{"gene":"IQGAP1","run_date":"2026-04-28T18:06:54","timeline":{"discoveries":[{"year":1996,"finding":"IQGAP1 binds to and inhibits the GTPase activity of Cdc42 and Rac1 (but not Ras) through its GRD domain, localizes to lamellipodia where it co-localizes with actin, and binds calmodulin via its IQ domain; expression of GRD fragment inhibits the CDC24/CDC42 pathway in yeast.","method":"Affinity chromatography purification, in vitro GTPase activity assay, co-immunoprecipitation, yeast genetic epistasis, immunofluorescence","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods (in vitro assay, co-IP, genetic epistasis, localization) in a foundational study with 342 citations","pmids":["8670801"],"is_preprint":false},{"year":2002,"finding":"IQGAP1 interacts directly with CLIP-170 at the growing ends of microtubules; activated Rac1/Cdc42 form a tripartite complex with IQGAP1 and CLIP-170 to capture microtubules at the cortical leading edge, establishing a polarized microtubule array and cell polarization.","method":"Co-immunoprecipitation, GFP live imaging, dominant-negative and deletion constructs, Vero fibroblast expression studies","journal":"Cell","confidence":"High","confidence_rationale":"Tier 2 — reciprocal co-IP, functional mutant analysis, live imaging with defined phenotype; 502 citations indicating broad replication","pmids":["12110184"],"is_preprint":false},{"year":2003,"finding":"IQGAP1 promotes cell motility and invasion in a Cdc42- and Rac1-dependent manner; it increases the amount of active Cdc42 in vitro and in cells; dominant-negative IQGAP1ΔGRD attenuates invasion driven by constitutively active Cdc42.","method":"siRNA knockdown, dominant-negative construct overexpression, in vitro GTPase activity assay, migration/invasion assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 — loss-of-function (siRNA + dominant-negative) with mechanistic epistasis and in vitro activity assay","pmids":["12900413"],"is_preprint":false},{"year":2004,"finding":"IQGAP1 directly binds ERK2 (demonstrated with pure proteins), and manipulation of IQGAP1 levels significantly reduces growth factor-stimulated ERK1/2 activity; the ERK2-binding region of IQGAP1 is required for this modulation.","method":"In vitro binding with purified proteins, co-immunoprecipitation from cell lysates, siRNA knockdown, IQGAP1 deletion mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding plus co-IP plus functional mutant analysis in single rigorous study","pmids":["14970219"],"is_preprint":false},{"year":2005,"finding":"IQGAP1 functions as a molecular scaffold for the MAPK pathway by directly binding MEK1 and MEK2 as well as ERK2; MEK-ERK binding to IQGAP1 is cooperative and both knockdown and overexpression of IQGAP1 reduce EGF-stimulated MEK and ERK activation.","method":"In vitro binding assays, co-immunoprecipitation, siRNA knockdown, IQGAP1 mutant constructs, EGF stimulation assays","journal":"Molecular and cellular biology","confidence":"High","confidence_rationale":"Tier 1-2 — in vitro direct binding confirmed by co-IP plus loss-of-function with mechanistic mutant analysis","pmids":["16135787"],"is_preprint":false},{"year":2006,"finding":"The C-terminal half of IQGAP1 activates N-WASP by interacting with its BR-CRIB domain in a Cdc42-like manner to stimulate Arp2/3-dependent actin assembly; the N-terminal half of IQGAP1 autoinhibits this activation by associating with the C-terminal region.","method":"Pull-down experiments with GST-tagged fragments, kinetic actin polymerization assays, co-immunoprecipitation, siRNA knockdown, quantitative co-localization analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstituted actin polymerization assay with domain mapping and autoinhibition mechanism defined","pmids":["17085436"],"is_preprint":false},{"year":2007,"finding":"IQGAP1 directly binds the small GTPase Rap1; interaction is enhanced by GTP-loading of Rap1 and is eliminated by calmodulin; Rap1 binds to the IQ region of IQGAP1; overexpression of IQGAP1 attenuates adhesion- and cAMP-mediated Rap1 activation.","method":"In vitro binding with pure proteins, co-immunoprecipitation, confocal microscopy, point mutants of IQGAP1, Rap1 activation assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding plus functional modulation assays plus domain mapping","pmids":["17517894"],"is_preprint":false},{"year":2007,"finding":"IQGAP1-stimulated cell migration requires direct interaction with actin; Ca2+/calmodulin binding to IQGAP1 negatively regulates its pro-migratory function; Cdc42 localization at the leading edge is not required for maximal IQGAP1-driven migration.","method":"IQGAP1 point mutant constructs, calmodulin inhibitory peptide, confocal microscopy, migration assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 — functional domain dissection with defined phenotype but single study","pmids":["17544257"],"is_preprint":false},{"year":2007,"finding":"The IQGAP1-Rac1 and IQGAP1-Cdc42 binding interfaces differ: switch II mutations abolish Rac1 binding but not Cdc42 binding; switch I residues 32 and 36 are important for both; the Rho insert loop does not contribute to IQGAP1 binding.","method":"Site-directed mutagenesis of Rac1/Cdc42, quantitative affinity measurements, competition assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — rigorous mutagenesis with quantitative thermodynamic analysis defining binding interfaces","pmids":["17984089"],"is_preprint":false},{"year":2008,"finding":"IQGAP1 integrates Ca2+/calmodulin with B-Raf signaling: Ca2+ promotes direct IQGAP1-B-Raf binding, which is inhibited by calmodulin in a Ca2+-dependent manner; chelation of intracellular Ca2+ enhances EGF-stimulated B-Raf activity in an IQGAP1-dependent manner.","method":"In vitro binding with pure proteins, co-immunoprecipitation, Ca2+ ionophore/chelator treatments, B-Raf activity assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding with mechanistic calcium regulation confirmed by co-IP and functional assays","pmids":["18567582"],"is_preprint":false},{"year":2008,"finding":"IQGAP1 associates and co-localizes with the exocyst-septin complex; CDC42 activation abolishes this association and inhibits secretion; the N-terminus of IQGAP1 binds the exocyst-septin complex and enhances secretion, while the C-terminus (binding CDC42) inhibits secretion.","method":"Co-immunoprecipitation, co-localization, pulse-chase secretion assays, dominant-negative constructs in pancreatic beta-cells","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with functional domain dissection and phenotypic readout but single study","pmids":["18216334"],"is_preprint":false},{"year":2009,"finding":"IQGAP1 regulates cell proliferation through a CDC42-mTOR pathway; the N-terminus of IQGAP1 interacts with mTOR, which is required for IQGAP1-mediated cell proliferation; IQGAP1 requires phosphorylation and CDC42 binding for this activity.","method":"Deletion constructs, co-immunoprecipitation, cell size measurement, transformation/migration assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with functional domain analysis and defined proliferative phenotype, single study","pmids":["19454477"],"is_preprint":false},{"year":2010,"finding":"S100P, a Ca2+-binding protein, directly and Ca2+-dependently binds IQGAP1 primarily through the IQ domain (K_D ~0.2 µM), and S100P overexpression reduces EGF-induced IQGAP1 tyrosine phosphorylation and attenuates B-Raf binding to IQGAP1 and downstream MEK1/2 activation.","method":"Affinity approach with S100P dimer, pull-down, co-immunoprecipitation, kinase activation assays, S100P mutants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct binding with Kd measurement plus functional downstream consequences using specific S100P mutants","pmids":["21177863"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 directly binds EGFR through the IQ and kinase domains respectively; calmodulin disrupts this interaction; EGF induces IQGAP1 Ser1443 phosphorylation via PKCα; loss of IQGAP1 severely attenuates EGF-stimulated EGFR autophosphorylation, which is rescued by wild-type IQGAP1 reconstitution.","method":"Co-immunoprecipitation, in vitro binding with pure proteins, MS-based phosphorylation assay, siRNA, IQGAP1 null cells reconstitution, PKC inhibitors","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding, MS-identified phosphosite, rescue experiment in null cells with multiple orthogonal methods","pmids":["21349850"],"is_preprint":false},{"year":2011,"finding":"CLIP-170 and IQGAP1 cooperatively regulate dendrite morphology of neurons by coordinating microtubule-actin cytoskeleton interaction; mTOR kinase interacts with CLIP-170 and is needed for efficient CLIP-170/IQGAP1 complex formation; dynamic microtubules, CLIP-170, and IQGAP1 are required for PI3K-mTOR-induced increases in dendritic arbor complexity.","method":"Knockdown in rat neurons, live imaging, co-immunoprecipitation, dendritic arbor morphometry","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with knockdown and quantitative morphological readout, single study","pmids":["21430156"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 is a component of NMDAR multiprotein complexes and functionally interacts with NR2A subunits and ERK1/2; IQGAP1 knockout mice show decreased surface NR2A expression and impaired ERK signaling upon NR2A-dependent NMDAR stimulation, accompanied by reduced hippocampal dendritic spine density and long-term memory deficits.","method":"IQGAP1 knockout mice, co-immunoprecipitation, surface biotinylation, hippocampal LTP recordings","journal":"The Journal of neuroscience","confidence":"High","confidence_rationale":"Tier 2 — genetic KO with multiple orthogonal mechanistic readouts (co-IP, surface expression, LTP, behavior)","pmids":["21653857"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 scaffolds c-Raf, MEK1/2, ERK1/2, and AKT in the heart; IQGAP1-null mice show impaired delayed (4-day) but not acute (10-min) MEK/ERK and AKT phosphorylation after pressure