["33672268"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP with RhoA to promote RhoA inactivation, thereby suppressing airway smooth muscle contractility. IQGAP1 knockdown or knockout increases RhoA activity and airway responsiveness; proximity ligation shows RhoA–p190A-RhoGAP colocalization is lost without IQGAP1.","method":"Co-IP, proximity ligation assay, Iqgap1-null mice, siRNA in human airway smooth muscle cells, RhoA activity assay, tracheal ring contractility, airway resistance measurement","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 / Strong — null mouse model, proximity ligation, Co-IP, human cell KD, in vivo functional readout","pmids":["25271629"],"is_preprint":false},{"year":2022,"finding":"IQGAP1 bridges GSDMD to the ESCRT machinery (specifically Tsg101) to promote exosomal release of pro-IL-1β following NLRP3 inflammasome activation; this process requires LPS-induced GTP-bound CDC42 activation of IQGAP1. IQGAP1 was identified as a GSDMD-interacting protein by unbiased proteomics.","method":"Unbiased proteomics, Co-IP, siRNA knockdown, exosome isolation, NLRP3 inflammasome activation assay, CDC42 activation assay","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 / Strong — unbiased proteomics identification, Co-IP, mechanistic pathway with multiple components, functional exosome release assay","pmids":["36373462"],"is_preprint":false},{"year":2019,"finding":"TRIM56 promotes K48-to-K63-linked poly-ubiquitination transition of IQGAP1 at Lys-1230 by interacting with it, which in turn promotes CDC42 activation to drive glioma cell migration and invasion.","method":"Co-IP, ubiquitination site mutagenesis, CDC42 activation assay, siRNA/overexpression, in vivo glioma model","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, site mutagenesis, functional assays; single lab","pmids":["36870986"],"is_preprint":false},{"year":2010,"finding":"Rap1b colocalization with IQGAP1 upon NK cell activation facilitates sequential phosphorylation of B-Raf, C-Raf, and ERK1/2 and formation of a large IQGAP1-containing signalosome in the perinuclear region, required for NKG2D/Ly49D/NCR1-mediated cytokine production.","method":"Rap1a/b knockout mice, immunofluorescence co-localization, kinase phosphorylation analysis, cytokine assays","journal":"The Journal of experimental medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — KO mice with defined signaling and functional readouts; Co-localization evidence for complex","pmids":["20733035"],"is_preprint":false},{"year":2017,"finding":"IQGAP1 associates with the co-stimulatory receptor OX40 after OX40L ligation, mediated by the C-terminal IQGAP1 region, with TRAF2 bridging these two proteins. IQGAP1 deficiency enhances OX40 cosignaling (proliferation and cytokines) in CD4+ T cells; C-terminal IQGAP1 reconstitution restores normal responses.","method":"Co-IP, IQGAP1-null mice, IQGAP1 domain construct reconstitution, T-cell activation assays, EAE autoimmune model","journal":"FASEB journal","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, null mouse model, reconstitution; single lab","pmids":["31914585"],"is_preprint":false},{"year":2017,"finding":"IQGAP1 associates with NLRC3 and disrupts the NLRC3–STING interaction in the cytosol; IQGAP1 knockdown phenocopies NLRC3 deficiency, causing significantly more IFN-β production in response to cytosolic nucleic acids.","method":"Yeast two-hybrid (interaction identification), Co-IP in human epithelial cells, siRNA knockdown, IFN-β reporter assay","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, siRNA KD with functional IFN-β readout; single lab","pmids":["28864474"],"is_preprint":false},{"year":2023,"finding":"ANGPTL4 (secreted by cancer-associated fibroblasts) binds IQGAP1 on the prostate cancer cell membrane, activating the Raf-MEK-ERK-PGC1α axis to promote mitochondrial biogenesis and OXPHOS metabolism, facilitating tumor growth and chemoresistance.","method":"GST pulldown, Co-IP, metabolomics, ELISA, siRNA/overexpression, drug screening, xenograft model","journal":"Journal of advanced research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pulldown and Co-IP with functional metabolic and proliferative readouts; single lab","pmids":["39647634"],"is_preprint":false}],"current_model":"IQGAP1 is a ubiquitously expressed scaffold protein that directly binds and cross-links F-actin (via its calponin homology domain), inhibits GTPase activity of Cdc42 and Rac1 by stabilizing their GTP-bound state (via its GRD domain), and integrates multiple signaling cascades—including Ras/MAPK (by scaffolding B-Raf, MEK, and ERK), PI3K/AKT, Wnt/β-catenin, Hippo/YAP, AMPK, insulin, VEGFR2, EGFR, and HER2 pathways—through direct protein-protein interactions regulated by Ca2+/calmodulin, post-translational modifications (phosphorylation by PKCε and GLK/MAP4K3, ubiquitination by HECTD1 and TRIM56, SUMOylation at K1445), and self-association, thereby coordinating cell polarity, directed migration, microtubule capture at the cell cortex (via CLIP-170), cytokinesis, cell–cell adhesion, and immune cell function."},"narrative":{"mechanistic_narrative":"IQGAP1 is a ubiquitously expressed multidomain scaffold that integrates actin cytoskeletal dynamics with Rho-family GTPase signaling to coordinate cell polarity, migration, adhesion, and division [PMID:8670801, PMID:12900413]. Through its GAP-related domain it binds selectively to the GTP-bound forms of Cdc42 and Rac1—but not Ras—and inhibits their intrinsic GTPase activity, thereby stabilizing the active state of these GTPases rather than accelerating their inactivation [PMID:8670801, PMID:17984089]; it similarly engages GTP-loaded RhoA/RhoC and Rap1 [PMID:22992742, PMID:17517894]. IQGAP1 directly binds and cross-links F-actin via its calponin homology domain, and as a dimer it caps barbed ends, organizes filaments into bundles, and stimulates Arp2/3-dependent branched nucleation by activating N-WASP, linking receptor inputs such as FGFR1 to lamellipodial actin assembly [PMID:9199170, PMID:34731043, PMID:17085436, PMID:17264147]. By capturing microtubule plus-ends at the cell cortex through a tripartite complex with activated Cdc42/Rac1 and CLIP-170, it generates polarized microtubule arrays that direct migration [PMID:12110184]. A central output is its role as the scaffold of the Ras/MAPK module, binding B-Raf, MEK1/2, and ERK1/2 to enable EGF- and growth-factor-stimulated kinase activation [PMID:14970219, PMID:16135787, PMID:18567582]; disrupting the IQGAP1–ERK interaction with a WW-domain peptide blocks RAS/RAF-driven tumorigenesis and overcomes BRAF-inhibitor resistance [PMID:23603816]. Beyond MAPK, IQGAP1 scaffolds AMPK/CaMKK2, the insulin receptor/IRS-1, VEGFR2, EGFR, and HER2, and acts as a negative regulator of Hippo/YAP signaling by binding YAP and the MST2–LATS1 kinases [PMID:33191271, PMID:28082684, PMID:32783108, PMID:21349850, PMID:21724847, PMID:27440047, PMID:33672268]. Its many interactions are gated by Ca2+/calmodulin, which competes with F-actin, Cdc42, E-cadherin, Rap1, B-Raf and EGFR for distinct IQGAP1 domains [PMID:9867866, PMID:10608854, PMID:18567582, PMID:21349850], and by post-translational modifications including PKCε/PKCα phosphorylation at Ser-1443, GLK-mediated Ser-480 phosphorylation, K1445 SUMOylation, and ubiquitination within the GAP-related domain that tunes its GTPase binding and stability [PMID:15695813, PMID:21349850, PMID:31431460, PMID:28987385, PMID:32094223, PMID:28073378]. IQGAP1 also supports immune effector functions, including NK-cell MTOC polarization and cytotoxicity and the calibration of T-cell activation [PMID:21681737, PMID:22573807].","teleology":[{"year":1996,"claim":"Established the founding biochemical identity of IQGAP1 as a Cdc42/Rac1-selective binding protein that inhibits their GTPase activity and associates with calmodulin and cortical actin, distinguishing it from Ras-targeting regulators.","evidence":"Affinity pulldown, GTPase activity assay, Co-IP, and immunofluorescence in a foundational study","pmids":["8670801"],"confidence":"High","gaps":["Did not resolve whether IQGAP1 acts as a true GAP or an effector that stabilizes GTP-bound state","structural basis of selectivity for Cdc42/Rac1 over Ras not defined"]},{"year":1997,"claim":"Defined IQGAP1 as a direct F-actin cross-linker, providing the structural basis for its cytoskeletal scaffolding function.","evidence":"F-actin co-sedimentation, electron microscopy with purified bovine IQGAP1","pmids":["9199170"],"confidence":"High","gaps":["Single-filament kinetics of actin organization not yet resolved","in vivo consequence of cross-linking not tested"]},{"year":1999,"claim":"Showed that Ca2+/calmodulin is a master switch dissociating IQGAP1 from Cdc42, F-actin and E-cadherin, establishing calmodulin as a competitive regulator that toggles IQGAP1 between signaling and adhesion roles.","evidence":"In vitro competition binding, GTPase assays, and adhesion assays in MCF-7/MDA-MB-231 cells","pmids":["9867866","10608854"],"confidence":"High","gaps":["Quantitative