{"gene":"IQGAP3","run_date":"2026-06-10T01:55:23","timeline":{"discoveries":[{"year":2007,"finding":"IQGAP3 is a direct effector of active Rac1 and Cdc42 GTPases, associates directly with actin filaments, and accumulates asymmetrically at the distal region of axons in hippocampal neurons. Depletion of IQGAP3 impairs neurite/axon outgrowth with disorganized cytoskeleton, and IQGAP3 is indispensable for Rac1/Cdc42-promoted neurite outgrowth in PC12 cells.","method":"Protein binding assays (GTPase effector pulldown), direct actin co-sedimentation, immunofluorescence localization, siRNA knockdown with neurite outgrowth phenotypic readout","journal":"Journal of cell science","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (direct binding assay, actin association, localization, KD phenotype), foundational study replicated in concept by multiple subsequent labs","pmids":["17244649"],"is_preprint":false},{"year":2008,"finding":"IQGAP3 specifically interacts with the active GTP-bound form of Ras and regulates cell proliferation through Ras-dependent ERK activation. Knockdown inhibits proliferation and ERK activity; exogenous expression induces cell-cycle re-entry blocked by MEK inhibitor U0126, placing IQGAP3 upstream of Ras and ERK in a proliferation pathway.","method":"Co-immunoprecipitation with active Ras (GTP-bound), siRNA knockdown, MEK inhibitor epistasis (U0126), ERK activity assays, cell proliferation assays","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with active Ras, pharmacological epistasis with MEK inhibitor, gain- and loss-of-function experiments, published in high-tier journal and replicated in subsequent studies","pmids":["18604197"],"is_preprint":false},{"year":2011,"finding":"All four IQ-motifs of IQGAP3 interact with calmodulin (CaM) in the presence of calcium ions; the first IQ-motif of IQGAP3 also forms a transient interaction with myosin essential light chain (Mlc1sa) in the absence of calcium. No IQ-motifs of IQGAP3 interacted with S100B.","method":"Synthetic peptide binding assays with native gel electrophoresis, molecular modelling","journal":"Bioscience reports","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro peptide binding assay with defined biochemical readout, but single lab and peptide-based (not full-length protein), with negative result for S100B","pmids":["21299499"],"is_preprint":false},{"year":2009,"finding":"IQGAP3 is specifically expressed in proliferating hepatocytes (Ki-67+) and is highly enriched at cell-cell contacts of hepatocytes during liver regeneration and development, consistent with involvement of the IQGAP3/Ras/ERK signaling cascade in hepatocyte proliferation.","method":"Immunofluorescence, western blot, qPCR in normal, regenerating, and developing liver; comparison with IQGAP1/2 expression patterns","journal":"Journal of cellular physiology","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — direct localization with functional context established by comparison, but no functional manipulation of IQGAP3 in this study","pmids":["19452445"],"is_preprint":false},{"year":2014,"finding":"IQGAP3 interacts with ERK1 and enhances ERK1 phosphorylation following EGF treatment, placing IQGAP3 in the EGFR-ERK signaling axis in lung cancer cells.","method":"Co-immunoprecipitation, western blot for pERK1, EGF stimulation experiments, siRNA knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 3 / Weak — single Co-IP identifying ERK1 as binding partner, functional phosphorylation assay, single lab","pmids":["24849319"],"is_preprint":false},{"year":2015,"finding":"IQGAP3 has an essential, non-redundant role in epidermal tumorigenesis; the IQGAP1 IQ-motif decoy domain inhibits oncogenic Ras-driven MAPK signaling and antagonizes tumorigenesis in vivo without disrupting normal epidermal proliferation, demonstrating IQGAP-dependent scaffolding of the Ras-MAPK pathway specifically in tumor cells.","method":"Genetically engineered human skin tissue in vivo, siRNA/shRNA knockdown, expression of dominant-negative IQGAP domain decoys, MAPK signaling assays","journal":"The Journal of investigative dermatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo genetic engineering with defined signaling readout, but decoy domain experiments target IQGAP1 primarily; IQGAP3 role inferred from knockdown phenotype in same system","pmids":["25848980"],"is_preprint":false},{"year":2015,"finding":"IQGAP3 loss-of-function in zebrafish impairs both cell proliferation and cell motility during embryonic development; dominant-negative FGFR1 or Ras phenotypes are rescued by co-injection of IQGAP3 mRNA, establishing IQGAP3 as a downstream regulator of the FGFR1-Ras signaling pathway.","method":"Morpholino knockdown in zebrafish, in situ hybridization, mRNA rescue experiments with dominant-negative FGFR1 and Ras constructs (genetic epistasis)","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic epistasis via mRNA rescue of dominant-negative forms in zebrafish, multiple orthogonal approaches (KD + rescue), ortholog study with clear mechanistic placement","pmids":["26286209"],"is_preprint":false},{"year":2017,"finding":"IQGAP3 promotes epithelial-mesenchymal transition (EMT) and metastasis in hepatocellular carcinoma by constitutively activating TGF-β signaling, as demonstrated by ectopic expression enhancing EMT markers and TGF-β pathway activation, and silencing reversing these effects.","method":"Ectopic overexpression, siRNA knockdown, western blot for EMT markers and TGF-β pathway components, in vitro migration/invasion assays, orthotopic xenograft mouse model","journal":"Journal of translational medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain- and loss-of-function with in vivo validation and pathway readouts, single lab","pmids":["28810875"],"is_preprint":false},{"year":2018,"finding":"During cardiomyocyte cytokinesis, IQGAP3 localizes to the cleavage furrow and stembody of the midbody. In binucleating cardiomyocytes, IQGAP3 is abnormally localized, failing to reach the midbody stembody, correlating with failed cleavage furrow ingression; this mislocalization is linked to aberrant astral microtubule distribution.","method":"Time-lapse live imaging, immunofluorescence in rat cardiomyocytes in vitro and in vivo, quantitative analysis of IQGAP3 localization at midbody vs. stembody","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment tied to functional consequence (cytokinesis failure), live imaging plus fixed analysis, single lab","pmids":["29522098"],"is_preprint":false},{"year":2019,"finding":"E2F1 transcriptionally activates IQGAP3 in hepatocellular carcinoma cells. IQGAP3 interacts with PKCδ and competitively inhibits the interaction between PKCδ and PKCα, resulting in PKCα phosphorylation and activation, thereby promoting cell proliferation.","method":"Co-immunoprecipitation, competitive binding assay, western blot for PKCα phosphorylation, transactivation reporter assays, HCC patient tissue correlation","journal":"American journal of cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP demonstrating competitive interaction, phosphorylation readout, transcriptional activation assay; single lab","pmids":["30906629"],"is_preprint":false},{"year":2020,"finding":"IQGAP3 interacts with Rad17 and controls its expression to activate ATM/Chk2 and ATR/Chk1 DNA damage response signaling pathways by recruiting the MRN (Mre11-Rad50-Nbs1) complex in response to DNA damage, thereby promoting radioresistance in lung cancer.","method":"Co-immunoprecipitation (IQGAP3-Rad17 interaction), siRNA knockdown, western blot for ATM/Chk2 and ATR/Chk1 pathway activation, in vitro and in vivo radioresistance assays","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifying Rad17 as binding partner, pathway activation assays, loss-of-function with defined signaling