overload, leading to accelerated maladaptive cardiac remodeling.","method":"IQGAP1-null mice, aortic banding model, pull-down assays, phosphorylation time-course analysis","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 — in vivo KO with temporal dissection of signaling and pull-down validation of scaffold complex","pmids":["21493702"],"is_preprint":false},{"year":2011,"finding":"IQGAP1 acts as a dual negative regulator in T cells: it limits TCR-mediated signaling (LCK activation, IL-2/IFN-γ production) and F-actin assembly dynamics via distinct IQGAP1 domain-dependent mechanisms.","method":"IQGAP1-null T cells, siRNA in Jurkat cells, IQGAP1 domain constructs, F-actin imaging, cytokine measurement","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with defined cellular phenotypes and domain dissection, single study","pmids":["22573807"],"is_preprint":false},{"year":2012,"finding":"IQGAP1 acts upstream of RhoA/C (regulating their GTP loading) and downstream of RhoA/C (mediating their effects on proliferation/migration); it interacts directly with GTP-bound, prenylated RhoA and RhoC but not RhoB.","method":"Proteomics screen, co-immunoprecipitation, GTP-loading measurements in constitutively active mutants, siRNA knockdown, adenoviral constructs","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — isoform-specific direct binding plus epistatic placement upstream and downstream, single study","pmids":["22992742"],"is_preprint":false},{"year":2012,"finding":"IQGAP1 conserved role in regulating TORC1: yeast two-hybrid identified Tco89p (TORC1-specific subunit) as an Iqg1p partner; mammalian IQGAP1 binds mTORC1 and Akt1 and modulates the mTORC1-S6K1→Akt1 negative feedback loop.","method":"Yeast two-hybrid, complementary yeast and mammalian experiments, co-immunoprecipitation, kinase activity assays","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 — cross-species genetic/biochemical evidence with co-IP and activity measurements, single lab","pmids":["22328503"],"is_preprint":false},{"year":2013,"finding":"Activated Cdc42 bound to IQGAP1 recruits GDP-bound Rab27a to the plasma membrane to regulate endocytosis of insulin secretory membranes; IQGAP1 silencing inhibits endocytosis and glucose-induced redistribution of Rab27a and coronin 3.","method":"Identification of IQGAP1 as Rab27a-interacting protein, co-immunoprecipitation, silencing, dominant-negative IQGAP1, endocytosis assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP plus loss-of-function with defined endocytic phenotype, single study","pmids":["24100016"],"is_preprint":false},{"year":2013,"finding":"IQGAP1 binds TGF-β receptor II (TβRII) and promotes SMURF1-mediated ubiquitination and degradation of TβRII, thereby suppressing TGF-β-dependent myofibroblast differentiation; IQGAP1 knockdown stabilizes TβRII and potentiates TGF-β1 signaling.","method":"Co-immunoprecipitation, IQGAP1 knockdown in hepatic stellate cells, ubiquitination assay, in vivo tumor implantation","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — co-IP with ubiquitination mechanism and in vivo validation, multiple orthogonal approaches","pmids":["23454766"],"is_preprint":false},{"year":2013,"finding":"The IQGAP1 WW domain peptide disrupts IQGAP1-ERK1/2 interactions and inhibits RAS/RAF-driven tumorigenesis; IQGAP1 is required for RAS-driven tumorigenesis in mouse and human tissue.","method":"WW domain peptide competition, IQGAP1 knockout/knockdown in mouse models, tumor growth assays, systemic peptide delivery","journal":"Nature medicine","confidence":"High","confidence_rationale":"Tier 2 — mechanistic scaffold-kinase disruption confirmed in vivo with genetic and pharmacologic approaches, high citation count","pmids":["23603816"],"is_preprint":false},{"year":2013,"finding":"IQGAP1 regulates nuclear localization of β-catenin via importin-β5 in Wnt signaling; IQGAP1 depletion in Xenopus embryos reduces Wnt-induced nuclear β-catenin accumulation and Wnt target gene expression; Ran1 GTPase also contributes.","method":"Xenopus embryo depletion, co-immunoprecipitation, nuclear fractionation, Wnt target gene expression assays","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — in vivo loss-of-function in Xenopus with mechanistic co-IP, single study","pmids":["24196961"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 interacts with LGR4 and DVL following RSPO stimulation to bring RSPO-LGR4 to the Wnt signaling complex; this promotes MEK1/2-mediated phosphorylation of LRP5/6 and potentiates both canonical and non-canonical Wnt signaling.","method":"Yeast two-hybrid/proteomics identification, co-immunoprecipitation, IQGAP1 siRNA, luciferase Wnt reporter assay, kinase assays","journal":"Proceedings of the National Academy of Sciences","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with functional signaling assays and loss-of-function, single study","pmids":["24639526"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 directly binds ERα and ERβ; interaction is mediated by the IQ domain of IQGAP1 and the hinge region of ERα; knockdown of IQGAP1 attenuates estradiol-induced transcription of estrogen-responsive genes (pS2, progesterone receptor, cyclin D1).","method":"In vitro binding with pure proteins, co-immunoprecipitation, domain mapping constructs, siRNA knockdown, transcription assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro interaction with domain mapping plus functional transcriptional readout","pmids":["24550401"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 forms a complex with Asef (a Rac/Cdc42 GEF) following HGF stimulation, mediated by the C-terminal domain of IQGAP1; this complex localizes to the cell cortex and promotes Rac activation, leading to IQGAP1 interaction with Arp3 and cortactin to enhance endothelial barrier function.","method":"Co-immunoprecipitation, siRNA knockdown, domain-mapping constructs, Rac activation assays, transendothelial resistance measurement","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with domain mapping and functional barrier readout, single study","pmids":["25492863"],"is_preprint":false},{"year":2014,"finding":"IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP with RhoA to inactivate RhoA and suppress airway smooth muscle contraction; IQGAP1 knockout mice have enhanced RhoA activity and increased airway hyperresponsiveness.","method":"IQGAP1 knockout mice, co-immunoprecipitation, proximity ligation assay, RhoA activity assays, tracheal ring contraction force measurement, primary human airway smooth muscle cell knockdown","journal":"The Journal of clinical investigation","confidence":"High","confidence_rationale":"Tier 2 — KO mice with proximity ligation assay confirming complex colocalization and functional contraction readout, multiple orthogonal methods","pmids":["25271629"],"is_preprint":false},{"year":2015,"finding":"IQGAP1 directly promotes CXCR4 cell surface expression and recycling via EEA-1+ endosomes; IQGAP1 depletion disrupts CXCR4 trafficking to late endosomes, reduces surface CXCR4, and blocks SDF-1-induced ERK activation and cell migration; upon SDF-1 treatment IQGAP1 binds α-tubulin and localizes to CXCR4-containing endosomes.","method":"siRNA knockdown, forced overexpression, endosomal fractionation, co-immunoprecipitation, confocal imaging, migration assays","journal":"The Journal of cell biology","confidence":"Medium","confidence_rationale":"Tier 2 — loss-of-function with endosomal trafficking mechanism and co-IP, single study","pmids":["26195666"],"is_preprint":false},{"year":2015,"finding":"The IQ3 motif of IQGAP1 specifically scaffolds PI3K-Akt pathway components (PIPKIα, PI3K); deletion or blocking of IQ3 reduces Akt activation without affecting ERK or EGFR binding to IQGAP1.","method":"IQ3 deletion mutant, IQ3 peptide inhibitor, co-immunoprecipitation, Akt/ERK activation assays, cell migration/invasion assays","journal":"Scientific reports","confidence":"Medium","confidence_rationale":"Tier 2 — domain deletion plus competitive peptide with functional selectivity demonstrated, single study","pmids":["31235839"],"is_preprint":false},{"year":2016,"finding":"IQGAP1 directly binds YAP via its IQ domain (interacting with the TEAD-binding domain of YAP); IQGAP1 knockout or knockdown increases nuclear YAP-TEAD complex formation and YAP-TEAD-mediated transcription.","method":"Co-immunoprecipitation, in vitro binding with pure proteins, domain mapping, CRISPR/Cas9 IQGAP1 knockout, transcription reporter assays","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding with domain mapping plus CRISPR KO with transcriptional readout","pmids":["27440047"],"is_preprint":false},{"year":2017,"finding":"AKT-phosphorylated FOXO1 (at Ser319) binds IQGAP1 and impedes IQGAP1-dependent ERK1/2 phosphorylation; decreased FOXO1 increases pERK1/2 in cancer cells; a FOXO1-derived phospho-mimicking peptide reverses IQGAP1-mediated ERK activation.","method":"Co-immunoprecipitation, FOXO1 phospho-mutants, IQGAP1 interaction assays, ERK phosphorylation assays, in vivo mouse experiments","journal":"The EMBO journal","confidence":"High","confidence_rationale":"Tier 2 — mechanistic co-IP with PTM-specific interaction, peptide validation, and in vivo confirmation","pmids":["28279977"],"is_preprint":false},{"year":2017,"finding":"SUMO1 SUMOylates IQGAP1 at K1445, stabilizing IQGAP1 by reducing ubiquitination; IQGAP1 SUMOylation activates ERK, MEK, and AKT phosphorylation; K1445 mutation reduces CRC cell growth, migration, and tumor formation.","method":"SUMO modification mapping, K1445 mutant, ubiquitination assay, ERK/MEK/AKT phosphorylation assays, in vitro and xenograft models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — specific SUMOylation site identified with functional consequences via mutagenesis, single study","pmids":["28987385"],"is_preprint":false},{"year":2017,"finding":"The IQ domain of IQGAP1 (not the WW domain) is both necessary and sufficient for binding ERK1/2 and MEK1/2; WW domain peptides