relationship between local Ca2+ flux and partner exchange in vivo not defined","did not address how calmodulin coordinates simultaneous competing partners"]},{"year":2002,"claim":"Resolved how IQGAP1 links GTPase activation to microtubule capture, defining a Cdc42/Rac1–IQGAP1–CLIP-170 tripartite complex that polarizes the microtubule array for directed migration.","evidence":"Co-IP, mutant constructs, and GFP-CLIP-170 live imaging in Vero fibroblasts","pmids":["12110184"],"confidence":"High","gaps":["Stoichiometry and assembly order of the tripartite complex unresolved","how the complex is spatially restricted to the leading edge not defined"]},{"year":2003,"claim":"Demonstrated that IQGAP1 levels bidirectionally control cell migration and invasion in a Cdc42/Rac1-dependent manner, connecting its biochemistry to a functional motility phenotype.","evidence":"siRNA knockdown, dominant-negative GRD construct, transwell migration/invasion assays","pmids":["12900413"],"confidence":"High","gaps":["Did not separate scaffolding from actin cross-linking contributions to motility","in vivo invasion not tested in this study"]},{"year":2007,"claim":"Established IQGAP1 as an activator of Arp2/3-mediated branched actin nucleation through N-WASP, with intramolecular autoinhibition, linking receptor signaling (FGFR1) to lamellipodial actin assembly.","evidence":"Reconstituted actin polymerization with purified proteins/Arp2/3, Co-IP, siRNA, migration assays","pmids":["17085436","17264147"],"confidence":"High","gaps":["Physiological signal that relieves intramolecular autoinhibition not identified","interplay between cross-linking and nucleation activities not resolved"]},{"year":2005,"claim":"Identified IQGAP1 as the scaffold of the Ras/MAPK cascade, binding ERK2, MEK1/2 and B-Raf and required for growth-factor-stimulated kinase activation, defining its central signaling output.","evidence":"Direct in vitro binding, Co-IP, bidirectional manipulation, EGF/IGF-I stimulation kinase assays","pmids":["14970219","16135787","18567582"],"confidence":"High","gaps":["How EGF differentially partitions MEK1 versus MEK2 binding mechanistically unresolved","stoichiometry of the assembled MAPK module on IQGAP1 not defined"]},{"year":2005,"claim":"Showed IQGAP1 self-association (residues 763–863) and PKCε phosphorylation at Ser-1443 are required for its cellular functions, establishing oligomerization and phosphorylation as regulatory layers.","evidence":"Co-IP, gel filtration, competing peptide, MS phosphosite ID, kinase assay, neurite outgrowth in N1E-115 cells","pmids":["16105843","15695813"],"confidence":"High","gaps":["Structural form of physiologically active oligomer unresolved","the upstream signal triggering self-association in cells not defined"]},{"year":2011,"claim":"Extended IQGAP1's receptor scaffolding to EGFR and HER2, showing it is required for receptor autophosphorylation and signaling, with phosphorylation- and calmodulin-gated control and therapeutic relevance to trastuzumab resistance.","evidence":"Direct in vitro binding, null-cell reconstitution, MS phosphosite, knockdown, drug-sensitivity assays","pmids":["21349850","21724847"],"confidence":"High","gaps":["Whether IQGAP1 directly enhances receptor kinase activity or stabilizes receptor not fully separated","structural basis of IQ-domain/receptor binding not defined"]},{"year":2013,"claim":"Validated IQGAP1 scaffold disruption as a therapeutic strategy, showing a WW-domain peptide blocks RAS/RAF-driven tumors and bypasses BRAF-inhibitor resistance in vivo.","evidence":"WW-domain peptide competition, IQGAP1-null tumor model, in vivo survival studies","pmids":["23603816"],"confidence":"High","gaps":["Generality across additional RAS/RAF-driven tumor types not fully mapped","off-pathway effects of WW-peptide on other IQGAP1 functions not characterized"]},{"year":2016,"claim":"Defined IQGAP1 as a negative regulator of Hippo/YAP output, directly binding YAP and later the MST2–LATS1 kinases to suppress TEAD-dependent transcription, broadening its role beyond MAPK.","evidence":"Direct binding, IQGAP1-null MEFs/CRISPR KD, TEAD reporter, kinase assays","pmids":["27440047","33672268"],"confidence":"High","gaps":["How IQGAP1 simultaneously coordinates Hippo, MAPK and adhesion modules unresolved","context determining activation versus suppression of YAP not defined"]},{"year":2017,"claim":"Established a post-translational code governing IQGAP1 stability and GTPase binding, with SUMOylation at K1445, GLK-mediated Ser-480 phosphorylation, and ubiquitination within the GRD all tuning Cdc42/Rac1 activation and migration.","evidence":"Site mutagenesis, MS site identification, ubiquitination assays, null-cell reconstitution, in vivo metastasis models","pmids":["28987385","31431460","32094223","28073378","36870986"],"confidence":"High","gaps":["Hierarchy and cross-talk among the modifications not integrated","the enzymes responsible for several modifications only partially identified"]},{"year":2020,"claim":"Expanded IQGAP1's scaffolding to metabolic and vascular signaling, showing it directly assembles AMPK/CaMKK2 and IR/IRS-1 modules and sustains VEGFR2–Rac1 signaling, with in vivo glucose-homeostasis and angiogenesis phenotypes.","evidence":"Direct binding, Co-IP, IQGAP1-null mice, rescue, kinase and GTPase activation assays","pmids":["33191271","28082684","32783108"],"confidence":"High","gaps":["How a single scaffold partitions among competing metabolic and growth modules unresolved","tissue-specific selectivity of these complexes not defined"]},{"year":2022,"claim":"Connected IQGAP1 to inflammasome-driven secretion, showing CDC42-activated IQGAP1 bridges GSDMD to ESCRT/Tsg101 for exosomal pro-IL-1β release, illustrating a non-migratory effector role.","evidence":"Unbiased proteomics, Co-IP, knockdown, exosome isolation, NLRP3 activation, CDC42 activation assay","pmids":["36373462"],"confidence":"High","gaps":["Whether this is a general route for cargo secretion beyond IL-1β not established","structural basis of GSDMD–IQGAP1–Tsg101 bridging unresolved"]},{"year":null,"claim":"How IQGAP1 dynamically prioritizes and spatially segregates its many competing partners—across Rho GTPases, MAPK, Hippo, metabolic and immune modules—into discrete functional outcomes within a single cell remains unresolved.","evidence":"No single study reconstitutes the integrated decision logic; competition is documented partner-by-partner","pmids":[],"confidence":"Low","gaps":["No structural model of full-length multidomain IQGAP1 with multiple partners","quantitative rules governing partner exchange under physiological Ca2+/PTM states not established","spatial organization of distinct IQGAP1 signalosomes within one cell not defined"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,7,8,36,42,46,48]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[1,11,38]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,9,16,27]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[1,38]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[1,4,38]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,3,21,28]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[30,35]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[37]},{"term_id":"GO:0005815","term_label":"microtubule organizing center","supporting_discovery_ids":[4,24,37]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[7,8,17,36,42,46]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[4,10,19,26]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[24,25,49,51,52,53]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[42,46,54]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[37,49]}],"complexes":["Ras/MAPK scaffold module (B-Raf/MEK1/2/ERK1/2)","Cdc42/Rac1–IQGAP1–CLIP-170 microtubule-capture complex"],"partners":["CDC42","RAC1","CALM1","MAP2K1","MAPK1","BRAF","EGFR","CLIP-170"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P46940","full_name":"Ras GTPase-activating-like protein IQGAP1","aliases":["p195"],"length_aa":1657,"mass_kda":189.3,"function":"Plays a crucial role in regulating the dynamics and assembly of the actin cytoskeleton. Recruited to the cell cortex by interaction with ILK which allows it to cooperate with its effector DIAPH1 to locally stabilize microtubules and allow stable insertion of caveolae into the plasma membrane (By similarity). Binds to activated CDC42 but does not stimulate its GTPase activity. Associates with calmodulin. May promote neurite outgrowth (PubMed:15695813). May play a possible role in cell cycle regulation by contributing to cell cycle progression after DNA replication arrest (PubMed:20883816)","subcellular_location":"Cell membrane; Nucleus; Cytoplasm; Cytoplasm, cell cortex; Apical cell membrane; Basolateral cell membrane","url":"https://www.uniprot.org/uniprotkb/P46940/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/IQGAP1","classification":"Not