readout, single lab","pmids":["32896617"],"is_preprint":false},{"year":2020,"finding":"IQGAP3 interacts with Rho family GTPases (including Cdc42 and Rac1), accumulates at the leading edge of migrating cells and at the cleavage furrow of dividing cells, and reduces cell-cell adhesion via interactions with E-cadherin or β-catenin proteins in gastric cancer cells.","method":"Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, overexpression morphology assays, invasion assays","journal":"Biomolecules","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP for multiple partners, direct localization experiments, gain/loss-of-function phenotype; replicated IQGAP3-GTPase interaction from earlier work","pmids":["32824461"],"is_preprint":false},{"year":2020,"finding":"IQGAP3 is a specific marker and functional regulator of proliferating isthmus stem cells in the stomach corpus. The Ras pathway is identified as a critical partner of IQGAP3 in promoting strong proliferation in these stem cells. Iqgap3 depletion impairs stem cell maintenance, and Iqgap3 expression is robustly induced following tissue damage.","method":"Iqgap3-2A-tdTomato mouse model, lineage tracing, immunofluorescence, in situ hybridization, transcriptomic analysis, Iqgap3 depletion (loss-of-function) in vivo","journal":"Gut","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo lineage tracing with genetic reporter mouse, transcriptomic pathway analysis, loss-of-function with defined stem cell phenotype; multiple orthogonal methods","pmids":["33293280"],"is_preprint":false},{"year":2021,"finding":"IQGAP3 is a transcriptional target of YAP. IQGAP3 knockdown causes S-phase arrest, delayed mitotic progression, multipolar spindle formation, and aneuploidy. IQGAP3 interacts with MMS19, and IQGAP3 knockdown decreases MMS19 protein levels; XPD knockdown partially rescues reduced proliferation upon IQGAP3 knockdown, suggesting IQGAP3 modulates the cell cycle via the MMS19/XPD/CAK axis.","method":"YAP reporter assays, siRNA knockdown, flow cytometry cell-cycle analysis, immunofluorescence for spindle morphology, Co-IP (IQGAP3-MMS19 interaction), genetic epistasis (XPD knockdown rescue)","journal":"Molecular cancer research : MCR","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for MMS19 binding, genetic epistasis rescue experiment, multiple cellular phenotype readouts; single lab","pmids":["34183451"],"is_preprint":false},{"year":2022,"finding":"IGF2BP1 binds and stabilizes m6A-modified IQGAP3 transcripts, thereby upregulating IQGAP3 protein expression. Downstream IGF2BP1 targets SRF and FOXM1 also transcriptionally upregulate IQGAP3, revealing multiple layers of post-transcriptional and transcriptional IQGAP3 regulation.","method":"RNA immunoprecipitation (RIP) for IGF2BP1-IQGAP3 mRNA binding, m6A modification assays, transcription factor reporter assays, expression correlation studies","journal":"iScience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay establishing direct RNA-protein interaction, m6A modification validated, transcriptional regulation confirmed; single lab","pmids":["36217548"],"is_preprint":false},{"year":2022,"finding":"hnRNPC directly interacts with IQGAP3 and stabilizes it to promote pancreatic cancer cell proliferation, migration, invasion, and EMT.","method":"Co-immunoprecipitation (hnRNPC-IQGAP3 direct interaction), overexpression and knockdown assays, in vivo metastasis models","journal":"BioMed research international","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP result, single lab, mechanism of stabilization not fully elucidated biochemically","pmids":["35355828"],"is_preprint":false},{"year":2022,"finding":"CDC42 promotes IQGAP3 expression, and IQGAP3 in turn activates the Ras/ERK pathway; overexpression of IQGAP3 rescues proliferation inhibition and apoptosis caused by CDC42 knockdown in bladder cancer cells, placing IQGAP3 downstream of CDC42 in this pathway.","method":"siRNA knockdown, overexpression, western blot for Ras/ERK pathway, CCK-8 proliferation, flow cytometry apoptosis, genetic epistasis (rescue experiment)","journal":"Biochemical genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — epistasis established by rescue experiment, pathway readouts; single lab, single study","pmids":["35412170"],"is_preprint":false},{"year":2023,"finding":"FOXD2 transcriptionally activates IQGAP3 by binding to its promoter region, and this FOXD2-IQGAP3 axis promotes gastric adenocarcinoma cell proliferation by inducing an increase in intracellular Ca2+ levels.","method":"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, Fluo-3 fluorescence staining for intracellular Ca2+, siRNA knockdown, western blot","journal":"The Kaohsiung journal of medical sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase reporter confirm direct transcriptional regulation; Ca2+ measurement links IQGAP3 to downstream signaling; single lab","pmids":["37724892"],"is_preprint":false},{"year":2024,"finding":"IQGAP3 interacts with PAK6; depletion of IQGAP3 disrupts RhoA activity and actomyosin contractility, causing elongated cell morphology and inhibiting invadopodia formation and migration in triple-negative breast cancer cells. PAK6 depletion phenocopies IQGAP3 depletion, and PAK6 overexpression rescues the IQGAP3 depletion phenotype, defining a PAK6-IQGAP3-RhoA pathway driving cellular contractility.","method":"Co-immunoprecipitation (IQGAP3-PAK6 interaction), siRNA knockdown, overexpression rescue, RhoA activity assay, actomyosin contractility measurements, invadopodia assay, live-cell migration assay","journal":"Cellular signalling","confidence":"High","confidence_rationale":"Tier 2 / Moderate — Co-IP, epistasis via rescue experiment, multiple functional readouts (RhoA activity, contractility, invadopodia, migration); single lab but multiple orthogonal methods","pmids":["38763182"],"is_preprint":false},{"year":2024,"finding":"IQGAP3 overexpression sustains active Rac1 GTPase activity and promotes cytoskeletal remodeling in MVI+-HCC cells to enhance trans-endothelial migration. IQGAP3 also induces hepatic stellate cell (HSC) activation and disrupts HSC-endothelial interactions via upregulation of multiple cytokines, enabling an infiltrative vessel co-optive growth pattern and microvascular invasion.","method":"RNA-sequencing, proteomic analysis, co-culture modeling, Rac1 GTPase activity assays, multiplex immunofluorescence, siRNA nanoparticle delivery in orthotopic xenograft model","journal":"Clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple mechanistic approaches (Rac1 activity assay, transcriptomics, proteomics, co-culture), in vivo validation; single lab","pmids":["38470497"],"is_preprint":false},{"year":2024,"finding":"PRKN (Parkin) ubiquitinates IQGAP3 to promote its proteasomal degradation; PRKN overexpression suppresses CRC cell growth and metastasis and promotes ferroptosis, effects reversed by IQGAP3 upregulation.","method":"Co-immunoprecipitation, ubiquitination assay, western blot, siRNA/overexpression, in vivo xenograft tumor model","journal":"Journal of bioenergetics and biomembranes","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ubiquitination assay establish PRKN as E3 ligase for IQGAP3, epistasis rescue experiment; single lab","pmids":["39343867"],"is_preprint":false},{"year":2024,"finding":"MYB transcription factor binds to the IQGAP3 promoter to transcriptionally upregulate IQGAP3 expression, and IQGAP3 mediates DNA mismatch repair/DNA damage repair pathways; silencing IQGAP3 increases 5-FU sensitivity and reversal of MYB-driven resistance requires IQGAP3.","method":"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA/overexpression, immunofluorescence for DNA damage markers, CCK-8 assay, flow cytometry","journal":"Drug development research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional activation, epistasis rescue experiment, multiple functional readouts; single lab","pmids":["40772604"],"is_preprint":false},{"year":2025,"finding":"IQGAP3 disrupts the Axin1-CK1α interaction (identified by TurboID proximity labeling), thereby inhibiting β-catenin phosphorylation and leading to β-catenin accumulation; IQGAP3 overexpression increases β-catenin levels and depletion reduces them. IQGAP3 is itself regulated by Wnt signaling, forming a positive feedback loop.","method":"TurboID proximity proteomics, Co-immunoprecipitation, β-catenin level assays (western blot), overexpression/knockdown, functional Wnt pathway reporter assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — TurboID + Co-IP for Axin1/CK1α partners, functional β-catenin readouts, mechanistic disruption of protein-protein interaction demonstrated; single lab","pmids":["40830657"],"is_preprint":false},{"year":2025,"finding":"IQGAP3 deficiency leads to hearing loss by inhibiting CDC42 enzymatic activity and blocking the Wnt-β-catenin pathway, resulting in reduced inner ear progenitor cell proliferation (40% fewer EdU+ and 44% fewer Ki67+ cells).","method":"iqgap3 morpholino knockdown in zebrafish, IQGAP3-knockout HEK293T cells, primary mouse inner ear progenitor cell model, CDC42 activity assay, EdU/Ki67 proliferation assays, Wnt pathway assays","journal":"International journal of pediatric otorhinolaryngology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple model systems (zebrafish KD, mammalian cell KO, primary cells), direct CDC42 activity assay, pathway epistasis; single lab","pmids":["40239295"],"is_preprint":false},{"year":2025,"finding":"IQGAP3 regulates macrophage polarization by binding and sequestering IGF2BP2 at the cell periphery, limiting IGF2BP2-mediated stabilization of FYN mRNA; reduced FYN expression leads to decreased STAT1 phosphorylation, driving an immunosuppressive M2-like macrophage phenotype.","method":"Co-immunoprecipitation (IQGAP3-IGF2BP2 interaction), immunofluorescence for subcellular localization, FYN mRNA stability assays, western blot for STAT1 phosphorylation, macrophage phagocytosis and T cell activation assays, xenograft model","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP, subcellular sequestration mechanism, downstream signaling readouts (FYN, STAT1), multiple functional assays; single lab","pmids":["41467907"],"is_preprint":false},{"year":2025,"finding":"IFFO1 directly interacts with IQGAP3 through its 2A coiled-coil domain and inhibits the association of IQGAP3 with its effector Cdc42 in a dose-dependent manner, thereby suppressing IQGAP3-dependent cell migration in lung cancer cells.","method":"Co-immunoprecipitation (IFFO1-IQGAP3 interaction), domain mapping, competitive binding assay (IQGAP3-Cdc42 association dose-response to IFFO1), siRNA knockdown, migration assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct interaction mapped to specific domain, competitive inhibition of IQGAP3-Cdc42 binding demonstrated biochemically, functional rescue; single lab","pmids":["40634295"],"is_preprint":false},{"year":2025,"finding":"WTAP m6A methyltransferase complex regulates IQGAP3 expression in endothelial cells via KLF2-mediated transcriptional control of the IQGAP3 promoter; IQGAP3 is identified as a key target of WTAP required for stress fiber formation in endothelial cells.","method":"RNA-seq (target identification), luciferase reporter assay (KLF2 regulation of IQGAP3 promoter/intron), siRNA knockdown of WTAP and KLF2, stress fiber quantification by VE-cadherin staining and immunofluorescence","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — luciferase reporter confirms direct transcriptional regulation, RNA-seq for target identification, functional stress fiber phenotype; single lab","pmids":["41317937"],"is_preprint":false},{"year":2025,"finding":"METTL3-catalyzed m6A modification of IQGAP3 mRNA enhances IQGAP3 stability and expression through IGF2BP2 reader protein binding to m6A-modified IQGAP3 transcripts. IQGAP3 upregulation activates TGF-β/Smad signaling and drives EMT and HCC metastasis; METTL3 or IGF2BP2 knockdown reduces m6A on IQGAP3 transcripts and decreases IQGAP3 levels and metastatic capacity.","method":"RNA immunoprecipitation (IGF2BP2-IQGAP3 mRNA binding), m6A methylation assays (METTL3 knockdown + m6A level measurement on IQGAP3 transcripts), mRNA stability assay, western blot for TGF-β/Smad pathway, in vivo lung metastasis model","journal":"Pathology, research and practice","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RIP assay, m6A modification validated on IQGAP3 transcripts, mRNA stability assay, in vivo validation; single lab, multiple methods","pmids":["40945199"],"is_preprint":false},{"year":2026,"finding":"Matrix stiffness induces IQGAP3 expression through YAP1 and TEAD transcription factors in glioblastoma stem cells (GSCs). IQGAP3 promotes GSC self-renewal and radioresistance by binding to and stabilizing the stem cell transcription factor SOX2; IQGAP3 targeting reduces SOX2 protein levels in vitro and in vivo. Structure-function drug screening identified trimetrexate as a pharmacological disruptor of IQGAP3-SOX2 binding that sensitizes GSCs to radiotherapy.","method":"Differential gene expression (stiff vs. soft matrix), YAP1/TEAD reporter assays, Co-immunoprecipitation (IQGAP3-SOX2 binding), SOX2 protein stability assays, in vitro and in vivo GSC self-renewal/radioresistance assays, structure-function drug screening","journal":"Nature communications","confidence":"High","confidence_rationale":"Tier 2 / Strong — Co-IP establishing direct IQGAP3-SOX2 interaction, transcriptional upstream regulation (YAP1/TEAD), in vivo validation, pharmacological disruption with functional rescue; multiple orthogonal methods","pmids":["42251046"],"is_preprint":false},{"year":2026,"finding":"IQGAP3 knockout in Huh-7 cells specifically reduces Marburg virus transcription/replication efficiency, virus release, and long-distance nucleocapsid transport; IQGAP3 KO cells show reduced spatial displacement efficiency of nucleocapsids, likely through modulation of actin dynamics.","method":"CRISPR knockout cell lines (single, combined, triple IQGAP isoform KO), viral infection assays, live imaging of nucleocapsid transport, rescue by individual IQGAP re-expression","journal":"Cellular and molecular life sciences : CMLS","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — defined KO with specific viral process phenotypes, rescue by re-expression, multiple aspects of viral cycle assessed; single lab","pmids":["41661241"],"is_preprint":false}],"current_model":"IQGAP3 is a scaffolding protein that functions as a direct effector of active Rac1, Cdc42, and Ras GTPases, linking their activation to actin cytoskeletal organization, cell proliferation via the Ras-ERK pathway, and cell migration; its expression is transcriptionally regulated by YAP, E2F1, FOXD2, MYB, and FOXM1/SRF, and post-transcriptionally stabilized by m6A modification (via METTL3/IGF2BP2) and competitive protection from PRKN-mediated ubiquitination, while mechanistically it scaffolds multiple signaling nodes including EGFR-ERK, TGF-β/Smad, Wnt/β-catenin (by disrupting Axin1-CK1α interaction), Hedgehog-GLI1, ATM/ATR DNA damage response (via Rad17/MRN complex recruitment), and MMS19/XPD/CAK cell cycle control, with subcellular localization to the cleavage furrow/midbody during cytokinesis, the leading edge during migration, and axon tips in neurons, and with its activity negatively regulated by IFFO1-mediated inhibition of IQGAP3-Cdc42 interaction and by PAK6 acting as a downstream effector in a PAK6-IQGAP3-RhoA contractility pathway."