contribute little binding energy to ERK-IQGAP1 interaction; ERK2-IQGAP1 binding does not require ERK2 phosphorylation and the Kd is ~8 µM.","method":"Quantitative in vitro binding assays, IQ and WW domain deletion constructs, phospho-ERK2 and kinase-dead ERK2 variants","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 — quantitative in vitro reconstitution with domain deletion and Kd measurement","pmids":["28396345"],"is_preprint":false},{"year":2017,"finding":"IQGAP1 associates with NLRC3 and disrupts the NLRC3-STING interaction; IQGAP1 knockdown phenocopies NLRC3 deficiency by increasing IFN-β production in response to cytosolic nucleic acids.","method":"Yeast two-hybrid identification, co-immunoprecipitation, siRNA knockdown in THP1 and HeLa cells, IFN-β ELISA","journal":"Journal of immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — co-IP with functional phenocopy via knockdown, single study","pmids":["28864474"],"is_preprint":false},{"year":2017,"finding":"IQGAP1 directly binds both insulin receptor (IR) via its IQ region and IRS-1 via the IRS-1 phosphotyrosine-binding domain interacting with the IQGAP1 C-terminal tail; loss of IQGAP1 reduces insulin-stimulated Akt and ERK phosphorylation and impairs glucose homeostasis in vivo.","method":"In vitro binding with pure proteins, co-immunoprecipitation, domain mapping, IQGAP1 knockout mice, in vivo glucose tolerance","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding with domain mapping plus in vivo metabolic phenotype in KO mice","pmids":["28082684"],"is_preprint":false},{"year":2017,"finding":"HECTD1 (E3 ubiquitin ligase) interacts with IQGAP1 and regulates its degradation through ubiquitination; loss of HECTD1 increases IQGAP1 levels, accelerating cell spreading and impairing directional migration; IQGAP1 overexpression phenocopies HECTD1 loss, and IQGAP1 knockdown rescues HECTD1-null migration defects.","method":"HECTD1 mutant MEFs, co-immunoprecipitation, ubiquitination assay, siRNA rescue experiments, cell migration analysis","journal":"Cell communication and signaling","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitination mechanism with epistatic rescue, single study","pmids":["28073378"],"is_preprint":false},{"year":2019,"finding":"GLK/MAP4K3 directly phosphorylates IQGAP1 at Ser-480 via interaction of GLK proline-rich regions with the IQGAP1 WW domain; this phosphorylation enhances Cdc42 activation and subsequent cell migration and lung cancer metastasis; IQGAP1 depletion abolishes GLK-induced migration.","method":"In vitro kinase assay, co-immunoprecipitation, domain mapping, phospho-specific assay, IQGAP1 knockdown in migration and metastasis models, GLK transgenic mice","journal":"Cancer research","confidence":"High","confidence_rationale":"Tier 1-2 — direct kinase assay identifying phosphosite, genetic models in vitro and in vivo with defined signaling mechanism","pmids":["31431460"],"is_preprint":false},{"year":2019,"finding":"CD13 tethers the IQGAP1-ARF6-EFA6 complex to the plasma membrane to promote ARF6 GTPase activation and β1 integrin recycling during cell migration; phosphorylated CD13, IQGAP1, GTP-bound ARF6, and EFA6 form a complex at the leading edge.","method":"Co-immunoprecipitation, mass spectrometry, ARF6 activation assays, β1 integrin trafficking assays, migration assays, siRNA knockdown","journal":"Science signaling","confidence":"Medium","confidence_rationale":"Tier 2 — co-IP with trafficking phenotype and GTPase activation assay, single study","pmids":["31040262"],"is_preprint":false},{"year":2020,"finding":"IQGAP1 binds directly to the α1 subunit of AMPK and to CaMKK2 via its IQ domain; IQGAP1 is required for maximum AMPK activation by metformin and Ca2+; IQGAP1-null mice show impaired gluconeogenesis and fatty acid synthesis gene regulation in fasting.","method":"In vitro binding with fusion proteins, co-immunoprecipitation, siRNA knockdown, IQGAP1-null mice, AMPK phosphorylation rescue experiments","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1-2 — direct in vitro binding for both AMPK and CaMKK2 plus in vivo metabolic phenotype in KO mice","pmids":["33191271"],"is_preprint":false},{"year":2021,"finding":"Full-length IQGAP1 forms dimers that stably bind actin filament sides and transiently cap barbed ends; these interactions bundle filaments, suppress barbed end growth, and inhibit filament disassembly; each activity depends on distinct combinations of IQGAP1 domains and/or dimerization.","method":"Single-molecule TIRF microscopy, single-filament imaging, domain deletion constructs, dimerization mutants","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 — direct single-molecule reconstitution with mechanistic domain dissection","pmids":["34731043"],"is_preprint":false},{"year":2022,"finding":"IQGAP1 functions as an adaptor bridging GSDMD to the ESCRT component Tsg101 to promote packaging of GSDMD and IL-1β into exosomes; this process requires LPS-induced GTP-bound CDC42 activation of IQGAP1 and is identified through non-biased proteomics.","method":"Proteomic identification, co-immunoprecipitation, exosome isolation, siRNA knockdown, CDC42 activation assays, NLRP3 inflammasome stimulation","journal":"The EMBO journal","confidence":"Medium","confidence_rationale":"Tier 2 — proteomic identification with co-IP and loss-of-function defining adaptor role, single study","pmids":["36373462"],"is_preprint":false},{"year":2023,"finding":"TRIM56 promotes K48-to-K63-linked poly-ubiquitination transition of IQGAP1 at Lys-1230 by interacting with IQGAP1, which in turn promotes CDC42 activation and glioma cell migration and invasion.","method":"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K1230), CDC42 activation assay, in vitro and in vivo migration models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — ubiquitin site-specific mutagenesis with mechanistic downstream consequence, single study","pmids":["36870986"],"is_preprint":false}],"current_model":"IQGAP1 is a large multidomain scaffold protein that integrates diverse signaling pathways by directly binding and coordinating the activities of Rho-family GTPases (Cdc42, Rac1, RhoA/C, Rap1), MAPK cascade components (B-Raf, MEK1/2, ERK1/2), receptor tyrosine kinases (EGFR, IR), actin and microtubule regulators (CLIP-170, N-WASP/Arp2/3), and many other partners including calmodulin, β-catenin, YAP, AMPK, and GSDMD; its activity is regulated by post-translational modifications (SUMOylation at K1445, ubiquitination by HECTD1, phosphorylation at S480 by GLK and S1443 by PKCα) and by Ca2+/calmodulin-dependent conformational changes, enabling IQGAP1 to control actin dynamics (filament bundling and barbed-end capping), microtubule capture at the leading edge, cell polarity, migration, exocytosis, receptor recycling, and ERK/Akt/mTOR signal transmission in processes ranging from normal cell homeostasis to tumorigenesis."},"narrative":{"teleology":[{"year":1996,"claim":"Identification of IQGAP1 as a Cdc42/Rac1 effector and calmodulin-binding protein localized to lamellipodia established the founding biochemical framework: a GTPase-regulated, IQ-domain-containing scaffold at the actin cortex.","evidence":"Affinity purification, in vitro GTPase assays, co-IP, yeast epistasis, and immunofluorescence in mammalian cells and S. cerevisiae","pmids":["8670801"],"confidence":"High","gaps":["Mechanism of GAP-like inhibition versus stabilization of GTP-Cdc42 was ambiguous","In vivo phenotype of IQGAP1 loss unknown","Downstream effectors beyond actin not identified"]},{"year":2002,"claim":"Discovery that IQGAP1 bridges Rac1/Cdc42 to CLIP-170 at microtubule plus-ends resolved how GTPase signaling achieves cortical microtubule capture and cell polarization.","evidence":"Reciprocal co-IP, GFP live imaging, dominant-negative constructs in Vero fibroblasts","pmids":["12110184"],"confidence":"High","gaps":["Whether IQGAP1-CLIP-170 interaction is direct or bridged was not resolved with purified proteins","Contribution of IQGAP1 to microtubule dynamics in vivo untested"]},{"year":2003,"claim":"Functional evidence that IQGAP1 promotes cell motility and invasion through Cdc42/Rac1 connected the scaffold to a cancer-relevant phenotype and showed it sustains active GTPase pools rather than simply acting as a GAP.","evidence":"siRNA knockdown and dominant-negative ΔGRD in invasion/migration assays with in vitro GTPase activity measurements","pmids":["12900413"],"confidence":"High","gaps":["Mechanism by which IQGAP1 increases GTP-Cdc42 (GDI displacement vs. GEF recruitment) unresolved","Relative contributions of Rac1 vs. Cdc42 to IQGAP1-driven invasion unclear"]},{"year":2005,"claim":"Demonstration that IQGAP1 directly and cooperatively scaffolds MEK1/2 and ERK1/2 (and later B-Raf) established IQGAP1 as a bona fide MAPK scaffold that tunes signal amplitude rather than simply relaying it.","evidence":"In vitro binding with purified proteins, co-IP, siRNA knockdown, IQGAP1 mutant constructs, EGF stimulation in multiple studies","pmids":["14970219","16135787"],"confidence":"High","gaps":["Stoichiometry and spatial organization of the scaffold-kinase complex unknown","Whether IQGAP1 scaffolding confers switch-like vs. graded ERK activation untested"]},{"year":2006,"claim":"Reconstitution of IQGAP1-stimulated N-WASP/Arp2/3-dependent actin polymerization, gated by an intramolecular autoinhibition mechanism, revealed how IQGAP1 directly nucleates branched actin independently of Cdc42.","evidence":"Kinetic actin polymerization assays with GST-tagged IQGAP1 fragments, co-IP, siRNA","pmids":["17085436"],"confidence":"High","gaps":["In vivo relevance of the autoinhibition not demonstrated","How autoinhibition is relieved in cells (signal or PTM) undetermined"]},{"year":2007,"claim":"Mapping distinct binding interfaces for Rac1 vs. Cdc42 on IQGAP1's GRD, and identification of Rap1 as an additional IQ-domain GTPase partner regulated by calmodulin, expanded the GTPase repertoire and introduced Ca²⁺-dependent