Classified","n_dependent_lines":34,"n_total_lines":1208,"dependency_fraction":0.028145695364238412},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"CALM1","stoichiometry":0.2},{"gene":"CALM2","stoichiometry":0.2},{"gene":"CALM3","stoichiometry":0.2},{"gene":"CDC42","stoichiometry":0.2},{"gene":"MYL6","stoichiometry":0.2},{"gene":"MYL6B","stoichiometry":0.2},{"gene":"RAC1","stoichiometry":0.2},{"gene":"RAC3","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/IQGAP1","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":"619865","title":"TRANSMEMBRANE PROTEIN 14B; TMEM14B","url":"https://www.omim.org/entry/619865"},{"mim_id":"618649","title":"HECT DOMAIN E3 UBIQUITIN PROTEIN LIGASE 1; HECTD1","url":"https://www.omim.org/entry/618649"},{"mim_id":"611731","title":"APC REGULATOR OF WNT SIGNALING PATHWAY; APC","url":"https://www.omim.org/entry/611731"},{"mim_id":"609618","title":"NONCODING REPRESSOR OF NFAT; NRON","url":"https://www.omim.org/entry/609618"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Plasma membrane","reliability":"Supported"},{"location":"Cell Junctions","reliability":"Supported"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/IQGAP1"},"hgnc":{"alias_symbol":["p195","KIAA0051","SAR1","HUMORFA01"],"prev_symbol":[]},"alphafold":{"accession":"P46940","domains":[{"cath_id":"1.10.418.10","chopping":"29-212","consensus_level":"high","plddt":81.8137,"start":29,"end":212},{"cath_id":"-","chopping":"217-272_288-381","consensus_level":"medium","plddt":83.8765,"start":217,"end":381},{"cath_id":"-","chopping":"487-602","consensus_level":"medium","plddt":87.0747,"start":487,"end":602},{"cath_id":"-","chopping":"616-731","consensus_level":"high","plddt":88.3113,"start":616,"end":731},{"cath_id":"-","chopping":"785-861","consensus_level":"medium","plddt":78.8091,"start":785,"end":861},{"cath_id":"-","chopping":"870-885_1373-1512","consensus_level":"high","plddt":76.9466,"start":870,"end":1512},{"cath_id":"1.10.506.10","chopping":"1048-1089_1121-1256","consensus_level":"medium","plddt":84.9901,"start":1048,"end":1256},{"cath_id":"-","chopping":"1562-1656","consensus_level":"medium","plddt":77.1173,"start":1562,"end":1656}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P46940","model_url":"https://alphafold.ebi.ac.uk/files/AF-P46940-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P46940-F1-predicted_aligned_error_v6.png","plddt_mean":78.38},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=IQGAP1","jax_strain_url":"https://www.jax.org/strain/search?query=IQGAP1"},"sequence":{"accession":"P46940","fasta_url":"https://rest.uniprot.org/uniprotkb/P46940.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P46940/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P46940"}},"corpus_meta":[{"pmid":"12110184","id":"PMC_12110184","title":"Rac1 and Cdc42 capture microtubules through IQGAP1 and CLIP-170.","date":"2002","source":"Cell","url":"https://pubmed.ncbi.nlm.nih.gov/12110184","citation_count":503,"is_preprint":false},{"pmid":"8670801","id":"PMC_8670801","title":"IQGAP1, a calmodulin-binding protein with a rasGAP-related domain, is a potential effector for cdc42Hs.","date":"1996","source":"The EMBO journal","url":"https://pubmed.ncbi.nlm.nih.gov/8670801","citation_count":342,"is_preprint":false},{"pmid":"15890984","id":"PMC_15890984","title":"IQGAP1: a key regulator of adhesion and migration.","date":"2005","source":"Journal of cell science","url":"https://pubmed.ncbi.nlm.nih.gov/15890984","citation_count":304,"is_preprint":false},{"pmid":"16595175","id":"PMC_16595175","title":"IQGAP1 in cellular signaling: bridging the GAP.","date":"2006","source":"Trends in cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/16595175","citation_count":256,"is_preprint":false},{"pmid":"9199170","id":"PMC_9199170","title":"IQGAP1, a 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Pathway.","date":"2021","source":"Cells","url":"https://pubmed.ncbi.nlm.nih.gov/33672268","citation_count":17,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":50868,"output_tokens":13751,"usd":0.179434,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":25346,"output_tokens":5432,"usd":0.131265,"stage2_stop_reason":"end_turn"},"total_usd":0.310699,"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\": \"IQGAP1 (p195) binds directly to GTP-bound Cdc42 and Rac1 but not to Ras, inhibiting their intrinsic GTPase activity; the C-terminal half containing the GRD mediates this interaction in a GRD-dependent fashion. Calmodulin co-immunoprecipitates with IQGAP1 via its IQ domain. IQGAP1 localizes to lamellipodia and ruffling membranes where it co-localizes with actin.\",\n      \"method\": \"Affinity chromatography pulldown, Co-IP, GTPase activity assay, yeast functional complementation, immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — multiple orthogonal methods (biochemical pulldown, GTPase assay, Co-IP, yeast genetics, immunofluorescence) in a single foundational study\",\n      \"pmids\": [\"8670801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Purified native IQGAP1 directly binds F-actin and cross-links actin filaments into bundles with gel-like properties. Exogenous calmodulin (especially Ca2+-free form) partially inhibits IQGAP1 binding to F-actin, acting at the calponin homology domain.\",\n      \"method\": \"Protein purification from bovine adrenal, F-actin co-sedimentation assay, electron microscopy, immunofluorescence with cytochalasin D\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstituted in vitro with purified proteins, multiple orthogonal assays\",\n      \"pmids\": [\"9199170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Ca2+/calmodulin dissociates Cdc42 from IQGAP1 and abrogates IQGAP1's inhibition of Cdc42 GTPase activity. Calmodulin binds both the calponin homology domain and IQ motifs of IQGAP1; F-actin competes with Ca2+/calmodulin for the calponin homology domain only. Increasing Ca2+ enhances calmodulin–IQGAP1 association with concomitant decrease in Cdc42–IQGAP1 association.\",\n      \"method\": \"In vitro binding assays with purified proteins, GTPase activity assay, cell lysate co-immunoprecipitation\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution with purified proteins plus multiple domain-mapping and functional assays\",\n      \"pmids\": [\"9867866\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Calmodulin and E-cadherin compete for binding to IQGAP1 in vitro and in cells. E-cadherin is required for accumulation of IQGAP1 at cell–cell junctions. Calmodulin antagonism increases IQGAP1 at cell–cell contacts and decreases E-cadherin there, impairing homophilic E-cadherin adhesion.\",\n      \"method\": \"In vitro competition binding assay, immunocytochemistry in MCF-7 and MDA-MB-231 cells, calmodulin antagonist (CGS9343B) treatment, cell adhesion assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal competition assays, cell biology with functional adhesion readout, multiple cell lines\",\n      \"pmids\": [\"10608854\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IQGAP1 interacts with CLIP-170, and activated Rac1/Cdc42 form a tripartite complex with IQGAP1 and CLIP-170 to capture microtubule plus ends at the cell cortex, generating a polarized microtubule array. Expression of a C-terminal IQGAP1 fragment delocalizes CLIP-170 from microtubule tips and alters the microtubule array; an IQGAP1 mutant defective in Rac1/Cdc42 binding induces multiple leading edges.\",\n      \"method\": \"Co-IP, dominant-negative and mutant construct expression, GFP-CLIP-170 live imaging, immunofluorescence in Vero fibroblasts\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple mutant constructs, Co-IP, live imaging, functional cell polarity readouts\",\n      \"pmids\": [\"12110184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IQGAP1 overexpression enhances cell migration and invasion in a Cdc42- and Rac1-dependent manner; knockdown of endogenous IQGAP1 by siRNA significantly decreases cell motility and invasion. A dominant-negative construct lacking the GRD (IQGAP1ΔGRD) also inhibits invasion mediated by constitutively active Cdc42.\",\n      \"method\": \"siRNA knockdown, dominant-negative construct transfection, transwell migration and invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — bidirectional manipulation (KD and dominant-negative), multiple functional assays\",\n      \"pmids\": [\"12900413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IQGAP1 associates with AKAP79, which bridges PKA to the C-terminal domain of IQGAP1, forming an IQGAP1/AKAP79/PKA complex in beta-cells and linking cAMP/PKA signaling to Ca2+/calmodulin and GTPase pathways.\",\n      \"method\": \"cAMP affinity chromatography, co-immunoprecipitation, in vitro binding with GST fusion proteins\",\n      \"journal\": \"Journal of cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — Co-IP and pulldown but single lab, single study\",\n      \"pmids\": [\"12938160\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"ERK2 binds directly to IQGAP1 in vitro; endogenous ERK2 co-immunoprecipitates with IQGAP1 in cells. Manipulation of IQGAP1 levels significantly reduces EGF- and IGF-I-stimulated ERK1/2 activity; an IQGAP1 construct lacking the ERK2-binding region does not affect EGF-stimulated ERK activation.