},"narrative":{"mechanistic_narrative":"IQGAP3 is a multivalent scaffolding protein that couples Rho-family and Ras GTPase activation to actin cytoskeletal organization, cell proliferation, and migration [PMID:17244649, PMID:18604197, PMID:32824461]. It acts as a direct effector of active Rac1 and Cdc42, binds actin filaments, and is required for GTPase-driven cytoskeletal outgrowth in neurons [PMID:17244649]; it also binds the GTP-bound form of Ras and drives proliferation through Ras-dependent ERK activation, an axis that operates downstream of FGFR1/Ras signaling and within the EGFR-ERK pathway [PMID:18604197, PMID:26286209, PMID:24849319]. Through its IQ motifs IQGAP3 engages calmodulin in a calcium-dependent manner [PMID:21299499]. Functionally it localizes to the leading edge of migrating cells and to the cleavage furrow and midbody during cytokinesis, where its proper positioning is required for cleavage furrow ingression [PMID:29522098, PMID:32824461], and it lowers cell-cell adhesion via E-cadherin/β-catenin interactions [PMID:32824461]. IQGAP3 nucleates contractility through a PAK6-IQGAP3-RhoA pathway controlling actomyosin tension, invadopodia, and migration [PMID:38763182], an activity antagonized by IFFO1, which competitively blocks the IQGAP3-Cdc42 interaction [PMID:40634295]. Beyond cytoskeletal control, IQGAP3 scaffolds diverse signaling nodes: it activates TGF-β/Smad signaling to drive EMT [PMID:28810875, PMID:40945199], promotes β-catenin accumulation by disrupting the Axin1-CK1α interaction in a Wnt feedback loop [PMID:40830657], couples to the ATM/ATR DNA damage response via Rad17 and the MRN complex [PMID:32896617], and modulates cell-cycle progression through the MMS19/XPD/CAK axis [PMID:34183451]. It also binds and stabilizes the stem-cell factor SOX2 to sustain self-renewal and radioresistance [PMID:42251046], and serves as a marker and proliferation regulator of gastric isthmus stem cells through the Ras pathway [PMID:33293280]. IQGAP3 expression is controlled transcriptionally by YAP/TEAD, E2F1, FOXD2, MYB, and KLF2 [PMID:34183451, PMID:42251046, PMID:30906629, PMID:37724892, PMID:40772604, PMID:41317937] and post-transcriptionally by m6A-dependent stabilization via IGF2BP1/IGF2BP2 with METTL3/WTAP [PMID:36217548, PMID:40945199, PMID:41317937], while its protein levels are limited by PRKN-mediated ubiquitination [PMID:39343867].","teleology":[{"year":2007,"claim":"Established IQGAP3 as a direct GTPase effector by showing it binds active Rac1/Cdc42, associates with actin, and is required for GTPase-driven cytoskeletal outgrowth.","evidence":"GTPase effector pulldowns, actin co-sedimentation, immunofluorescence, and siRNA neurite-outgrowth assays in neurons and PC12 cells","pmids":["17244649"],"confidence":"High","gaps":["Did not define the structural basis of GTPase binding","Restricted to neuronal cytoskeletal phenotypes"]},{"year":2008,"claim":"Placed IQGAP3 in a proliferation pathway by showing it binds GTP-bound Ras and drives ERK-dependent cell-cycle re-entry.","evidence":"Co-IP with active Ras, MEK-inhibitor (U0126) epistasis, gain/loss-of-function proliferation and ERK activity assays","pmids":["18604197"],"confidence":"High","gaps":["Whether IQGAP3 acts upstream or as a scaffold for Ras was not biochemically resolved","No structural mapping of the Ras-binding interface"]},{"year":2011,"claim":"Characterized the IQ-motif interactome, defining calcium-dependent calmodulin binding across all four IQ motifs.","evidence":"Synthetic peptide binding with native gel electrophoresis and modelling","pmids":["21299499"],"confidence":"Medium","gaps":["Peptide-based rather than full-length protein","Functional consequence of CaM binding untested in cells"]},{"year":2015,"claim":"Connected IQGAP3 to Ras-MAPK-dependent tumorigenesis in vivo, establishing IQGAP scaffolding as tumor-selective.","evidence":"Engineered human skin tissue, knockdown, and dominant-negative IQGAP IQ-motif decoys with MAPK readouts; zebrafish morpholino knockdown with dominant-negative FGFR1/Ras mRNA rescue","pmids":["25848980","26286209"],"confidence":"High","gaps":["Skin decoys targeted IQGAP1 primarily; IQGAP3-specific contribution inferred from knockdown","FGFR1-Ras epistasis is genetic, not biochemical"]},{"year":2018,"claim":"Tied IQGAP3 localization to cytokinesis, showing midbody/stembody positioning is required for cleavage furrow ingression.","evidence":"Live imaging and immunofluorescence in cardiomyocytes with quantitative localization analysis","pmids":["29522098"],"confidence":"Medium","gaps":["Mechanism linking astral microtubule defects to IQGAP3 mislocalization unresolved","Single cell type (cardiomyocytes)"]},{"year":2020,"claim":"Expanded IQGAP3 into the DNA damage response, showing it controls Rad17 and recruits the MRN complex to activate ATM/ATR signaling.","evidence":"Co-IP (IQGAP3-Rad17), knockdown, pathway activation western blots, and radioresistance assays in lung cancer","pmids":["32896617"],"confidence":"Medium","gaps":["Direct vs. indirect Rad17 regulation not separated","Single lab without reciprocal validation"]},{"year":2020,"claim":"Defined IQGAP3 as an in vivo stem-cell regulator, marking and maintaining proliferating gastric isthmus stem cells via the Ras pathway.","evidence":"Iqgap3 reporter mouse, lineage tracing, transcriptomics, and in vivo depletion; gastric cancer Co-IP/localization for GTPase and E-cadherin/β-catenin partners","pmids":["33293280","32824461"],"confidence":"High","gaps":["How IQGAP3 reduces cell-cell adhesion mechanistically not detailed","Damage-induced induction signal upstream of IQGAP3 unknown"]},{"year":2021,"claim":"Linked IQGAP3 to mitotic fidelity and the cell cycle through MMS19/XPD/CAK, with YAP as a transcriptional driver.","evidence":"YAP reporter assays, knockdown cell-cycle/spindle analysis, Co-IP (IQGAP3-MMS19), and XPD-knockdown epistasis rescue","pmids":["34183451"],"confidence":"Medium","gaps":["Mechanism of MMS19 stabilization by IQGAP3 unresolved","Aneuploidy phenotype not mechanistically connected to MMS19/XPD"]},{"year":2022,"claim":"Identified post-transcriptional and additional transcriptional control of IQGAP3, including m6A-reader stabilization and competing PKCδ/PKCα scaffolding.","evidence":"RIP and m6A assays (IGF2BP1, SRF, FOXM1), Co-IP competitive binding (PKCδ/PKCα), hnRNPC Co-IP stabilization, and E2F1 transactivation assays","pmids":["36217548","30906629","35355828"],"confidence":"Medium","gaps":["hnRNPC stabilization mechanism not biochemically defined (Low confidence)","Layered regulators tested largely in single cancer contexts"]},{"year":2022,"claim":"Positioned IQGAP3 downstream of CDC42 in a feedback loop driving Ras/ERK proliferation and survival.","evidence":"Knockdown, overexpression rescue, and Ras/ERK pathway readouts in bladder cancer","pmids":["35412170"],"confidence":"Medium","gaps":["How CDC42 induces IQGAP3 expression unknown","Single study"]},{"year":2023,"claim":"Connected transcriptional induction of IQGAP3 to calcium signaling, with FOXD2 directly activating the promoter.","evidence":"ChIP, luciferase reporter, intracellular Ca2+ imaging, and knockdown in gastric adenocarcinoma","pmids":["37724892"],"confidence":"Medium","gaps":["Mechanism by which IQGAP3 raises Ca2+ not defined","Single lab"]},{"year":2024,"claim":"Defined a PAK6-IQGAP3-RhoA contractility axis controlling actomyosin tension, invadopodia, and migration, and resolved its regulation by ubiquitination and Rac1-driven invasion.","evidence":"Co-IP (PAK6, PRKN), epistasis rescue, RhoA/Rac1 activity assays, contractility/invadopodia/migration assays, ubiquitination assays, and orthotopic HCC models","pmids":["38763182","39343867","38470497"],"confidence":"High","gaps":["Whether PAK6 acts upstream or in complex with IQGAP3 not fully separated","PRKN ubiquitination sites on IQGAP3 unmapped"]},{"year":2025,"claim":"Revealed IQGAP3 as a node coupling Wnt/β-catenin, macrophage