selectivity.","evidence":"Site-directed mutagenesis with quantitative affinity measurements (Rac1/Cdc42); in vitro binding and Rap1 activation assays","pmids":["17984089","17517894"],"confidence":"High","gaps":["Structural basis for differential switch-II recognition unresolved","Functional consequence of Rap1 regulation on adhesion in vivo not established"]},{"year":2008,"claim":"Integration of Ca²⁺/calmodulin with B-Raf binding and identification of IQGAP1 in exocyst-septin-mediated secretion revealed that IQGAP1 coordinates MAPK signaling and vesicle trafficking, both modulated by Ca²⁺.","evidence":"Direct in vitro binding with Ca²⁺ manipulation for B-Raf; co-IP and pulse-chase secretion assays in β-cells for exocyst","pmids":["18567582","18216334"],"confidence":"High","gaps":["Whether calmodulin and B-Raf compete for identical IQGAP1 residues was not mapped","Exocyst interaction not validated with purified proteins"]},{"year":2011,"claim":"In vivo knockout studies revealed physiological scaffold functions: IQGAP1-null mice showed impaired cardiac MAPK/AKT stress signaling, reduced hippocampal NR2A surface expression with LTP/memory deficits, and dysregulated T-cell activation, establishing organ-level requirements.","evidence":"IQGAP1 KO mice with aortic banding, hippocampal electrophysiology and behavior, and T-cell cytokine assays; co-IP in each system","pmids":["21493702","21653857","22573807"],"confidence":"High","gaps":["Cell-type-specific conditional KO phenotypes not dissected","Whether cardiac and neuronal phenotypes are ERK-dependent or involve other scaffolded pathways unclear"]},{"year":2011,"claim":"Direct binding to EGFR and identification of PKCα-mediated S1443 phosphorylation showed that IQGAP1 amplifies receptor tyrosine kinase autophosphorylation via a calmodulin-sensitive, phosphorylation-gated mechanism.","evidence":"In vitro binding, MS phosphosite identification, siRNA and IQGAP1-null cell reconstitution, PKC inhibitors","pmids":["21349850"],"confidence":"High","gaps":["Whether S1443 phosphorylation directly modulates EGFR affinity not determined","Generalizability to other RTKs beyond EGFR and IR not tested at this point"]},{"year":2013,"claim":"A WW-domain-derived peptide disrupting IQGAP1-ERK interaction inhibited RAS/RAF-driven tumorigenesis in vivo, providing pharmacologic proof that the scaffold function is essential for oncogenic RAS signaling and is therapeutically targetable.","evidence":"Peptide competition, IQGAP1 KO/knockdown in mouse tumor models, systemic peptide delivery","pmids":["23603816"],"confidence":"High","gaps":["Later work showed the IQ domain, not WW, is the primary ERK-binding site (PMID:28396345), raising questions about peptide mechanism of action","Pharmacokinetics and off-target effects of WW peptide not fully addressed"]},{"year":2017,"claim":"Quantitative reconstitution redefined the ERK/MEK binding site to the IQ domain (Kd ~8 µM) rather than WW, while identification of S480 phosphorylation by GLK, SUMOylation at K1445, and HECTD1-mediated ubiquitination revealed a multilayered PTM code controlling IQGAP1 stability and signaling output.","evidence":"Quantitative in vitro binding (IQ vs. WW), kinase assays, SUMOylation mapping, ubiquitination assays, KO/knockdown rescue experiments","pmids":["28396345","31431460","28987385","28073378"],"confidence":"High","gaps":["How SUMOylation and ubiquitination at distinct lysines are coordinated is unknown","Whether IQ3-dependent PI3K scaffolding and IQ-dependent ERK scaffolding are mutually exclusive on a single dimer not tested"]},{"year":2017,"claim":"Direct binding to insulin receptor and IRS-1 with impaired glucose homeostasis in IQGAP1-null mice established IQGAP1 as a metabolic scaffold, paralleled by its role in AMPK/CaMKK2 complex formation and fasting gene regulation.","evidence":"In vitro binding, domain mapping, IQGAP1 KO mice with glucose tolerance tests and AMPK phosphorylation rescue","pmids":["28082684","33191271"],"confidence":"High","gaps":["Tissue-specific contributions (hepatic vs. skeletal muscle vs. adipose) to metabolic phenotype not resolved","Whether AMPK and insulin receptor scaffolding occur on the same or separate IQGAP1 pools unknown"]},{"year":2021,"claim":"Single-molecule reconstitution demonstrated that IQGAP1 dimers bundle actin filaments, transiently cap barbed ends, and suppress disassembly through domain-specific and dimerization-dependent activities, providing a direct biophysical mechanism for cytoskeletal regulation.","evidence":"Single-molecule TIRF microscopy with domain deletion and dimerization-deficient mutants","pmids":["34731043"],"confidence":"High","gaps":["How barbed-end capping is relieved in vivo (e.g., by calmodulin or GTPase binding) not shown","Actin bundling geometry and filament spacing not structurally resolved"]},{"year":2022,"claim":"IQGAP1 was identified as an adaptor bridging GSDMD to ESCRT-Tsg101 for exosomal packaging of GSDMD and IL-1β, linking inflammasome effector export to CDC42-dependent IQGAP1 activation.","evidence":"Proteomic identification, co-IP, exosome isolation, siRNA knockdown with NLRP3 inflammasome stimulation","pmids":["36373462"],"confidence":"Medium","gaps":["Direct binding between IQGAP1 and GSDMD not shown with purified proteins","Generalizability beyond LPS/macrophage context untested","Whether IQGAP1 is required for all GSDMD exosomal export or only a subset unclear"]},{"year":null,"claim":"A full-length atomic structure of IQGAP1 (free and in complex with key partners), the rules governing competitive or cooperative binding of its >90 reported partners, and the in vivo consequences of individual domain disruptions in tissue-specific conditional knockouts remain unresolved.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of full-length IQGAP1 or its dimer","How the cell resolves competition among dozens of IQ-domain ligands (calmodulin, ERK, EGFR, AMPK, YAP, ER) is unknown","Conditional tissue-specific KO phenotypes largely unexplored"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[3,4,5,9,13,16,22,29,35,39,41]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,5,7,40]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,2,18,21,27,30]}],"localization":[{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,1,7,26,38]},{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,5,40]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[3,4,35]},{"term_id":"GO:0005768","term_label":"endosome","supporting_discovery_ids":[28]},{"term_id":"GO:0031410","term_label":"cytoplasmic vesicle","supporting_discovery_ids":[20,28,41]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[0,2,3,4,9,13,18,22,29,31,35,37]},{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[11,32]},{"term_id":"R-HSA-1500931","term_label":"Cell-Cell communication","supporting_discovery_ids":[23,24,26]},{"term_id":"R-HSA-5653656","term_label":"Vesicle-mediated transport","supporting_discovery_ids":[10,20,28,38,41]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[17,34,41]},{"term_id":"R-HSA-1430728","term_label":"Metabolism","supporting_discovery_ids":[35,39]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[22,32,37,42]}],"complexes":["IQGAP1-MEK-ERK MAPK scaffold","IQGAP1-CLIP-170-Cdc42/Rac1 cortical capture complex","Exocyst-septin-IQGAP1 complex"],"partners":["CDC42","RAC1","BRAF","MAP2K1","MAPK1","CLIP1","EGFR","PRKAA1"],"other_free_text":[]},"mechanistic_narrative":"IQGAP1 is a large multidomain scaffold protein that integrates cytoskeletal dynamics, small GTPase signaling, and mitogen-activated kinase cascades to coordinate cell polarity, migration, proliferation, and vesicular trafficking. It directly binds and stabilizes GTP-loaded Cdc42, Rac1, RhoA/C, and Rap1 through its GRD and IQ domains, while simultaneously recruiting MAPK pathway components (B-Raf, MEK1/2, ERK1/2) and PI3K-Akt-mTOR effectors via its IQ motifs to control growth factor signal output [PMID:8670801, PMID:16135787, PMID:22328503, PMID:31235839]. IQGAP1 dimerizes and directly engages actin filaments—bundling, capping barbed ends, and suppressing disassembly—while coupling to microtubule plus-ends through CLIP-170 to polarize the cytoskeleton at the leading edge, and activating N-WASP/Arp2/3-dependent actin nucleation through an autoinhibited C-terminal mechanism [PMID:34731043, PMID:12110184, PMID:17085436]. Its scaffolding activity is tuned by Ca²⁺/calmodulin-dependent conformational regulation, SUMOylation at K1445, ubiquitination by HECTD1 and TRIM56, and phosphorylation at S480 (by GLK) and S1443 (by PKCα), and it additionally scaffolds receptor complexes including EGFR and insulin receptor to modulate receptor autophosphorylation and downstream Akt/ERK signaling, with loss of IQGAP1 in mice impairing cardiac stress adaptation, glucose homeostasis, AMPK activation, and hippocampal synaptic plasticity [PMID:21349850, PMID:28082684, PMID:33191271, PMID:21653857, PMID:21493702, PMID:28987385, PMID:31431460]."},"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 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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 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immunofluorescence\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods (in vitro assay, co-IP, genetic epistasis, localization) in a foundational study with 342 citations\",\n      \"pmids\": [\"8670801\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2002,\n      \"finding\": \"IQGAP1 interacts directly with CLIP-170 at the growing ends of microtubules; activated Rac1/Cdc42 form a tripartite complex with IQGAP1 and CLIP-170 to capture microtubules at the cortical leading edge, establishing a polarized microtubule array and cell polarization.