\",\n      \"method\": \"In vitro binding with purified proteins, Co-IP, IQGAP1 overexpression/knockdown, ERK kinase activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro binding, Co-IP, loss- and gain-of-function with domain-mapping mutants\",\n      \"pmids\": [\"14970219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Both MEK1 and MEK2 bind directly to IQGAP1 in vitro and co-immunoprecipitate with it; ERK2 enhances MEK2–IQGAP1 interaction fourfold in vitro. EGF differentially regulates binding: enhancing MEK1 and reducing MEK2 interaction. Both knockdown and overexpression of IQGAP1 reduce EGF-stimulated MEK and ERK activation, establishing IQGAP1 as a scaffold for the Ras/MAPK cascade.\",\n      \"method\": \"In vitro binding, Co-IP, siRNA knockdown, EGF stimulation assays, selective mutant constructs\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding reconstitution, Co-IP, bidirectional manipulation, functional pathway assays\",\n      \"pmids\": [\"16135787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IQGAP1 self-associates, forming monomers, dimers, and larger oligomers; the self-association region maps to amino acids 763–863. Self-association is required for IQGAP1 to maintain active Cdc42 levels in cells; deletion of this region or competing peptide abolishes Cdc42 activation.\",\n      \"method\": \"Co-IP in cells, in vitro binding, gel filtration, competing peptide assay, active Cdc42 pulldown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — biochemical domain mapping, in vitro and in-cell assays, functional Cdc42 activation readout\",\n      \"pmids\": [\"16105843\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IQGAP1 is phosphorylated at Ser-1443 (and Ser-1441) by protein kinase Cε in vitro; Ser-1443 is the major site phosphorylated in intact cells after PMA stimulation. A non-phosphorylatable IQGAP1 S1441A/S1443A fails to promote neurite outgrowth, whereas the phosphomimetic S1441E/S1443D markedly enhances it, demonstrating phosphorylation-dependent regulation of IQGAP1 cytoskeletal function.\",\n      \"method\": \"Mass spectrometry phosphosite identification, in vitro kinase assay with purified PKCε, phosphomimetic and non-phosphorylatable mutant constructs, neurite outgrowth assay in N1E-115 cells\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro kinase reconstitution, MS identification, mutagenesis with functional readout\",\n      \"pmids\": [\"15695813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"IQGAP1 stimulates Arp2/3-dependent actin assembly by activating N-WASP through its C-terminal half (interacting with the BR-CRIB domain of N-WASP in a Cdc42-like manner); the N-terminal half of IQGAP1 antagonizes this activation via intramolecular binding. Signal-induced relief of autoinhibition is proposed to allow N-WASP activation.\",\n      \"method\": \"Pulldown, Co-IP, kinetic actin polymerization assays with purified proteins and Arp2/3 complex, quantitative co-localization analysis, IQGAP1 siRNA knockdown\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of actin polymerization with purified components plus domain-mapping and cellular validation\",\n      \"pmids\": [\"17085436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IQGAP1 interacts with the Diaphanous-related formin Dia1 through a region within the Diaphanous inhibitory domain after RhoA-mediated release of Dia1 autoinhibition; this interaction is required for Dia1 subcellular localization, phagocytic cup formation, and phagocytosis in macrophages.\",\n      \"method\": \"Co-IP, pulldown, immunofluorescence co-localization, siRNA knockdown, phagocytosis assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, pulldown, functional KD phenotype with phagocytosis readout, domain mapping\",\n      \"pmids\": [\"17620407\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IQGAP1 binds directly to the cytoplasmic tail of FGFR1 and to N-WASP; FGF2 stimulation promotes association of IQGAP1 with FGFR1, N-WASP, and Arp2/3 complex in lamellipodia. IQGAP1 stimulates branched actin filament nucleation in vitro in the presence of N-WASP and Arp2/3, linking FGF2 receptor signaling to actin assembly.\",\n      \"method\": \"In vitro binding with purified proteins, Co-IP, immunofluorescence, actin polymerization assay, siRNA knockdown, cell migration assay\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro reconstitution plus cellular Co-IP and functional migration readout\",\n      \"pmids\": [\"17264147\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IQGAP1 binds directly to Rap1; GTP-loading of Rap1 augments this interaction. Calmodulin (with or without Ca2+) eliminates Rap1–IQGAP1 binding, mapped to the IQ region of IQGAP1. Overexpression of IQGAP1 reduces adhesion- and cAMP-mediated Rap1 activation, while IQGAP1 loss enhances it.\",\n      \"method\": \"In vitro binding with purified proteins, Co-IP, confocal microscopy, gain- and loss-of-function manipulation, Rap1 activation assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding reconstitution, domain mapping, bidirectional functional assays\",\n      \"pmids\": [\"17517894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Actin binding (via the calponin homology domain) is essential for IQGAP1 to stimulate cell migration; elimination of Ca2+/calmodulin binding augments IQGAP1-stimulated migration. Both Cdc42 and Rac1 contribute to IQGAP1-stimulated migration.\",\n      \"method\": \"IQGAP1 point mutant constructs, calmodulin inhibitor peptide, wound-healing and transwell migration assays, immunofluorescence\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mutant constructs with functional readouts, single lab\",\n      \"pmids\": [\"17544257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Rac1 and Cdc42 use distinct switch-region residues to bind IQGAP1: switch I residues 32 and 36 are important for both; switch II mutations at Asp-63, Arg-68, or Leu-70 abrogate Rac1 binding but do not affect Cdc42 binding. The Rho insert loop does not contribute to IQGAP1 binding. Binding sites for IQGAP1 and RhoGAP on Rac1/Cdc42 only partially overlap.\",\n      \"method\": \"Site-directed mutagenesis of Rac1/Cdc42, affinity measurements, thermodynamic analysis, competition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — systematic mutagenesis with quantitative binding measurements and thermodynamic analysis\",\n      \"pmids\": [\"17984089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Ca2+ directly promotes IQGAP1 binding to B-Raf in vitro; calmodulin inhibits this interaction in a Ca2+-regulated manner. Chelation of intracellular Ca2+ enhances EGF-stimulated B-Raf activity in an IQGAP1-dependent manner; EGF promotes B-Raf–IQGAP1 association in cells; Ca2+ ionophores reduce this co-immunoprecipitation.\",\n      \"method\": \"In vitro binding with purified proteins, Co-IP, calmodulin competition, Ca2+ ionophore and chelator treatment, B-Raf kinase activity assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding reconstitution, mechanistic Ca2+ regulation, multiple orthogonal approaches\",\n      \"pmids\": [\"18567582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IQGAP1 is required for VEGFR2-mediated signaling: c-Src phosphorylates IQGAP1 on tyrosine and acts as an adaptor bridging IQGAP1 to VEGFR2; IQGAP1 then activates b-Raf and mediates endothelial cell proliferation and angiogenesis.\",\n      \"method\": \"Co-IP (SH2 domain pulldown), siRNA knockdown of IQGAP1 and b-Raf, in vivo CAM angiogenesis assay, kinase assays\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional knockdown, in vivo assay; single lab\",\n      \"pmids\": [\"19050761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Cdc42 acts upstream of IQGAP1 in mouse oocytes: Toxin B inhibition of Cdc42 relocates IQGAP1, inhibits polar body emission, and abolishes cortical actin without affecting meiotic spindle migration. IQGAP1 concentrates in the contractile ring during cytokinesis.\",\n      \"method\": \"Toxin B treatment, immunofluorescence, confocal microscopy in mouse oocytes and embryos\",\n      \"journal\": \"Developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via pharmacological inhibition with clear localization and functional readouts; single lab\",\n      \"pmids\": [\"18662680\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IQGAP1 interacts with mTOR through its N-terminus; this interaction is required for IQGAP1-mediated cell proliferation. The N-terminus increases cell size while the C-terminus reduces it, suggesting IQGAP1 is a phosphorylation-sensitive conformational switch coupling cell growth and division via a CDC42–mTOR pathway.