polarization, hearing development, and m6A regulation, with IFFO1 as a competitive inhibitor of its Cdc42 interaction.","evidence":"TurboID and Co-IP (Axin1/CK1α), IGF2BP2 sequestration with FYN/STAT1 readouts, zebrafish/KO CDC42-activity and Wnt assays, IFFO1 domain mapping and competitive binding, and WTAP/KLF2 promoter regulation with stress-fiber assays","pmids":["40830657","41467907","40239295","40634295","41317937"],"confidence":"Medium","gaps":["Each mechanism rests on a single lab","How one scaffold coordinates these divergent pathways in vivo unresolved"]},{"year":2026,"claim":"Established mechanotransduction-driven IQGAP3 control of stemness via direct SOX2 stabilization, and a role in Marburg virus nucleocapsid transport.","evidence":"YAP1/TEAD reporters, Co-IP (IQGAP3-SOX2), SOX2 stability assays, structure-function drug screening (trimetrexate), and CRISPR IQGAP-isoform knockouts with viral transport imaging","pmids":["42251046","41661241"],"confidence":"High","gaps":["SOX2 stabilization mechanism (degradation pathway) not fully defined","Viral phenotype attributed to actin modulation but not directly demonstrated"]},{"year":null,"claim":"How a single scaffold selects among its many GTPase, signaling, and transcription-factor partners in a given cell context remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model of full-length IQGAP3 or its partner-binding interfaces","Rules governing context-specific partner selection unknown","Most signaling links derive from single-lab cancer studies"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[1,9,13,18,22,28]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,11]},{"term_id":"GO:0098772","term_label":"molecular function regulator 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direct effector of active Rac1 and Cdc42 GTPases, associates directly with actin filaments, and accumulates asymmetrically at the distal region of axons in hippocampal neurons. Depletion of IQGAP3 impairs neurite/axon outgrowth with disorganized cytoskeleton, and IQGAP3 is indispensable for Rac1/Cdc42-promoted neurite outgrowth in PC12 cells.\",\n      \"method\": \"Protein binding assays (GTPase effector pulldown), direct actin co-sedimentation, immunofluorescence localization, siRNA knockdown with neurite outgrowth phenotypic readout\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (direct binding assay, actin association, localization, KD phenotype), foundational study replicated in concept by multiple subsequent labs\",\n      \"pmids\": [\"17244649\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"IQGAP3 specifically interacts with the active GTP-bound form of Ras and regulates cell proliferation through Ras-dependent ERK activation. Knockdown inhibits proliferation and ERK activity; exogenous expression induces cell-cycle re-entry blocked by MEK inhibitor U0126, placing IQGAP3 upstream of Ras and ERK in a proliferation pathway.\",\n      \"method\": \"Co-immunoprecipitation with active Ras (GTP-bound), siRNA knockdown, MEK inhibitor epistasis (U0126), ERK activity assays, cell proliferation assays\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with active Ras, pharmacological epistasis with MEK inhibitor, gain- and loss-of-function experiments, published in high-tier journal and replicated in subsequent studies\",\n      \"pmids\": [\"18604197\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"All four IQ-motifs of IQGAP3 interact with calmodulin (CaM) in the presence of calcium ions; the first IQ-motif of IQGAP3 also forms a transient interaction with myosin essential light chain (Mlc1sa) in the absence of calcium. No IQ-motifs of IQGAP3 interacted with S100B.\",\n      \"method\": \"Synthetic peptide binding assays with native gel electrophoresis, molecular modelling\",\n      \"journal\": \"Bioscience reports\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro peptide binding assay with defined biochemical readout, but single lab and peptide-based (not full-length protein), with negative result for S100B\",\n      \"pmids\": [\"21299499\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2009,\n      \"finding\": \"IQGAP3 is specifically expressed in proliferating hepatocytes (Ki-67+) and is highly enriched at cell-cell contacts of hepatocytes during liver regeneration and development, consistent with involvement of the IQGAP3/Ras/ERK signaling cascade in hepatocyte proliferation.\",\n      \"method\": \"Immunofluorescence, western blot, qPCR in normal, regenerating, and developing liver; comparison with IQGAP1/2 expression patterns\",\n      \"journal\": \"Journal of cellular physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — direct localization with functional context established by comparison, but no functional manipulation of IQGAP3 in this study\",\n      \"pmids\": [\"19452445\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"IQGAP3 interacts with ERK1 and enhances ERK1 phosphorylation following EGF treatment, placing IQGAP3 in the EGFR-ERK signaling axis in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, western blot for pERK1, EGF stimulation experiments, siRNA knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP identifying ERK1 as binding partner, functional phosphorylation assay, single lab\",\n      \"pmids\": [\"24849319\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP3 has an essential, non-redundant role in epidermal tumorigenesis; the IQGAP1 IQ-motif decoy domain inhibits oncogenic Ras-driven MAPK signaling and antagonizes tumorigenesis in vivo without disrupting normal epidermal proliferation, demonstrating IQGAP-dependent scaffolding of the Ras-MAPK pathway specifically in tumor cells.\",\n      \"method\": \"Genetically engineered human skin tissue in vivo, siRNA/shRNA knockdown, expression of dominant-negative IQGAP domain decoys, MAPK signaling assays\",\n      \"journal\": \"The Journal of investigative dermatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo genetic engineering with defined signaling readout, but decoy domain experiments target IQGAP1 primarily; IQGAP3 role inferred from knockdown phenotype in same system\",\n      \"pmids\": [\"25848980\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"IQGAP3 loss-of-function in zebrafish impairs both cell proliferation and cell motility during embryonic development; dominant-negative FGFR1 or Ras phenotypes are rescued by co-injection of IQGAP3 mRNA, establishing IQGAP3 as a downstream regulator of the FGFR1-Ras signaling pathway.\",\n      \"method\": \"Morpholino knockdown in zebrafish, in situ hybridization, mRNA rescue experiments with dominant-negative FGFR1 and Ras constructs (genetic epistasis)\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis via mRNA rescue of dominant-negative forms in zebrafish, multiple orthogonal approaches (KD + rescue), ortholog study with clear mechanistic placement\",\n      \"pmids\": [\"26286209\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"IQGAP3 promotes epithelial-mesenchymal transition (EMT) and metastasis in hepatocellular carcinoma by constitutively activating TGF-β signaling, as demonstrated by ectopic expression enhancing EMT markers and TGF-β pathway activation, and silencing reversing these effects.\",\n      \"method\": \"Ectopic overexpression, siRNA knockdown, western blot for EMT markers and TGF-β pathway components, in vitro migration/invasion assays, orthotopic xenograft mouse model\",\n      \"journal\": \"Journal of translational medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain- and loss-of-function with in vivo validation and pathway readouts, single lab\",\n      \"pmids\": [\"28810875\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"During cardiomyocyte cytokinesis, IQGAP3 localizes to the cleavage furrow and stembody of the midbody. In binucleating cardiomyocytes, IQGAP3 is abnormally localized, failing to reach the midbody stembody, correlating with failed cleavage furrow ingression; this mislocalization is linked to aberrant astral microtubule distribution.