\",\n      \"method\": \"Co-immunoprecipitation, GFP live imaging, dominant-negative and deletion constructs, Vero fibroblast expression studies\",\n      \"journal\": \"Cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — reciprocal co-IP, functional mutant analysis, live imaging with defined phenotype; 502 citations indicating broad replication\",\n      \"pmids\": [\"12110184\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"IQGAP1 promotes cell motility and invasion in a Cdc42- and Rac1-dependent manner; it increases the amount of active Cdc42 in vitro and in cells; dominant-negative IQGAP1ΔGRD attenuates invasion driven by constitutively active Cdc42.\",\n      \"method\": \"siRNA knockdown, dominant-negative construct overexpression, in vitro GTPase activity assay, migration/invasion assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function (siRNA + dominant-negative) with mechanistic epistasis and in vitro activity assay\",\n      \"pmids\": [\"12900413\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"IQGAP1 directly binds ERK2 (demonstrated with pure proteins), and manipulation of IQGAP1 levels significantly reduces growth factor-stimulated ERK1/2 activity; the ERK2-binding region of IQGAP1 is required for this modulation.\",\n      \"method\": \"In vitro binding with purified proteins, co-immunoprecipitation from cell lysates, siRNA knockdown, IQGAP1 deletion mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding plus co-IP plus functional mutant analysis in single rigorous study\",\n      \"pmids\": [\"14970219\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"IQGAP1 functions as a molecular scaffold for the MAPK pathway by directly binding MEK1 and MEK2 as well as ERK2; MEK-ERK binding to IQGAP1 is cooperative and both knockdown and overexpression of IQGAP1 reduce EGF-stimulated MEK and ERK activation.\",\n      \"method\": \"In vitro binding assays, co-immunoprecipitation, siRNA knockdown, IQGAP1 mutant constructs, EGF stimulation assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — in vitro direct binding confirmed by co-IP plus loss-of-function with mechanistic mutant analysis\",\n      \"pmids\": [\"16135787\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"The C-terminal half of IQGAP1 activates N-WASP by interacting with its BR-CRIB domain in a Cdc42-like manner to stimulate Arp2/3-dependent actin assembly; the N-terminal half of IQGAP1 autoinhibits this activation by associating with the C-terminal region.\",\n      \"method\": \"Pull-down experiments with GST-tagged fragments, kinetic actin polymerization assays, co-immunoprecipitation, siRNA knockdown, quantitative co-localization analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstituted actin polymerization assay with domain mapping and autoinhibition mechanism defined\",\n      \"pmids\": [\"17085436\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IQGAP1 directly binds the small GTPase Rap1; interaction is enhanced by GTP-loading of Rap1 and is eliminated by calmodulin; Rap1 binds to the IQ region of IQGAP1; overexpression of IQGAP1 attenuates adhesion- and cAMP-mediated Rap1 activation.\",\n      \"method\": \"In vitro binding with pure proteins, co-immunoprecipitation, confocal microscopy, point mutants of IQGAP1, Rap1 activation assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding plus functional modulation assays plus domain mapping\",\n      \"pmids\": [\"17517894\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"IQGAP1-stimulated cell migration requires direct interaction with actin; Ca2+/calmodulin binding to IQGAP1 negatively regulates its pro-migratory function; Cdc42 localization at the leading edge is not required for maximal IQGAP1-driven migration.\",\n      \"method\": \"IQGAP1 point mutant constructs, calmodulin inhibitory peptide, confocal microscopy, migration assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — functional domain dissection with defined phenotype but single study\",\n      \"pmids\": [\"17544257\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The IQGAP1-Rac1 and IQGAP1-Cdc42 binding interfaces differ: switch II mutations abolish Rac1 binding but not Cdc42 binding; switch I residues 32 and 36 are important for both; the Rho insert loop does not contribute to IQGAP1 binding.\",\n      \"method\": \"Site-directed mutagenesis of Rac1/Cdc42, quantitative affinity measurements, competition assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — rigorous mutagenesis with quantitative thermodynamic analysis defining binding interfaces\",\n      \"pmids\": [\"17984089\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IQGAP1 integrates Ca2+/calmodulin with B-Raf signaling: Ca2+ promotes direct IQGAP1-B-Raf binding, which is inhibited by calmodulin in a Ca2+-dependent manner; chelation of intracellular Ca2+ enhances EGF-stimulated B-Raf activity in an IQGAP1-dependent manner.\",\n      \"method\": \"In vitro binding with pure proteins, co-immunoprecipitation, Ca2+ ionophore/chelator treatments, B-Raf activity assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding with mechanistic calcium regulation confirmed by co-IP and functional assays\",\n      \"pmids\": [\"18567582\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IQGAP1 associates and co-localizes with the exocyst-septin complex; CDC42 activation abolishes this association and inhibits secretion; the N-terminus of IQGAP1 binds the exocyst-septin complex and enhances secretion, while the C-terminus (binding CDC42) inhibits secretion.\",\n      \"method\": \"Co-immunoprecipitation, co-localization, pulse-chase secretion assays, dominant-negative constructs in pancreatic beta-cells\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional domain dissection and phenotypic readout but single study\",\n      \"pmids\": [\"18216334\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IQGAP1 regulates cell proliferation through a CDC42-mTOR pathway; the N-terminus of IQGAP1 interacts with mTOR, which is required for IQGAP1-mediated cell proliferation; IQGAP1 requires phosphorylation and CDC42 binding for this activity.\",\n      \"method\": \"Deletion constructs, co-immunoprecipitation, cell size measurement, transformation/migration assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional domain analysis and defined proliferative phenotype, single study\",\n      \"pmids\": [\"19454477\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"S100P, a Ca2+-binding protein, directly and Ca2+-dependently binds IQGAP1 primarily through the IQ domain (K_D ~0.2 µM), and S100P overexpression reduces EGF-induced IQGAP1 tyrosine phosphorylation and attenuates B-Raf binding to IQGAP1 and downstream MEK1/2 activation.\",\n      \"method\": \"Affinity approach with S100P dimer, pull-down, co-immunoprecipitation, kinase activation assays, S100P mutants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct binding with Kd measurement plus functional downstream consequences using specific S100P mutants\",\n      \"pmids\": [\"21177863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 directly binds EGFR through the IQ and kinase domains respectively; calmodulin disrupts this interaction; EGF induces IQGAP1 Ser1443 phosphorylation via PKCα; loss of IQGAP1 severely attenuates EGF-stimulated EGFR autophosphorylation, which is rescued by wild-type IQGAP1 reconstitution.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding with pure proteins, MS-based phosphorylation assay, siRNA, IQGAP1 null cells reconstitution, PKC inhibitors\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding, MS-identified phosphosite, rescue experiment in null cells with multiple orthogonal methods\",\n      \"pmids\": [\"21349850\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"CLIP-170 and IQGAP1 cooperatively regulate dendrite morphology of neurons by coordinating microtubule-actin cytoskeleton interaction; mTOR kinase interacts with CLIP-170 and is needed for efficient CLIP-170/IQGAP1 complex formation; dynamic microtubules, CLIP-170, and IQGAP1 are required for PI3K-mTOR-induced increases in dendritic arbor complexity.\",\n      \"method\": \"Knockdown in rat neurons, live imaging, co-immunoprecipitation, dendritic arbor morphometry\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with knockdown and quantitative morphological readout, single study\",\n      \"pmids\": [\"21430156\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 is a component of NMDAR multiprotein complexes and functionally interacts with NR2A subunits and ERK1/2; IQGAP1 knockout mice show decreased surface NR2A expression and impaired ERK signaling upon NR2A-dependent NMDAR stimulation, accompanied by reduced hippocampal dendritic spine density and long-term memory deficits.\",\n      \"method\": \"IQGAP1 knockout mice, co-immunoprecipitation, surface biotinylation, hippocampal LTP recordings\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — genetic KO with multiple orthogonal mechanistic readouts (co-IP, surface expression, LTP, behavior)\",\n      \"pmids\": [\"21653857\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 scaffolds c-Raf, MEK1/2, ERK1/2, and AKT in the heart; IQGAP1-null mice show impaired delayed (4-day) but not acute (10-min) MEK/ERK and AKT phosphorylation after pressure overload, leading to accelerated maladaptive cardiac remodeling.\",\n      \"method\": \"IQGAP1-null mice, aortic banding model, pull-down assays, phosphorylation time-course analysis\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — in vivo KO with temporal dissection of signaling and pull-down validation of scaffold complex\",\n      \"pmids\": [\"21493702\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"IQGAP1 acts as a dual negative regulator in T cells: it limits TCR-mediated signaling (LCK activation, IL-2/IFN-γ production) and F-actin assembly dynamics via distinct IQGAP1 domain-dependent mechanisms.\",\n      \"method\": \"IQGAP1-null T cells, siRNA in Jurkat cells, IQGAP1 domain constructs, F-actin imaging, cytokine measurement\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with defined cellular phenotypes and domain dissection, single study\",\n      \"pmids\": [\"22573807\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IQGAP1 acts upstream of RhoA/C (regulating their GTP loading) and downstream of RhoA/C (mediating their effects on proliferation/migration); it interacts directly with GTP-bound, prenylated RhoA and RhoC but not RhoB.