\",\n      \"method\": \"Domain-specific fragment expression, Co-IP, cell size measurements, proliferation and transformation assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and domain constructs with functional readouts; single lab\",\n      \"pmids\": [\"19454477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 binds directly to EGFR through its IQ domain (and the EGFR kinase domain); calmodulin disrupts this interaction. EGF induces IQGAP1 Ser-1443 phosphorylation via PKCα downstream of EGFR. In IQGAP1-null cells, EGF-stimulated EGFR autophosphorylation is severely attenuated and restored by reconstituting wild-type IQGAP1; the S1443D phosphomimetic enhances it.\",\n      \"method\": \"Co-IP, in vitro binding domain mapping, MS-based phosphorylation assay, IQGAP1-null cell reconstitution with WT and S1443D mutant\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro binding, null-cell reconstitution, MS-based phosphosite, multiple orthogonal approaches\",\n      \"pmids\": [\"21349850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 binds directly to HER2; knockdown of IQGAP1 decreases HER2 expression, phosphorylation, and signaling; these effects are reversed by IQGAP1 reconstitution. IQGAP1 is overexpressed in trastuzumab-resistant breast cells, and reducing IQGAP1 restores trastuzumab sensitivity.\",\n      \"method\": \"In vitro binding with purified proteins, siRNA knockdown, reconstitution, immunoprecipitation, cell proliferation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding, reconstitution, bidirectional manipulation, functional drug-sensitivity readout\",\n      \"pmids\": [\"21724847\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 binds c-Raf, MEK1/2, ERK1/2, and AKT in the heart (pulldown). IQGAP1-null mice show impaired MEK1/2–ERK1/2 and AKT phosphorylation at 4 days (but not 10 min) after aortic banding, leading to accelerated adverse cardiac remodeling including impaired cardiomyocyte hypertrophy and increased apoptosis.\",\n      \"method\": \"Pulldown, IQGAP1-null mouse model, pressure overload (aortic banding), phosphorylation analysis, cardiac histology\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mouse model, pulldown with multiple components, in vivo functional cardiac phenotype\",\n      \"pmids\": [\"21493702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 is required for MTOC polarization to the NK immune synapse and for perigranular F-actin network formation; IQGAP1 silencing abolishes YTS NK cell cytotoxic activity without preventing conjugate formation.\",\n      \"method\": \"siRNA silencing, immunofluorescence, confocal microscopy, cytotoxicity assay in YTS and primary NK cells\",\n      \"journal\": \"European journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA KD with defined cellular phenotypes (MTOC, F-actin, cytotoxicity); single lab\",\n      \"pmids\": [\"21681737\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1-deficient CD8+ T cells are hyperresponsive, showing increased IL-2/IFN-γ production, heightened LCK activation, augmented global phosphorylation after TCR ligation, increased F-actin assembly, and amplified F-actin velocities during spreading. Discrete IQGAP1 regions regulate activation and F-actin accumulation via distinct mechanisms.\",\n      \"method\": \"IQGAP1-null and siRNA-knockdown T cells, IQGAP1 domain constructs, cytokine ELISA, phospho-flow cytometry, live-cell F-actin imaging\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null and KD cells, domain constructs, multiple orthogonal functional readouts\",\n      \"pmids\": [\"22573807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 and CLIP-170 cooperate to regulate dendritic arbor morphology; mTOR kinase interacts with CLIP-170 and is needed for efficient CLIP-170–IQGAP1 complex formation. Dynamic microtubules, CLIP-170, and IQGAP1 regulate dendritic arbor growth via actin cytoskeleton regulation.\",\n      \"method\": \"Co-IP, siRNA knockdown of CLIP-170 and IQGAP1 in rat neurons, confocal morphometry, mTOR inhibitor treatment\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and siRNA KD with morphological readouts; single lab\",\n      \"pmids\": [\"21430156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IQGAP1 interacts directly with GTP-bound, prenylated RhoA and RhoC but not RhoB, acting both upstream (stabilizing Rho-GTP) and downstream of RhoA/C to mediate proliferation and migration in breast cancer cells, respectively.\",\n      \"method\": \"Proteomics screen, Co-IP, siRNA knockdown, active Rho pulldown, adenoviral constitutively active RhoA, DNA synthesis assay, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — proteomics identification, Co-IP, multiple functional assays, epistasis established by constitutively active constructs plus KD\",\n      \"pmids\": [\"22992742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IQGAP1 binds TβRII and suppresses TGF-β signaling in hepatic stellate cells by targeting the E3 ligase SMURF1 to the plasma membrane, promoting TβRII ubiquitination and degradation; IQGAP1 knockdown stabilizes TβRII, potentiating TGF-β1-induced myofibroblastic transdifferentiation.\",\n      \"method\": \"Co-IP, siRNA knockdown, ubiquitination assay, SMURF1 membrane targeting assay, in vivo tumor implantation in Iqgap1-deficient mice\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP, ubiquitination assay, in vivo model, mechanistic pathway with multiple components\",\n      \"pmids\": [\"23454766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IQGAP1 WW domain peptide disrupts IQGAP1–ERK1/2 interactions and inhibits RAS- and RAF-driven tumorigenesis; disruption of IQGAP1 scaffold function bypasses acquired resistance to vemurafenib (BRAF inhibitor) and extends lifespan of tumor-bearing mice after systemic delivery.\",\n      \"method\": \"WW domain peptide competition, IQGAP1-null mouse tumorigenesis model, human tissue validation, in vivo survival studies\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — mechanistic peptide disruption, null mouse model, in vivo therapeutic efficacy\",\n      \"pmids\": [\"23603816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FOXO1 phosphorylated by AKT at Ser-319 binds IQGAP1 in the cytoplasm and impedes IQGAP1-dependent ERK1/2 phosphorylation, acting as a cytoplasmic tumor suppressor; this interaction is abolished by a non-phosphorylatable FOXO1 mutant.\",\n      \"method\": \"Co-IP, phospho-FOXO1 binding assays, siRNA, phosphomimetic/mutant FOXO1 constructs, pERK1/2 measurement in cells and patient specimens, in vivo peptide inhibitor studies\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP with phospho-specific conditions, mutant constructs, in vivo validation\",\n      \"pmids\": [\"28279977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 is identified as an LGR4-interacting protein that mediates RSPO-LGR4 interaction with the Wnt signalosome; RSPO stimulation enhances IQGAP1–DVL interaction, and IQGAP1 potentiates both canonical (via MEK1/2-mediated LRP5/6 phosphorylation) and non-canonical Wnt signaling through actin dynamics.\",\n      \"method\": \"Co-IP, pulldown, siRNA knockdown, Wnt reporter assay, LRP5/6 phosphorylation measurement\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, siRNA KD, functional signaling readouts; single lab\",\n      \"pmids\": [\"24639526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 binds directly to ERα and ERβ; the IQ domain of IQGAP1 and the hinge region of ERα mediate this interaction. Association is modulated by estradiol in cells. IQGAP1 knockdown attenuates estradiol-induced transcription of estrogen-responsive genes (pS2, progesterone receptor, cyclin D1).\",\n      \"method\": \"In vitro binding with purified proteins, Co-IP, domain-mapping constructs, siRNA knockdown, transcription reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding reconstitution, Co-IP, functional transcription assay, domain mapping\",\n      \"pmids\": [\"24550401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 interacts directly with PTPmu; amino acids 765–958 of PTPmu (juxtamembrane plus first phosphatase domain) mediate binding to IQGAP1. Constitutively active Cdc42 (and to a lesser extent Rac1) enhances this interaction. A peptide competing IQGAP1 binding to Rho GTPases blocks PTPmu-mediated neurite outgrowth.\",\n      \"method\": \"GST-fusion pulldown, direct binding assay, constitutively active Cdc42/Rac1 co-expression, competing peptide, neurite outgrowth assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding, domain mapping, functional neurite outgrowth readout; single lab\",\n      \"pmids\": [\"16380380\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 silencing abolishes HGF-induced endothelial barrier enhancement; IQGAP1 forms a complex with EB1 and cortactin in a Rac1-dependent manner, linking MT growth to peripheral cortactin and actin remodeling. IQGAP1ΔC (lacking C-terminal domain) attenuates cortactin–EB1 association.