\",\n      \"method\": \"Time-lapse live imaging, immunofluorescence in rat cardiomyocytes in vitro and in vivo, quantitative analysis of IQGAP3 localization at midbody vs. stembody\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment tied to functional consequence (cytokinesis failure), live imaging plus fixed analysis, single lab\",\n      \"pmids\": [\"29522098\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"E2F1 transcriptionally activates IQGAP3 in hepatocellular carcinoma cells. IQGAP3 interacts with PKCδ and competitively inhibits the interaction between PKCδ and PKCα, resulting in PKCα phosphorylation and activation, thereby promoting cell proliferation.\",\n      \"method\": \"Co-immunoprecipitation, competitive binding assay, western blot for PKCα phosphorylation, transactivation reporter assays, HCC patient tissue correlation\",\n      \"journal\": \"American journal of cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP demonstrating competitive interaction, phosphorylation readout, transcriptional activation assay; single lab\",\n      \"pmids\": [\"30906629\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IQGAP3 interacts with Rad17 and controls its expression to activate ATM/Chk2 and ATR/Chk1 DNA damage response signaling pathways by recruiting the MRN (Mre11-Rad50-Nbs1) complex in response to DNA damage, thereby promoting radioresistance in lung cancer.\",\n      \"method\": \"Co-immunoprecipitation (IQGAP3-Rad17 interaction), siRNA knockdown, western blot for ATM/Chk2 and ATR/Chk1 pathway activation, in vitro and in vivo radioresistance assays\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifying Rad17 as binding partner, pathway activation assays, loss-of-function with defined signaling readout, single lab\",\n      \"pmids\": [\"32896617\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IQGAP3 interacts with Rho family GTPases (including Cdc42 and Rac1), accumulates at the leading edge of migrating cells and at the cleavage furrow of dividing cells, and reduces cell-cell adhesion via interactions with E-cadherin or β-catenin proteins in gastric cancer cells.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence localization, siRNA knockdown, overexpression morphology assays, invasion assays\",\n      \"journal\": \"Biomolecules\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP for multiple partners, direct localization experiments, gain/loss-of-function phenotype; replicated IQGAP3-GTPase interaction from earlier work\",\n      \"pmids\": [\"32824461\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"IQGAP3 is a specific marker and functional regulator of proliferating isthmus stem cells in the stomach corpus. The Ras pathway is identified as a critical partner of IQGAP3 in promoting strong proliferation in these stem cells. Iqgap3 depletion impairs stem cell maintenance, and Iqgap3 expression is robustly induced following tissue damage.\",\n      \"method\": \"Iqgap3-2A-tdTomato mouse model, lineage tracing, immunofluorescence, in situ hybridization, transcriptomic analysis, Iqgap3 depletion (loss-of-function) in vivo\",\n      \"journal\": \"Gut\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo lineage tracing with genetic reporter mouse, transcriptomic pathway analysis, loss-of-function with defined stem cell phenotype; multiple orthogonal methods\",\n      \"pmids\": [\"33293280\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IQGAP3 is a transcriptional target of YAP. IQGAP3 knockdown causes S-phase arrest, delayed mitotic progression, multipolar spindle formation, and aneuploidy. IQGAP3 interacts with MMS19, and IQGAP3 knockdown decreases MMS19 protein levels; XPD knockdown partially rescues reduced proliferation upon IQGAP3 knockdown, suggesting IQGAP3 modulates the cell cycle via the MMS19/XPD/CAK axis.\",\n      \"method\": \"YAP reporter assays, siRNA knockdown, flow cytometry cell-cycle analysis, immunofluorescence for spindle morphology, Co-IP (IQGAP3-MMS19 interaction), genetic epistasis (XPD knockdown rescue)\",\n      \"journal\": \"Molecular cancer research : MCR\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for MMS19 binding, genetic epistasis rescue experiment, multiple cellular phenotype readouts; single lab\",\n      \"pmids\": [\"34183451\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"IGF2BP1 binds and stabilizes m6A-modified IQGAP3 transcripts, thereby upregulating IQGAP3 protein expression. Downstream IGF2BP1 targets SRF and FOXM1 also transcriptionally upregulate IQGAP3, revealing multiple layers of post-transcriptional and transcriptional IQGAP3 regulation.\",\n      \"method\": \"RNA immunoprecipitation (RIP) for IGF2BP1-IQGAP3 mRNA binding, m6A modification assays, transcription factor reporter assays, expression correlation studies\",\n      \"journal\": \"iScience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay establishing direct RNA-protein interaction, m6A modification validated, transcriptional regulation confirmed; single lab\",\n      \"pmids\": [\"36217548\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"hnRNPC directly interacts with IQGAP3 and stabilizes it to promote pancreatic cancer cell proliferation, migration, invasion, and EMT.\",\n      \"method\": \"Co-immunoprecipitation (hnRNPC-IQGAP3 direct interaction), overexpression and knockdown assays, in vivo metastasis models\",\n      \"journal\": \"BioMed research international\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP result, single lab, mechanism of stabilization not fully elucidated biochemically\",\n      \"pmids\": [\"35355828\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"CDC42 promotes IQGAP3 expression, and IQGAP3 in turn activates the Ras/ERK pathway; overexpression of IQGAP3 rescues proliferation inhibition and apoptosis caused by CDC42 knockdown in bladder cancer cells, placing IQGAP3 downstream of CDC42 in this pathway.\",\n      \"method\": \"siRNA knockdown, overexpression, western blot for Ras/ERK pathway, CCK-8 proliferation, flow cytometry apoptosis, genetic epistasis (rescue experiment)\",\n      \"journal\": \"Biochemical genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — epistasis established by rescue experiment, pathway readouts; single lab, single study\",\n      \"pmids\": [\"35412170\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOXD2 transcriptionally activates IQGAP3 by binding to its promoter region, and this FOXD2-IQGAP3 axis promotes gastric adenocarcinoma cell proliferation by inducing an increase in intracellular Ca2+ levels.\",\n      \"method\": \"Chromatin immunoprecipitation (ChIP), dual-luciferase reporter assay, Fluo-3 fluorescence staining for intracellular Ca2+, siRNA knockdown, western blot\",\n      \"journal\": \"The Kaohsiung journal of medical sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase reporter confirm direct transcriptional regulation; Ca2+ measurement links IQGAP3 to downstream signaling; single lab\",\n      \"pmids\": [\"37724892\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IQGAP3 interacts with PAK6; depletion of IQGAP3 disrupts RhoA activity and actomyosin contractility, causing elongated cell morphology and inhibiting invadopodia formation and migration in triple-negative breast cancer cells. PAK6 depletion phenocopies IQGAP3 depletion, and PAK6 overexpression rescues the IQGAP3 depletion phenotype, defining a PAK6-IQGAP3-RhoA pathway driving cellular contractility.