\",\n      \"method\": \"Proteomics screen, co-immunoprecipitation, GTP-loading measurements in constitutively active mutants, siRNA knockdown, adenoviral constructs\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — isoform-specific direct binding plus epistatic placement upstream and downstream, single study\",\n      \"pmids\": [\"22992742\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"IQGAP1 conserved role in regulating TORC1: yeast two-hybrid identified Tco89p (TORC1-specific subunit) as an Iqg1p partner; mammalian IQGAP1 binds mTORC1 and Akt1 and modulates the mTORC1-S6K1→Akt1 negative feedback loop.\",\n      \"method\": \"Yeast two-hybrid, complementary yeast and mammalian experiments, co-immunoprecipitation, kinase activity assays\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — cross-species genetic/biochemical evidence with co-IP and activity measurements, single lab\",\n      \"pmids\": [\"22328503\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Activated Cdc42 bound to IQGAP1 recruits GDP-bound Rab27a to the plasma membrane to regulate endocytosis of insulin secretory membranes; IQGAP1 silencing inhibits endocytosis and glucose-induced redistribution of Rab27a and coronin 3.\",\n      \"method\": \"Identification of IQGAP1 as Rab27a-interacting protein, co-immunoprecipitation, silencing, dominant-negative IQGAP1, endocytosis assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP plus loss-of-function with defined endocytic phenotype, single study\",\n      \"pmids\": [\"24100016\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IQGAP1 binds TGF-β receptor II (TβRII) and promotes SMURF1-mediated ubiquitination and degradation of TβRII, thereby suppressing TGF-β-dependent myofibroblast differentiation; IQGAP1 knockdown stabilizes TβRII and potentiates TGF-β1 signaling.\",\n      \"method\": \"Co-immunoprecipitation, IQGAP1 knockdown in hepatic stellate cells, ubiquitination assay, in vivo tumor implantation\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with ubiquitination mechanism and in vivo validation, multiple orthogonal approaches\",\n      \"pmids\": [\"23454766\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"The IQGAP1 WW domain peptide disrupts IQGAP1-ERK1/2 interactions and inhibits RAS/RAF-driven tumorigenesis; IQGAP1 is required for RAS-driven tumorigenesis in mouse and human tissue.\",\n      \"method\": \"WW domain peptide competition, IQGAP1 knockout/knockdown in mouse models, tumor growth assays, systemic peptide delivery\",\n      \"journal\": \"Nature medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic scaffold-kinase disruption confirmed in vivo with genetic and pharmacologic approaches, high citation count\",\n      \"pmids\": [\"23603816\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"IQGAP1 regulates nuclear localization of β-catenin via importin-β5 in Wnt signaling; IQGAP1 depletion in Xenopus embryos reduces Wnt-induced nuclear β-catenin accumulation and Wnt target gene expression; Ran1 GTPase also contributes.\",\n      \"method\": \"Xenopus embryo depletion, co-immunoprecipitation, nuclear fractionation, Wnt target gene expression assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — in vivo loss-of-function in Xenopus with mechanistic co-IP, single study\",\n      \"pmids\": [\"24196961\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 interacts with LGR4 and DVL following RSPO stimulation to bring RSPO-LGR4 to the Wnt signaling complex; this promotes MEK1/2-mediated phosphorylation of LRP5/6 and potentiates both canonical and non-canonical Wnt signaling.\",\n      \"method\": \"Yeast two-hybrid/proteomics identification, co-immunoprecipitation, IQGAP1 siRNA, luciferase Wnt reporter assay, kinase assays\",\n      \"journal\": \"Proceedings of the National Academy of Sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with functional signaling assays and loss-of-function, single study\",\n      \"pmids\": [\"24639526\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 directly binds ERα and ERβ; interaction is mediated by the IQ domain of IQGAP1 and the hinge region of ERα; knockdown of IQGAP1 attenuates estradiol-induced transcription of estrogen-responsive genes (pS2, progesterone receptor, cyclin D1).\",\n      \"method\": \"In vitro binding with pure proteins, co-immunoprecipitation, domain mapping constructs, siRNA knockdown, transcription assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro interaction with domain mapping plus functional transcriptional readout\",\n      \"pmids\": [\"24550401\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 forms a complex with Asef (a Rac/Cdc42 GEF) following HGF stimulation, mediated by the C-terminal domain of IQGAP1; this complex localizes to the cell cortex and promotes Rac activation, leading to IQGAP1 interaction with Arp3 and cortactin to enhance endothelial barrier function.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, domain-mapping constructs, Rac activation assays, transendothelial resistance measurement\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with domain mapping and functional barrier readout, single study\",\n      \"pmids\": [\"25492863\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP1 acts as a scaffold that colocalizes p190A-RhoGAP with RhoA to inactivate RhoA and suppress airway smooth muscle contraction; IQGAP1 knockout mice have enhanced RhoA activity and increased airway hyperresponsiveness.\",\n      \"method\": \"IQGAP1 knockout mice, co-immunoprecipitation, proximity ligation assay, RhoA activity assays, tracheal ring contraction force measurement, primary human airway smooth muscle cell knockdown\",\n      \"journal\": \"The Journal of clinical investigation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with proximity ligation assay confirming complex colocalization and functional contraction readout, multiple orthogonal methods\",\n      \"pmids\": [\"25271629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP1 directly promotes CXCR4 cell surface expression and recycling via EEA-1+ endosomes; IQGAP1 depletion disrupts CXCR4 trafficking to late endosomes, reduces surface CXCR4, and blocks SDF-1-induced ERK activation and cell migration; upon SDF-1 treatment IQGAP1 binds α-tubulin and localizes to CXCR4-containing endosomes.\",\n      \"method\": \"siRNA knockdown, forced overexpression, endosomal fractionation, co-immunoprecipitation, confocal imaging, migration assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — loss-of-function with endosomal trafficking mechanism and co-IP, single study\",\n      \"pmids\": [\"26195666\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"The IQ3 motif of IQGAP1 specifically scaffolds PI3K-Akt pathway components (PIPKIα, PI3K); deletion or blocking of IQ3 reduces Akt activation without affecting ERK or EGFR binding to IQGAP1.\",\n      \"method\": \"IQ3 deletion mutant, IQ3 peptide inhibitor, co-immunoprecipitation, Akt/ERK activation assays, cell migration/invasion assays\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — domain deletion plus competitive peptide with functional selectivity demonstrated, single study\",\n      \"pmids\": [\"31235839\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"IQGAP1 directly binds YAP via its IQ domain (interacting with the TEAD-binding domain of YAP); IQGAP1 knockout or knockdown increases nuclear YAP-TEAD complex formation and YAP-TEAD-mediated transcription.\",\n      \"method\": \"Co-immunoprecipitation, in vitro binding with pure proteins, domain mapping, CRISPR/Cas9 IQGAP1 knockout, transcription reporter assays\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding with domain mapping plus CRISPR KO with transcriptional readout\",\n      \"pmids\": [\"27440047\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"AKT-phosphorylated FOXO1 (at Ser319) binds IQGAP1 and impedes IQGAP1-dependent ERK1/2 phosphorylation; decreased FOXO1 increases pERK1/2 in cancer cells; a FOXO1-derived phospho-mimicking peptide reverses IQGAP1-mediated ERK activation.\",\n      \"method\": \"Co-immunoprecipitation, FOXO1 phospho-mutants, IQGAP1 interaction assays, ERK phosphorylation assays, in vivo mouse experiments\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — mechanistic co-IP with PTM-specific interaction, peptide validation, and in vivo confirmation\",\n      \"pmids\": [\"28279977\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"SUMO1 SUMOylates IQGAP1 at K1445, stabilizing IQGAP1 by reducing ubiquitination; IQGAP1 SUMOylation activates ERK, MEK, and AKT phosphorylation; K1445 mutation reduces CRC cell growth, migration, and tumor formation.\",\n      \"method\": \"SUMO modification mapping, K1445 mutant, ubiquitination assay, ERK/MEK/AKT phosphorylation assays, in vitro and xenograft models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — specific SUMOylation site identified with functional consequences via mutagenesis, single study\",\n      \"pmids\": [\"28987385\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"The IQ domain of IQGAP1 (not the WW domain) is both necessary and sufficient for binding ERK1/2 and MEK1/2; WW domain peptides contribute little binding energy to ERK-IQGAP1 interaction; ERK2-IQGAP1 binding does not require ERK2 phosphorylation and the Kd is ~8 µM.\",\n      \"method\": \"Quantitative in vitro binding assays, IQ and WW domain deletion constructs, phospho-ERK2 and kinase-dead ERK2 variants\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — quantitative in vitro reconstitution with domain deletion and Kd measurement\",\n      \"pmids\": [\"28396345\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IQGAP1 associates with NLRC3 and disrupts the NLRC3-STING interaction; IQGAP1 knockdown phenocopies NLRC3 deficiency by increasing IFN-β production in response to cytosolic nucleic acids.