\",\n      \"method\": \"siRNA knockdown, Co-IP, confocal microscopy, transendothelial electrical resistance measurement, dominant-negative construct\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, KD with functional barrier readout, domain construct; single lab\",\n      \"pmids\": [\"25022754\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IQGAP1 regulates β-catenin nuclear localization through importin-β5; depletion of IQGAP1 or importin-β5 in Xenopus embryos reduces Wnt-induced nuclear accumulation of β-catenin and expression of Wnt target genes. Ran GTPase contributes to IQGAP1/importin-β5-dependent β-catenin nuclear import.\",\n      \"method\": \"Morpholino knockdown in Xenopus embryos, nuclear fractionation, Wnt target gene expression assay, Co-IP\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo knockdown in Xenopus with functional readout, Co-IP; single lab\",\n      \"pmids\": [\"24196961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP1 binds YAP directly via the IQ domain of IQGAP1 and the TEAD-binding domain of YAP; IQGAP1 knockout increases nuclear YAP-TEAD complex formation and YAP-TEAD-mediated transcription, establishing IQGAP1 as a negative regulator of Hippo/YAP transcriptional output.\",\n      \"method\": \"Co-IP in cells, in vitro binding with purified proteins, domain-mapping constructs, IQGAP1-null MEFs and CRISPR/Cas9 KD cells, TEAD transcription reporter assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding reconstitution, null cells, CRISPR KD, functional transcription assay, domain mapping\",\n      \"pmids\": [\"27440047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP1 promotes CXCR4 expression and trafficking by regulating EEA-1+ endosome positioning relative to the MTOC; IQGAP1 depletion disrupts CXCR4 recycling, reduces SDF-1-induced ERK activation and cell migration. SDF-1 induces IQGAP1 binding to α-tubulin and localization to CXCR4-containing endosomes.\",\n      \"method\": \"siRNA knockdown, immunofluorescence, Co-IP, endosome positioning analysis, CXCR4 recycling assay, ERK activation assay, migration assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with mechanistic imaging, Co-IP, multiple functional readouts; single lab\",\n      \"pmids\": [\"26195666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP1 forms dimers that stably bind actin filament sides and transiently cap barbed ends, organizing filaments into thin bundles, suppressing barbed end growth, and inhibiting filament disassembly. Different activities depend on distinct combinations of IQGAP1 domains and/or dimerization.\",\n      \"method\": \"Single-molecule and single-filament TIRF microscopy with purified full-length human IQGAP1, domain construct analysis\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — single-molecule in vitro reconstitution with purified protein, domain dissection\",\n      \"pmids\": [\"34731043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP1 controls tight junction formation through differential regulation of claudin recruitment (reducing claudin-2 expression and TJ recruitment while increasing claudin-4 recruitment); and through CDC42-JNK pathway: IQGAP1 KD increases CDC42 effector JNK activity, and dominant-negative CDC42 prevents the TER increase caused by IQGAP1 silencing.\",\n      \"method\": \"siRNA knockdown, TER measurement, quantitative confocal microscopy, biochemical claudin analysis, JNK activity assay, dominant-negative CDC42\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — KD with functional TJ readout, epistasis via dominant-negative, multiple molecular mechanisms identified\",\n      \"pmids\": [\"25588839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The E3 ubiquitin ligase HECTD1 interacts with IQGAP1 and regulates its degradation through ubiquitination; loss of HECTD1 increases IQGAP1 levels, accelerates cell spreading and migration but impairs directionality. IQGAP1 overexpression phenocopies Hectd1-mutant cells; IQGAP1 knockdown rescues the migration defect.\",\n      \"method\": \"Hectd1 mutant MEFs, Co-IP, ubiquitination assay, siRNA, IQGAP1 overexpression rescue, cell migration and spreading assays\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic model (Hectd1 KO), ubiquitination assay, bidirectional rescue experiments, functional readouts\",\n      \"pmids\": [\"28073378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IQGAP1 is SUMOylated by SUMO1 at K1445; this modification stabilizes IQGAP1 by reducing ubiquitination. IQGAP1 SUMOylation activates ERK, MEK, and AKT phosphorylation; the K1445R mutation abolishes these effects and reduces proliferation, migration, and tumor growth in vivo.\",\n      \"method\": \"SUMO1 co-expression, mutagenesis (K1445R), ubiquitination assay, kinase phosphorylation analysis, xenograft tumor model\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — site mutagenesis, functional assays, in vivo model; single lab\",\n      \"pmids\": [\"28987385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IQGAP1 associates with IR (insulin receptor) via its IQ region binding the intracellular domain of IR, and with IRS-1 via the phosphotyrosine-binding domain of IRS-1 and the C-terminal tail of IQGAP1. In IQGAP1-null cells and mice, insulin-stimulated AKT and ERK phosphorylation, PI3K-IRS-1 association, and glucose homeostasis are significantly impaired.\",\n      \"method\": \"In vitro binding with purified proteins, Co-IP, IQGAP1-null mice, insulin signaling assays, glucose tolerance tests\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct in vitro binding, domain mapping, null mouse in vivo phenotype, multiple signaling readouts\",\n      \"pmids\": [\"28082684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"The kinase GLK/MAP4K3 directly phosphorylates IQGAP1 at Ser-480 via interaction through GLK proline-rich regions and the IQGAP1 WW domain, enhancing Cdc42 activation and cell migration; GLK-induced lung cancer metastasis is abolished by IQGAP1 depletion.\",\n      \"method\": \"Co-IP, in vitro kinase assay with purified proteins, phosphomimetic/phosphodeficient IQGAP1 constructs, Cdc42 activation assay, siRNA, GLK transgenic mice, lung metastasis model\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro kinase reconstitution, phosphosite identification, domain mapping, in vivo metastasis model\",\n      \"pmids\": [\"31431460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Ubiquitination of IQGAP1 at Lys-1155 and Lys-1230 in the GRD reduces its binding to CDC42 and RAC1; the non-ubiquitinatable GRD-2K mutant binds significantly more CDC42/RAC1, increases active CDC42 levels, and enhances cell migration compared to WT IQGAP1.\",\n      \"method\": \"MS-based ubiquitination site identification, K→R mutagenesis, GTPase pulldown, IQGAP1-null cell reconstitution, active CDC42/RAC1 assay, migration assay\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — MS site identification, mutagenesis, null-cell reconstitution, functional GTPase activation and migration readouts\",\n      \"pmids\": [\"32094223\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IQGAP1 sustains VEGFR2-mediated Rac1 activation in choroidal endothelial cells: IQGAP1-mediated Src activation initiates Rac1 activation; IQGAP1 binding to Rac1-GTP maintains sustained Rac1 activity necessary for endothelial cell migration and choroidal neovascularization. Iqgap1−/− mice have reduced laser-induced CNV volumes and decreased Rac1GTP and p-VEGFR2 in CNV lesions.\",\n      \"method\": \"Iqgap1-null mice, IQGAP1 Rac1-binding-deficient construct, siRNA, Rac1-GTP pulldown, p-VEGFR2 measurement, cell migration/tube formation assay\",\n      \"journal\": \"Angiogenesis\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mouse model, binding-deficient construct, multiple mechanistic assays\",\n      \"pmids\": [\"32783108\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IQGAP1 scaffolds AMPK by binding directly to the AMPK α1 subunit and to CaMKK2 (via the IQ domain); both associate with IQGAP1 in cells. IQGAP1 deletion reduces metformin- and Ca2+-stimulated AMPK activation; Ca2+-stimulated AMPK phosphorylation is rescued by IQGAP1 re-expression. IQGAP1-null mice show impaired transcriptional regulation of gluconeogenesis and fatty acid synthesis genes during fasting.\",\n      \"method\": \"In vitro binding with fusion proteins, Co-IP, siRNA KD, IQGAP1-null mice, reconstitution, AMPK kinase activity assay, gene expression analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — direct binding reconstitution, null mouse model, rescue experiments, multiple orthogonal approaches\",\n      \"pmids\": [\"33191271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IQGAP1 scaffolds the Hippo pathway core kinases MST2 and LATS1, suppressing their kinase activity and YAP1-dependent transcription; IQGAP1 is a negative regulator of the non-canonical pro-apoptotic Hippo pathway. Bile acids regulate the IQGAP1–MST2–LATS1 module in hepatocellular carcinoma cells.