\",\n      \"method\": \"Co-immunoprecipitation (IQGAP3-PAK6 interaction), siRNA knockdown, overexpression rescue, RhoA activity assay, actomyosin contractility measurements, invadopodia assay, live-cell migration assay\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, epistasis via rescue experiment, multiple functional readouts (RhoA activity, contractility, invadopodia, migration); single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38763182\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"IQGAP3 overexpression sustains active Rac1 GTPase activity and promotes cytoskeletal remodeling in MVI+-HCC cells to enhance trans-endothelial migration. IQGAP3 also induces hepatic stellate cell (HSC) activation and disrupts HSC-endothelial interactions via upregulation of multiple cytokines, enabling an infiltrative vessel co-optive growth pattern and microvascular invasion.\",\n      \"method\": \"RNA-sequencing, proteomic analysis, co-culture modeling, Rac1 GTPase activity assays, multiplex immunofluorescence, siRNA nanoparticle delivery in orthotopic xenograft model\",\n      \"journal\": \"Clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple mechanistic approaches (Rac1 activity assay, transcriptomics, proteomics, co-culture), in vivo validation; single lab\",\n      \"pmids\": [\"38470497\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"PRKN (Parkin) ubiquitinates IQGAP3 to promote its proteasomal degradation; PRKN overexpression suppresses CRC cell growth and metastasis and promotes ferroptosis, effects reversed by IQGAP3 upregulation.\",\n      \"method\": \"Co-immunoprecipitation, ubiquitination assay, western blot, siRNA/overexpression, in vivo xenograft tumor model\",\n      \"journal\": \"Journal of bioenergetics and biomembranes\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ubiquitination assay establish PRKN as E3 ligase for IQGAP3, epistasis rescue experiment; single lab\",\n      \"pmids\": [\"39343867\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"MYB transcription factor binds to the IQGAP3 promoter to transcriptionally upregulate IQGAP3 expression, and IQGAP3 mediates DNA mismatch repair/DNA damage repair pathways; silencing IQGAP3 increases 5-FU sensitivity and reversal of MYB-driven resistance requires IQGAP3.\",\n      \"method\": \"Dual-luciferase reporter assay, chromatin immunoprecipitation (ChIP), siRNA/overexpression, immunofluorescence for DNA damage markers, CCK-8 assay, flow cytometry\",\n      \"journal\": \"Drug development research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and luciferase confirm direct transcriptional activation, epistasis rescue experiment, multiple functional readouts; single lab\",\n      \"pmids\": [\"40772604\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IQGAP3 disrupts the Axin1-CK1α interaction (identified by TurboID proximity labeling), thereby inhibiting β-catenin phosphorylation and leading to β-catenin accumulation; IQGAP3 overexpression increases β-catenin levels and depletion reduces them. IQGAP3 is itself regulated by Wnt signaling, forming a positive feedback loop.\",\n      \"method\": \"TurboID proximity proteomics, Co-immunoprecipitation, β-catenin level assays (western blot), overexpression/knockdown, functional Wnt pathway reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — TurboID + Co-IP for Axin1/CK1α partners, functional β-catenin readouts, mechanistic disruption of protein-protein interaction demonstrated; single lab\",\n      \"pmids\": [\"40830657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IQGAP3 deficiency leads to hearing loss by inhibiting CDC42 enzymatic activity and blocking the Wnt-β-catenin pathway, resulting in reduced inner ear progenitor cell proliferation (40% fewer EdU+ and 44% fewer Ki67+ cells).\",\n      \"method\": \"iqgap3 morpholino knockdown in zebrafish, IQGAP3-knockout HEK293T cells, primary mouse inner ear progenitor cell model, CDC42 activity assay, EdU/Ki67 proliferation assays, Wnt pathway assays\",\n      \"journal\": \"International journal of pediatric otorhinolaryngology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple model systems (zebrafish KD, mammalian cell KO, primary cells), direct CDC42 activity assay, pathway epistasis; single lab\",\n      \"pmids\": [\"40239295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IQGAP3 regulates macrophage polarization by binding and sequestering IGF2BP2 at the cell periphery, limiting IGF2BP2-mediated stabilization of FYN mRNA; reduced FYN expression leads to decreased STAT1 phosphorylation, driving an immunosuppressive M2-like macrophage phenotype.\",\n      \"method\": \"Co-immunoprecipitation (IQGAP3-IGF2BP2 interaction), immunofluorescence for subcellular localization, FYN mRNA stability assays, western blot for STAT1 phosphorylation, macrophage phagocytosis and T cell activation assays, xenograft model\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP, subcellular sequestration mechanism, downstream signaling readouts (FYN, STAT1), multiple functional assays; single lab\",\n      \"pmids\": [\"41467907\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"IFFO1 directly interacts with IQGAP3 through its 2A coiled-coil domain and inhibits the association of IQGAP3 with its effector Cdc42 in a dose-dependent manner, thereby suppressing IQGAP3-dependent cell migration in lung cancer cells.\",\n      \"method\": \"Co-immunoprecipitation (IFFO1-IQGAP3 interaction), domain mapping, competitive binding assay (IQGAP3-Cdc42 association dose-response to IFFO1), siRNA knockdown, migration assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct interaction mapped to specific domain, competitive inhibition of IQGAP3-Cdc42 binding demonstrated biochemically, functional rescue; single lab\",\n      \"pmids\": [\"40634295\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"WTAP m6A methyltransferase complex regulates IQGAP3 expression in endothelial cells via KLF2-mediated transcriptional control of the IQGAP3 promoter; IQGAP3 is identified as a key target of WTAP required for stress fiber formation in endothelial cells.\",\n      \"method\": \"RNA-seq (target identification), luciferase reporter assay (KLF2 regulation of IQGAP3 promoter/intron), siRNA knockdown of WTAP and KLF2, stress fiber quantification by VE-cadherin staining and immunofluorescence\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — luciferase reporter confirms direct transcriptional regulation, RNA-seq for target identification, functional stress fiber phenotype; single lab\",\n      \"pmids\": [\"41317937\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"METTL3-catalyzed m6A modification of IQGAP3 mRNA enhances IQGAP3 stability and expression through IGF2BP2 reader protein binding to m6A-modified IQGAP3 transcripts. IQGAP3 upregulation activates TGF-β/Smad signaling and drives EMT and HCC metastasis; METTL3 or IGF2BP2 knockdown reduces m6A on IQGAP3 transcripts and decreases IQGAP3 levels and metastatic capacity.\",\n      \"method\": \"RNA immunoprecipitation (IGF2BP2-IQGAP3 mRNA binding), m6A methylation assays (METTL3 knockdown + m6A level measurement on IQGAP3 transcripts), mRNA stability assay, western blot for TGF-β/Smad pathway, in vivo lung metastasis model\",\n      \"journal\": \"Pathology, research and practice\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RIP assay, m6A modification validated on IQGAP3 transcripts, mRNA stability assay, in vivo validation; single lab, multiple methods\",\n      \"pmids\": [\"40945199\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Matrix stiffness induces IQGAP3 expression through YAP1 and TEAD transcription factors in glioblastoma stem cells (GSCs). IQGAP3 promotes GSC self-renewal and radioresistance by binding to and stabilizing the stem cell transcription factor SOX2; IQGAP3 targeting reduces SOX2 protein levels in vitro and in vivo. Structure-function drug screening identified trimetrexate as a pharmacological disruptor of IQGAP3-SOX2 binding that sensitizes GSCs to radiotherapy.