\",\n      \"method\": \"Yeast two-hybrid identification, co-immunoprecipitation, siRNA knockdown in THP1 and HeLa cells, IFN-β ELISA\",\n      \"journal\": \"Journal of immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — co-IP with functional phenocopy via knockdown, single study\",\n      \"pmids\": [\"28864474\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IQGAP1 directly binds both insulin receptor (IR) via its IQ region and IRS-1 via the IRS-1 phosphotyrosine-binding domain interacting with the IQGAP1 C-terminal tail; loss of IQGAP1 reduces insulin-stimulated Akt and ERK phosphorylation and impairs glucose homeostasis in vivo.\",\n      \"method\": \"In vitro binding with pure proteins, co-immunoprecipitation, domain mapping, IQGAP1 knockout mice, in vivo glucose tolerance\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding with domain mapping plus in vivo metabolic phenotype in KO mice\",\n      \"pmids\": [\"28082684\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"HECTD1 (E3 ubiquitin ligase) interacts with IQGAP1 and regulates its degradation through ubiquitination; loss of HECTD1 increases IQGAP1 levels, accelerating cell spreading and impairing directional migration; IQGAP1 overexpression phenocopies HECTD1 loss, and IQGAP1 knockdown rescues HECTD1-null migration defects.\",\n      \"method\": \"HECTD1 mutant MEFs, co-immunoprecipitation, ubiquitination assay, siRNA rescue experiments, cell migration analysis\",\n      \"journal\": \"Cell communication and signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitination mechanism with epistatic rescue, single study\",\n      \"pmids\": [\"28073378\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"GLK/MAP4K3 directly phosphorylates IQGAP1 at Ser-480 via interaction of GLK proline-rich regions with the IQGAP1 WW domain; this phosphorylation enhances Cdc42 activation and subsequent cell migration and lung cancer metastasis; IQGAP1 depletion abolishes GLK-induced migration.\",\n      \"method\": \"In vitro kinase assay, co-immunoprecipitation, domain mapping, phospho-specific assay, IQGAP1 knockdown in migration and metastasis models, GLK transgenic mice\",\n      \"journal\": \"Cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct kinase assay identifying phosphosite, genetic models in vitro and in vivo with defined signaling mechanism\",\n      \"pmids\": [\"31431460\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"CD13 tethers the IQGAP1-ARF6-EFA6 complex to the plasma membrane to promote ARF6 GTPase activation and β1 integrin recycling during cell migration; phosphorylated CD13, IQGAP1, GTP-bound ARF6, and EFA6 form a complex at the leading edge.\",\n      \"method\": \"Co-immunoprecipitation, mass spectrometry, ARF6 activation assays, β1 integrin trafficking assays, migration assays, siRNA knockdown\",\n      \"journal\": \"Science signaling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — co-IP with trafficking phenotype and GTPase activation assay, single study\",\n      \"pmids\": [\"31040262\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IQGAP1 binds directly to the α1 subunit of AMPK and to CaMKK2 via its IQ domain; IQGAP1 is required for maximum AMPK activation by metformin and Ca2+; IQGAP1-null mice show impaired gluconeogenesis and fatty acid synthesis gene regulation in fasting.\",\n      \"method\": \"In vitro binding with fusion proteins, co-immunoprecipitation, siRNA knockdown, IQGAP1-null mice, AMPK phosphorylation rescue experiments\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — direct in vitro binding for both AMPK and CaMKK2 plus in vivo metabolic phenotype in KO mice\",\n      \"pmids\": [\"33191271\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Full-length IQGAP1 forms dimers that stably bind actin filament sides and transiently cap barbed ends; these interactions bundle filaments, suppress barbed end growth, and inhibit filament disassembly; each activity depends on distinct combinations of IQGAP1 domains and/or dimerization.\",\n      \"method\": \"Single-molecule TIRF microscopy, single-filament imaging, domain deletion constructs, dimerization mutants\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — direct single-molecule reconstitution with mechanistic domain dissection\",\n      \"pmids\": [\"34731043\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IQGAP1 functions as an adaptor bridging GSDMD to the ESCRT component Tsg101 to promote packaging of GSDMD and IL-1β into exosomes; this process requires LPS-induced GTP-bound CDC42 activation of IQGAP1 and is identified through non-biased proteomics.\",\n      \"method\": \"Proteomic identification, co-immunoprecipitation, exosome isolation, siRNA knockdown, CDC42 activation assays, NLRP3 inflammasome stimulation\",\n      \"journal\": \"The EMBO journal\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — proteomic identification with co-IP and loss-of-function defining adaptor role, single study\",\n      \"pmids\": [\"36373462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"TRIM56 promotes K48-to-K63-linked poly-ubiquitination transition of IQGAP1 at Lys-1230 by interacting with IQGAP1, which in turn promotes CDC42 activation and glioma cell migration and invasion.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K1230), CDC42 activation assay, in vitro and in vivo migration models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — ubiquitin site-specific mutagenesis with mechanistic downstream consequence, single study\",\n      \"pmids\": [\"36870986\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IQGAP1 is a large multidomain scaffold protein that integrates diverse signaling pathways by directly binding and coordinating the activities of Rho-family GTPases (Cdc42, Rac1, RhoA/C, Rap1), MAPK cascade components (B-Raf, MEK1/2, ERK1/2), receptor tyrosine kinases (EGFR, IR), actin and microtubule regulators (CLIP-170, N-WASP/Arp2/3), and many other partners including calmodulin, β-catenin, YAP, AMPK, and GSDMD; its activity is regulated by post-translational modifications (SUMOylation at K1445, ubiquitination by HECTD1, phosphorylation at S480 by GLK and S1443 by PKCα) and by Ca2+/calmodulin-dependent conformational changes, enabling IQGAP1 to control actin dynamics (filament bundling and barbed-end capping), microtubule capture at the leading edge, cell polarity, migration, exocytosis, receptor recycling, and ERK/Akt/mTOR signal transmission in processes ranging from normal cell homeostasis to tumorigenesis.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"IQGAP1 is a large multidomain scaffold protein that integrates cytoskeletal dynamics, small GTPase signaling, and mitogen-activated kinase cascades to coordinate cell polarity, migration, proliferation, and vesicular trafficking. It directly binds and stabilizes GTP-loaded Cdc42, Rac1, RhoA/C, and Rap1 through its GRD and IQ domains, while simultaneously recruiting MAPK pathway components (B-Raf, MEK1/2, ERK1/2) and PI3K-Akt-mTOR effectors via its IQ motifs to control growth factor signal output [PMID:8670801, PMID:16135787, PMID:22328503, PMID:31235839]. IQGAP1 dimerizes and directly engages actin filaments—bundling, capping barbed ends, and suppressing disassembly—while coupling to microtubule plus-ends through CLIP-170 to polarize the cytoskeleton at the leading edge, and activating N-WASP/Arp2/3-dependent actin nucleation through an autoinhibited C-terminal mechanism [PMID:34731043, PMID:12110184, PMID:17085436]. Its scaffolding activity is tuned by Ca²⁺/calmodulin-dependent conformational regulation, SUMOylation at K1445, ubiquitination by HECTD1 and TRIM56, and phosphorylation at S480 (by GLK) and S1443 (by PKCα), and it additionally scaffolds receptor complexes including EGFR and insulin receptor to modulate receptor autophosphorylation and downstream Akt/ERK signaling, with loss of IQGAP1 in mice impairing cardiac stress adaptation, glucose homeostasis, AMPK activation, and hippocampal synaptic plasticity [PMID:21349850, PMID:28082684, PMID:33191271, PMID:21653857, PMID:21493702, PMID:28987385, PMID:31431460].\",\n  \"teleology\": [\n    {\n      \"year\": 1996,\n      \"claim\": \"Identification of IQGAP1 as a Cdc42/Rac1 effector and calmodulin-binding protein localized to lamellipodia established the founding biochemical framework: a GTPase-regulated, IQ-domain-containing scaffold at the actin cortex.\",\n      \"evidence\": \"Affinity purification, in vitro GTPase assays, co-IP, yeast epistasis, and immunofluorescence in mammalian cells and S. cerevisiae\",\n      \"pmids\": [\"8670801\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of GAP-like inhibition versus stabilization of GTP-Cdc42 was ambiguous\", \"In vivo phenotype of IQGAP1 loss unknown\", \"Downstream effectors beyond actin not identified\"]\n    },\n    {\n      \"year\": 2002,\n      \"claim\": \"Discovery that IQGAP1 bridges Rac1/Cdc42 to CLIP-170 at microtubule plus-ends resolved how GTPase signaling achieves cortical microtubule capture and cell polarization.\",\n      \"evidence\": \"Reciprocal co-IP, GFP live imaging, dominant-negative constructs in Vero fibroblasts\",\n      \"pmids\": [\"12110184\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IQGAP1-CLIP-170 interaction is direct or bridged was not resolved with purified proteins\", \"Contribution of IQGAP1 to microtubule dynamics in vivo untested\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Functional evidence that IQGAP1 promotes cell motility and invasion through Cdc42/Rac1 connected the scaffold to a cancer-relevant phenotype and showed it sustains active GTPase pools rather than simply acting as a GAP.