\",\n      \"method\": \"Co-IP, kinase activity assays, YAP transcription reporter, IQGAP1 knockdown/overexpression, bile acid treatment\",\n      \"journal\": \"Cells\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, functional kinase and transcription assays; single lab\",\n      \"pmids\": [\"33672268\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP with RhoA to promote RhoA inactivation, thereby suppressing airway smooth muscle contractility. IQGAP1 knockdown or knockout increases RhoA activity and airway responsiveness; proximity ligation shows RhoA–p190A-RhoGAP colocalization is lost without IQGAP1.\",\n      \"method\": \"Co-IP, proximity ligation assay, Iqgap1-null mice, siRNA in human airway smooth muscle cells, RhoA activity assay, tracheal ring contractility, airway resistance measurement\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — null mouse model, proximity ligation, Co-IP, human cell KD, in vivo functional readout\",\n      \"pmids\": [\"25271629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IQGAP1 bridges GSDMD to the ESCRT machinery (specifically Tsg101) to promote exosomal release of pro-IL-1β following NLRP3 inflammasome activation; this process requires LPS-induced GTP-bound CDC42 activation of IQGAP1. IQGAP1 was identified as a GSDMD-interacting protein by unbiased proteomics.\",\n      \"method\": \"Unbiased proteomics, Co-IP, siRNA knockdown, exosome isolation, NLRP3 inflammasome activation assay, CDC42 activation assay\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — unbiased proteomics identification, Co-IP, mechanistic pathway with multiple components, functional exosome release assay\",\n      \"pmids\": [\"36373462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"TRIM56 promotes K48-to-K63-linked poly-ubiquitination transition of IQGAP1 at Lys-1230 by interacting with it, which in turn promotes CDC42 activation to drive glioma cell migration and invasion.\",\n      \"method\": \"Co-IP, ubiquitination site mutagenesis, CDC42 activation assay, siRNA/overexpression, in vivo glioma model\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, site mutagenesis, functional assays; single lab\",\n      \"pmids\": [\"36870986\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Rap1b colocalization with IQGAP1 upon NK cell activation facilitates sequential phosphorylation of B-Raf, C-Raf, and ERK1/2 and formation of a large IQGAP1-containing signalosome in the perinuclear region, required for NKG2D/Ly49D/NCR1-mediated cytokine production.\",\n      \"method\": \"Rap1a/b knockout mice, immunofluorescence co-localization, kinase phosphorylation analysis, cytokine assays\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — KO mice with defined signaling and functional readouts; Co-localization evidence for complex\",\n      \"pmids\": [\"20733035\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IQGAP1 associates with the co-stimulatory receptor OX40 after OX40L ligation, mediated by the C-terminal IQGAP1 region, with TRAF2 bridging these two proteins. IQGAP1 deficiency enhances OX40 cosignaling (proliferation and cytokines) in CD4+ T cells; C-terminal IQGAP1 reconstitution restores normal responses.\",\n      \"method\": \"Co-IP, IQGAP1-null mice, IQGAP1 domain construct reconstitution, T-cell activation assays, EAE autoimmune model\",\n      \"journal\": \"FASEB journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, null mouse model, reconstitution; single lab\",\n      \"pmids\": [\"31914585\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IQGAP1 associates with NLRC3 and disrupts the NLRC3–STING interaction in the cytosol; IQGAP1 knockdown phenocopies NLRC3 deficiency, causing significantly more IFN-β production in response to cytosolic nucleic acids.\",\n      \"method\": \"Yeast two-hybrid (interaction identification), Co-IP in human epithelial cells, siRNA knockdown, IFN-β reporter assay\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, siRNA KD with functional IFN-β readout; single lab\",\n      \"pmids\": [\"28864474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ANGPTL4 (secreted by cancer-associated fibroblasts) binds IQGAP1 on the prostate cancer cell membrane, activating the Raf-MEK-ERK-PGC1α axis to promote mitochondrial biogenesis and OXPHOS metabolism, facilitating tumor growth and chemoresistance.\",\n      \"method\": \"GST pulldown, Co-IP, metabolomics, ELISA, siRNA/overexpression, drug screening, xenograft model\",\n      \"journal\": \"Journal of advanced research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pulldown and Co-IP with functional metabolic and proliferative readouts; single lab\",\n      \"pmids\": [\"39647634\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IQGAP1 is a ubiquitously expressed scaffold protein that directly binds and cross-links F-actin (via its calponin homology domain), inhibits GTPase activity of Cdc42 and Rac1 by stabilizing their GTP-bound state (via its GRD domain), and integrates multiple signaling cascades—including Ras/MAPK (by scaffolding B-Raf, MEK, and ERK), PI3K/AKT, Wnt/β-catenin, Hippo/YAP, AMPK, insulin, VEGFR2, EGFR, and HER2 pathways—through direct protein-protein interactions regulated by Ca2+/calmodulin, post-translational modifications (phosphorylation by PKCε and GLK/MAP4K3, ubiquitination by HECTD1 and TRIM56, SUMOylation at K1445), and self-association, thereby coordinating cell polarity, directed migration, microtubule capture at the cell cortex (via CLIP-170), cytokinesis, cell–cell adhesion, and immune cell function.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IQGAP1 is a ubiquitously expressed multidomain scaffold that integrates actin cytoskeletal dynamics with Rho-family GTPase signaling to coordinate cell polarity, migration, adhesion, and division [#0, #5]. Through its GAP-related domain it binds selectively to the GTP-bound forms of Cdc42 and Rac1—but not Ras—and inhibits their intrinsic GTPase activity, thereby stabilizing the active state of these GTPases rather than accelerating their inactivation [#0, #16]; it similarly engages GTP-loaded RhoA/RhoC and Rap1 [#27, #14]. IQGAP1 directly binds and cross-links F-actin via its calponin homology domain, and as a dimer it caps barbed ends, organizes filaments into bundles, and stimulates Arp2/3-dependent branched nucleation by activating N-WASP, linking receptor inputs such as FGFR1 to lamellipodial actin assembly [#1, #38, #11, #13]. By capturing microtubule plus-ends at the cell cortex through a tripartite complex with activated Cdc42/Rac1 and CLIP-170, it generates polarized microtubule arrays that direct migration [#4]. A central output is its role as the scaffold of the Ras/MAPK module, binding B-Raf, MEK1/2, and ERK1/2 to enable EGF- and growth-factor-stimulated kinase activation [#7, #8, #17]; disrupting the IQGAP1–ERK interaction with a WW-domain peptide blocks RAS/RAF-driven tumorigenesis and overcomes BRAF-inhibitor resistance [#29]. Beyond MAPK, IQGAP1 scaffolds AMPK/CaMKK2, the insulin receptor/IRS-1, VEGFR2, EGFR, and HER2, and acts as a negative regulator of Hippo/YAP signaling by binding YAP and the MST2–LATS1 kinases [#46, #42, #45, #21, #22, #36, #47]. Its many interactions are gated by Ca2+/calmodulin, which competes with F-actin, Cdc42, E-cadherin, Rap1, B-Raf and EGFR for distinct IQGAP1 domains [#2, #3, #17, #21], and by post-translational modifications including PKCε/PKCα phosphorylation at Ser-1443, GLK-mediated Ser-480 phosphorylation, K1445 SUMOylation, and ubiquitination within the GAP-related domain that tunes its GTPase binding and stability [#10, #21, #43, #41, #44, #40]. IQGAP1 also supports immune effector functions, including NK-cell MTOC polarization and cytotoxicity and the calibration of T-cell activation [#24, #25].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Established the founding biochemical identity of IQGAP1 as a Cdc42/Rac1-selective binding protein that inhibits their GTPase activity and associates with calmodulin and cortical actin, distinguishing it from Ras-targeting regulators.\",\n      \"evidence\": \"Affinity pulldown, GTPase activity assay, Co-IP, and immunofluorescence in a foundational study\",\n      \"pmids\": [\"8670801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve whether IQGAP1 acts as a true GAP or an effector that stabilizes GTP-bound state\", \"structural basis of selectivity for Cdc42/Rac1 over Ras not defined\"]\n    },\n    {\n      \"year\": 1997,\n      \"claim\": \"Defined IQGAP1 as a direct F-actin cross-linker, providing the structural basis for its cytoskeletal scaffolding function.\",\n      \"evidence\": \"F-actin co-sedimentation, electron microscopy with purified bovine IQGAP1\",\n      \"pmids\": [\"9199170\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Single-filament kinetics of actin organization not yet resolved\", \"in vivo consequence of cross-linking not tested\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Showed that Ca2+/calmodulin is a master switch dissociating IQGAP1 from Cdc42, F-actin and E-cadherin, establishing calmodulin as a competitive regulator that toggles IQGAP1 between signaling and adhesion roles.\",\n      \"evidence\": \"In vitro competition binding, GTPase assays, and adhesion assays in MCF-7/MDA-MB-231 cells\",\n      \"pmids\": [\"9867866\", \"10608854\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Quantitative relationship between local Ca2+ flux and partner exchange in vivo not defined\", \"did not address how calmodulin coordinates simultaneous competing partners\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Resolved how IQGAP1 links GTPase activation to microtubule capture, defining a Cdc42/Rac1–IQGAP1–CLIP-170 tripartite complex that polarizes the microtubule array for directed migration.\",\n      \"evidence\": \"Co-IP, mutant constructs, and GFP-CLIP-170 live imaging in Vero fibroblasts\",\n      \"pmids\": [\"12110184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and assembly order of the tripartite complex unresolved\", \"how the complex is spatially restricted to the leading edge not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Demonstrated that IQGAP1 levels bidirectionally control cell migration and invasion in a Cdc42/Rac1-dependent manner, connecting its biochemistry to a functional motility phenotype.\",\n      \"evidence\": \"siRNA knockdown, dominant-negative GRD construct, transwell migration/invasion assays\",\n      \"pmids\": [\"12900413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not separate scaffolding from actin cross-linking contributions to motility\", \"in vivo invasion not tested in this study\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Established IQGAP1 as an activator of Arp2/3-mediated branched actin nucleation through N-WASP, with intramolecular autoinhibition, linking receptor signaling (FGFR1) to lamellipodial actin assembly.\",\n      \"evidence\": \"Reconstituted actin polymerization with purified proteins/Arp2/3, Co-IP, siRNA, migration assays\",\n      \"pmids\": [\"17085436\", \"17264147\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signal that relieves intramolecular autoinhibition not identified\", \"interplay between cross-linking and nucleation activities not resolved\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Identified IQGAP1 as the scaffold of the Ras/MAPK cascade, binding ERK2, MEK1/2 and B-Raf and required for growth-factor-stimulated kinase activation, defining its central signaling output.\",\n      \"evidence\": \"Direct in vitro binding, Co-IP, bidirectional manipulation, EGF/IGF-I stimulation kinase assays\",\n      \"pmids\": [\"14970219\", \"16135787\", \"18567582\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How EGF differentially partitions MEK1 versus MEK2 binding mechanistically unresolved\", \"stoichiometry of the assembled MAPK module on IQGAP1 not defined\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Showed IQGAP1 self-association (residues 763–863) and PKCε phosphorylation at Ser-1443 are required for its cellular functions, establishing oligomerization and phosphorylation as regulatory layers.\",\n      \"evidence\": \"Co-IP, gel filtration, competing peptide, MS phosphosite ID, kinase assay, neurite outgrowth in N1E-115 cells\",\n      \"pmids\": [\"16105843\", \"15695813\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural form of physiologically active oligomer unresolved\", \"the upstream signal triggering self-association in cells not defined\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Extended IQGAP1's receptor scaffolding to EGFR and HER2, showing it is required for receptor autophosphorylation and signaling, with phosphorylation- and calmodulin-gated control and therapeutic relevance to trastuzumab resistance.\",\n      \"evidence\": \"Direct in vitro binding, null-cell reconstitution, MS phosphosite, knockdown, drug-sensitivity assays\",\n      \"pmids\": [\"21349850\", \"21724847\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IQGAP1 directly enhances receptor kinase activity or stabilizes receptor not fully separated\", \"structural basis of IQ-domain/receptor binding not defined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Validated IQGAP1 scaffold disruption as a therapeutic strategy, showing a WW-domain peptide blocks RAS/RAF-driven tumors and bypasses BRAF-inhibitor resistance in vivo.\",\n      \"evidence\": \"WW-domain peptide competition, IQGAP1-null tumor model, in vivo survival studies\",\n      \"pmids\": [\"23603816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Generality across additional RAS/RAF-driven tumor types not fully mapped\", \"off-pathway effects of WW-peptide on other IQGAP1 functions not characterized\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined IQGAP1 as a negative regulator of Hippo/YAP output, directly binding YAP and later the MST2–LATS1 kinases to suppress TEAD-dependent transcription, broadening its role beyond MAPK.\",\n      \"evidence\": \"Direct binding, IQGAP1-null MEFs/CRISPR KD, TEAD reporter, kinase assays\",\n      \"pmids\": [\"27440047\", \"33672268\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IQGAP1 simultaneously coordinates Hippo, MAPK and adhesion modules unresolved\", \"context determining activation versus suppression of YAP not defined\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Established a post-translational code governing IQGAP1 stability and GTPase binding, with SUMOylation at K1445, GLK-mediated Ser-480 phosphorylation, and ubiquitination within the GRD all tuning Cdc42/Rac1 activation and migration.\",\n      \"evidence\": \"Site mutagenesis, MS site identification, ubiquitination assays, null-cell reconstitution, in vivo metastasis models\",\n      \"pmids\": [\"28987385\", \"31431460\", \"32094223\", \"28073378\", \"36870986\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Hierarchy and cross-talk among the modifications not integrated\", \"the enzymes responsible for several modifications only partially identified\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded IQGAP1's scaffolding to metabolic and vascular signaling, showing it directly assembles AMPK/CaMKK2 and IR/IRS-1 modules and sustains VEGFR2–Rac1 signaling, with in vivo glucose-homeostasis and angiogenesis phenotypes.\",\n      \"evidence\": \"Direct binding, Co-IP, IQGAP1-null mice, rescue, kinase and GTPase activation assays\",\n      \"pmids\": [\"33191271\", \"28082684\", \"32783108\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How a single scaffold partitions among competing metabolic and growth modules unresolved\", \"tissue-specific selectivity of these complexes not defined\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Connected IQGAP1 to inflammasome-driven secretion, showing CDC42-activated IQGAP1 bridges GSDMD to ESCRT/Tsg101 for exosomal pro-IL-1β release, illustrating a non-migratory effector role.\",\n      \"evidence\": \"Unbiased proteomics, Co-IP, knockdown, exosome isolation, NLRP3 activation, CDC42 activation assay\",\n      \"pmids\": [\"36373462\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether this is a general route for cargo secretion beyond IL-1β not established\", \"structural basis of GSDMD–IQGAP1–Tsg101 bridging unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How IQGAP1 dynamically prioritizes and spatially segregates its many competing partners—across Rho GTPases, MAPK, Hippo, metabolic and immune modules—into discrete functional outcomes within a single cell remains unresolved.\",\n      \"evidence\": \"No single study reconstitutes the integrated decision logic; competition is documented partner-by-partner\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No structural model of full-length multidomain IQGAP1 with multiple partners\", \"quantitative rules governing partner exchange under physiological Ca2+/PTM states not established\", \"spatial organization of distinct IQGAP1 signalosomes within one cell not defined\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 7, 8, 36, 42, 46, 48]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [1, 11, 38]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 9, 16, 27]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [1, 38]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [1, 4, 38]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 3, 21, 28]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [30, 35]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [37]},\n      {\"term_id\": \"GO:0005815\", \"supporting_discovery_ids\": [4, 24, 37]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [7, 8, 17, 36, 42, 46]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [4, 10, 19, 26]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [24, 25, 49, 51, 52, 53]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [42, 46, 54]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [37, 49]}\n    ],\n    \"complexes\": [\"Ras/MAPK scaffold module (B-Raf/MEK1/2/ERK1/2)\", \"Cdc42/Rac1–IQGAP1–CLIP-170 microtubule-capture complex\"],\n    \"partners\": [\"CDC42\", \"RAC1\", \"CALM1\", \"MAP2K1\", \"MAPK1\", \"BRAF\", \"EGFR\", \"CLIP-170\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":8,"faith_total":8,"faith_pct":100.0}}