\",\n      \"evidence\": \"siRNA knockdown and dominant-negative ΔGRD in invasion/migration assays with in vitro GTPase activity measurements\",\n      \"pmids\": [\"12900413\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism by which IQGAP1 increases GTP-Cdc42 (GDI displacement vs. GEF recruitment) unresolved\", \"Relative contributions of Rac1 vs. Cdc42 to IQGAP1-driven invasion unclear\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Demonstration that IQGAP1 directly and cooperatively scaffolds MEK1/2 and ERK1/2 (and later B-Raf) established IQGAP1 as a bona fide MAPK scaffold that tunes signal amplitude rather than simply relaying it.\",\n      \"evidence\": \"In vitro binding with purified proteins, co-IP, siRNA knockdown, IQGAP1 mutant constructs, EGF stimulation in multiple studies\",\n      \"pmids\": [\"14970219\", \"16135787\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry and spatial organization of the scaffold-kinase complex unknown\", \"Whether IQGAP1 scaffolding confers switch-like vs. graded ERK activation untested\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Reconstitution of IQGAP1-stimulated N-WASP/Arp2/3-dependent actin polymerization, gated by an intramolecular autoinhibition mechanism, revealed how IQGAP1 directly nucleates branched actin independently of Cdc42.\",\n      \"evidence\": \"Kinetic actin polymerization assays with GST-tagged IQGAP1 fragments, co-IP, siRNA\",\n      \"pmids\": [\"17085436\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"In vivo relevance of the autoinhibition not demonstrated\", \"How autoinhibition is relieved in cells (signal or PTM) undetermined\"]\n    },\n    {\n      \"year\": 2007,\n      \"claim\": \"Mapping distinct binding interfaces for Rac1 vs. Cdc42 on IQGAP1's GRD, and identification of Rap1 as an additional IQ-domain GTPase partner regulated by calmodulin, expanded the GTPase repertoire and introduced Ca²⁺-dependent selectivity.\",\n      \"evidence\": \"Site-directed mutagenesis with quantitative affinity measurements (Rac1/Cdc42); in vitro binding and Rap1 activation assays\",\n      \"pmids\": [\"17984089\", \"17517894\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis for differential switch-II recognition unresolved\", \"Functional consequence of Rap1 regulation on adhesion in vivo not established\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Integration of Ca²⁺/calmodulin with B-Raf binding and identification of IQGAP1 in exocyst-septin-mediated secretion revealed that IQGAP1 coordinates MAPK signaling and vesicle trafficking, both modulated by Ca²⁺.\",\n      \"evidence\": \"Direct in vitro binding with Ca²⁺ manipulation for B-Raf; co-IP and pulse-chase secretion assays in β-cells for exocyst\",\n      \"pmids\": [\"18567582\", \"18216334\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether calmodulin and B-Raf compete for identical IQGAP1 residues was not mapped\", \"Exocyst interaction not validated with purified proteins\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"In vivo knockout studies revealed physiological scaffold functions: IQGAP1-null mice showed impaired cardiac MAPK/AKT stress signaling, reduced hippocampal NR2A surface expression with LTP/memory deficits, and dysregulated T-cell activation, establishing organ-level requirements.\",\n      \"evidence\": \"IQGAP1 KO mice with aortic banding, hippocampal electrophysiology and behavior, and T-cell cytokine assays; co-IP in each system\",\n      \"pmids\": [\"21493702\", \"21653857\", \"22573807\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Cell-type-specific conditional KO phenotypes not dissected\", \"Whether cardiac and neuronal phenotypes are ERK-dependent or involve other scaffolded pathways unclear\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Direct binding to EGFR and identification of PKCα-mediated S1443 phosphorylation showed that IQGAP1 amplifies receptor tyrosine kinase autophosphorylation via a calmodulin-sensitive, phosphorylation-gated mechanism.\",\n      \"evidence\": \"In vitro binding, MS phosphosite identification, siRNA and IQGAP1-null cell reconstitution, PKC inhibitors\",\n      \"pmids\": [\"21349850\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether S1443 phosphorylation directly modulates EGFR affinity not determined\", \"Generalizability to other RTKs beyond EGFR and IR not tested at this point\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"A WW-domain-derived peptide disrupting IQGAP1-ERK interaction inhibited RAS/RAF-driven tumorigenesis in vivo, providing pharmacologic proof that the scaffold function is essential for oncogenic RAS signaling and is therapeutically targetable.\",\n      \"evidence\": \"Peptide competition, IQGAP1 KO/knockdown in mouse tumor models, systemic peptide delivery\",\n      \"pmids\": [\"23603816\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Later work showed the IQ domain, not WW, is the primary ERK-binding site (PMID:28396345), raising questions about peptide mechanism of action\", \"Pharmacokinetics and off-target effects of WW peptide not fully addressed\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Quantitative reconstitution redefined the ERK/MEK binding site to the IQ domain (Kd ~8 µM) rather than WW, while identification of S480 phosphorylation by GLK, SUMOylation at K1445, and HECTD1-mediated ubiquitination revealed a multilayered PTM code controlling IQGAP1 stability and signaling output.\",\n      \"evidence\": \"Quantitative in vitro binding (IQ vs. WW), kinase assays, SUMOylation mapping, ubiquitination assays, KO/knockdown rescue experiments\",\n      \"pmids\": [\"28396345\", \"31431460\", \"28987385\", \"28073378\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How SUMOylation and ubiquitination at distinct lysines are coordinated is unknown\", \"Whether IQ3-dependent PI3K scaffolding and IQ-dependent ERK scaffolding are mutually exclusive on a single dimer not tested\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Direct binding to insulin receptor and IRS-1 with impaired glucose homeostasis in IQGAP1-null mice established IQGAP1 as a metabolic scaffold, paralleled by its role in AMPK/CaMKK2 complex formation and fasting gene regulation.\",\n      \"evidence\": \"In vitro binding, domain mapping, IQGAP1 KO mice with glucose tolerance tests and AMPK phosphorylation rescue\",\n      \"pmids\": [\"28082684\", \"33191271\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Tissue-specific contributions (hepatic vs. skeletal muscle vs. adipose) to metabolic phenotype not resolved\", \"Whether AMPK and insulin receptor scaffolding occur on the same or separate IQGAP1 pools unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Single-molecule reconstitution demonstrated that IQGAP1 dimers bundle actin filaments, transiently cap barbed ends, and suppress disassembly through domain-specific and dimerization-dependent activities, providing a direct biophysical mechanism for cytoskeletal regulation.\",\n      \"evidence\": \"Single-molecule TIRF microscopy with domain deletion and dimerization-deficient mutants\",\n      \"pmids\": [\"34731043\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How barbed-end capping is relieved in vivo (e.g., by calmodulin or GTPase binding) not shown\", \"Actin bundling geometry and filament spacing not structurally resolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"IQGAP1 was identified as an adaptor bridging GSDMD to ESCRT-Tsg101 for exosomal packaging of GSDMD and IL-1β, linking inflammasome effector export to CDC42-dependent IQGAP1 activation.\",\n      \"evidence\": \"Proteomic identification, co-IP, exosome isolation, siRNA knockdown with NLRP3 inflammasome stimulation\",\n      \"pmids\": [\"36373462\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding between IQGAP1 and GSDMD not shown with purified proteins\", \"Generalizability beyond LPS/macrophage context untested\", \"Whether IQGAP1 is required for all GSDMD exosomal export or only a subset unclear\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A full-length atomic structure of IQGAP1 (free and in complex with key partners), the rules governing competitive or cooperative binding of its >90 reported partners, and the in vivo consequences of individual domain disruptions in tissue-specific conditional knockouts remain unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of full-length IQGAP1 or its dimer\", \"How the cell resolves competition among dozens of IQ-domain ligands (calmodulin, ERK, EGFR, AMPK, YAP, ER) is unknown\", \"Conditional tissue-specific KO phenotypes largely unexplored\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [3, 4, 5, 9, 13, 16, 22, 29, 35, 39, 41]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 5, 7, 40]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 2, 18, 21, 27, 30]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 1, 7, 26, 38]},\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 5, 40]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [3, 4, 35]},\n      {\"term_id\": \"GO:0005768\", \"supporting_discovery_ids\": [28]},\n      {\"term_id\": \"GO:0031410\", \"supporting_discovery_ids\": [20, 28, 41]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 2, 3, 4, 9, 13, 18, 22, 29, 31, 35, 37]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [11, 32]},\n      {\"term_id\": \"R-HSA-1500931\", \"supporting_discovery_ids\": [23, 24, 26]},\n      {\"term_id\": \"R-HSA-5653656\", \"supporting_discovery_ids\": [10, 20, 28, 38, 41]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [17, 34, 41]},\n      {\"term_id\": \"R-HSA-1430728\", \"supporting_discovery_ids\": [35, 39]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [22, 32, 37, 42]}\n    ],\n    \"complexes\": [\n      \"IQGAP1-MEK-ERK MAPK scaffold\",\n      \"IQGAP1-CLIP-170-Cdc42/Rac1 cortical capture complex\",\n      \"Exocyst-septin-IQGAP1 complex\"\n    ],\n    \"partners\": [\n      \"CDC42\",\n      \"RAC1\",\n      \"BRAF\",\n      \"MAP2K1\",\n      \"MAPK1\",\n      \"CLIP1\",\n      \"EGFR\",\n      \"PRKAA1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}