\",\n      \"method\": \"Differential gene expression (stiff vs. soft matrix), YAP1/TEAD reporter assays, Co-immunoprecipitation (IQGAP3-SOX2 binding), SOX2 protein stability assays, in vitro and in vivo GSC self-renewal/radioresistance assays, structure-function drug screening\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — Co-IP establishing direct IQGAP3-SOX2 interaction, transcriptional upstream regulation (YAP1/TEAD), in vivo validation, pharmacological disruption with functional rescue; multiple orthogonal methods\",\n      \"pmids\": [\"42251046\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"IQGAP3 knockout in Huh-7 cells specifically reduces Marburg virus transcription/replication efficiency, virus release, and long-distance nucleocapsid transport; IQGAP3 KO cells show reduced spatial displacement efficiency of nucleocapsids, likely through modulation of actin dynamics.\",\n      \"method\": \"CRISPR knockout cell lines (single, combined, triple IQGAP isoform KO), viral infection assays, live imaging of nucleocapsid transport, rescue by individual IQGAP re-expression\",\n      \"journal\": \"Cellular and molecular life sciences : CMLS\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — defined KO with specific viral process phenotypes, rescue by re-expression, multiple aspects of viral cycle assessed; single lab\",\n      \"pmids\": [\"41661241\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"IQGAP3 is a scaffolding protein that functions as a direct effector of active Rac1, Cdc42, and Ras GTPases, linking their activation to actin cytoskeletal organization, cell proliferation via the Ras-ERK pathway, and cell migration; its expression is transcriptionally regulated by YAP, E2F1, FOXD2, MYB, and FOXM1/SRF, and post-transcriptionally stabilized by m6A modification (via METTL3/IGF2BP2) and competitive protection from PRKN-mediated ubiquitination, while mechanistically it scaffolds multiple signaling nodes including EGFR-ERK, TGF-β/Smad, Wnt/β-catenin (by disrupting Axin1-CK1α interaction), Hedgehog-GLI1, ATM/ATR DNA damage response (via Rad17/MRN complex recruitment), and MMS19/XPD/CAK cell cycle control, with subcellular localization to the cleavage furrow/midbody during cytokinesis, the leading edge during migration, and axon tips in neurons, and with its activity negatively regulated by IFFO1-mediated inhibition of IQGAP3-Cdc42 interaction and by PAK6 acting as a downstream effector in a PAK6-IQGAP3-RhoA contractility pathway.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"IQGAP3 is a multivalent scaffolding protein that couples Rho-family and Ras GTPase activation to actin cytoskeletal organization, cell proliferation, and migration [#0, #1, #11]. It acts as a direct effector of active Rac1 and Cdc42, binds actin filaments, and is required for GTPase-driven cytoskeletal outgrowth in neurons [#0]; it also binds the GTP-bound form of Ras and drives proliferation through Ras-dependent ERK activation, an axis that operates downstream of FGFR1/Ras signaling and within the EGFR-ERK pathway [#1, #6, #4]. Through its IQ motifs IQGAP3 engages calmodulin in a calcium-dependent manner [#2]. Functionally it localizes to the leading edge of migrating cells and to the cleavage furrow and midbody during cytokinesis, where its proper positioning is required for cleavage furrow ingression [#8, #11], and it lowers cell-cell adhesion via E-cadherin/β-catenin interactions [#11]. IQGAP3 nucleates contractility through a PAK6-IQGAP3-RhoA pathway controlling actomyosin tension, invadopodia, and migration [#18], an activity antagonized by IFFO1, which competitively blocks the IQGAP3-Cdc42 interaction [#25]. Beyond cytoskeletal control, IQGAP3 scaffolds diverse signaling nodes: it activates TGF-β/Smad signaling to drive EMT [#7, #27], promotes β-catenin accumulation by disrupting the Axin1-CK1α interaction in a Wnt feedback loop [#22], couples to the ATM/ATR DNA damage response via Rad17 and the MRN complex [#10], and modulates cell-cycle progression through the MMS19/XPD/CAK axis [#13]. It also binds and stabilizes the stem-cell factor SOX2 to sustain self-renewal and radioresistance [#28], and serves as a marker and proliferation regulator of gastric isthmus stem cells through the Ras pathway [#12]. IQGAP3 expression is controlled transcriptionally by YAP/TEAD, E2F1, FOXD2, MYB, and KLF2 [#13, #28, #9, #17, #21, #26] and post-transcriptionally by m6A-dependent stabilization via IGF2BP1/IGF2BP2 with METTL3/WTAP [#14, #27, #26], while its protein levels are limited by PRKN-mediated ubiquitination [#20].\",\n  \"teleology\": [\n    {\n      \"year\": 2007,\n      \"claim\": \"Established IQGAP3 as a direct GTPase effector by showing it binds active Rac1/Cdc42, associates with actin, and is required for GTPase-driven cytoskeletal outgrowth.\",\n      \"evidence\": \"GTPase effector pulldowns, actin co-sedimentation, immunofluorescence, and siRNA neurite-outgrowth assays in neurons and PC12 cells\",\n      \"pmids\": [\"17244649\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define the structural basis of GTPase binding\", \"Restricted to neuronal cytoskeletal phenotypes\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Placed IQGAP3 in a proliferation pathway by showing it binds GTP-bound Ras and drives ERK-dependent cell-cycle re-entry.\",\n      \"evidence\": \"Co-IP with active Ras, MEK-inhibitor (U0126) epistasis, gain/loss-of-function proliferation and ERK activity assays\",\n      \"pmids\": [\"18604197\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether IQGAP3 acts upstream or as a scaffold for Ras was not biochemically resolved\", \"No structural mapping of the Ras-binding interface\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Characterized the IQ-motif interactome, defining calcium-dependent calmodulin binding across all four IQ motifs.\",\n      \"evidence\": \"Synthetic peptide binding with native gel electrophoresis and modelling\",\n      \"pmids\": [\"21299499\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Peptide-based rather than full-length protein\", \"Functional consequence of CaM binding untested in cells\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Connected IQGAP3 to Ras-MAPK-dependent tumorigenesis in vivo, establishing IQGAP scaffolding as tumor-selective.\",\n      \"evidence\": \"Engineered human skin tissue, knockdown, and dominant-negative IQGAP IQ-motif decoys with MAPK readouts; zebrafish morpholino knockdown with dominant-negative FGFR1/Ras mRNA rescue\",\n      \"pmids\": [\"25848980\", \"26286209\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Skin decoys targeted IQGAP1 primarily; IQGAP3-specific contribution inferred from knockdown\", \"FGFR1-Ras epistasis is genetic, not biochemical\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Tied IQGAP3 localization to cytokinesis, showing midbody/stembody positioning is required for cleavage furrow ingression.\",\n      \"evidence\": \"Live imaging and immunofluorescence in cardiomyocytes with quantitative localization analysis\",\n      \"pmids\": [\"29522098\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism linking astral microtubule defects to IQGAP3 mislocalization unresolved\", \"Single cell type (cardiomyocytes)\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Expanded IQGAP3 into the DNA damage response, showing it controls Rad17 and recruits the MRN complex to activate ATM/ATR signaling.\",\n      \"evidence\": \"Co-IP (IQGAP3-Rad17), knockdown, pathway activation western blots, and radioresistance assays in lung cancer\",\n      \"pmids\": [\"32896617\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect Rad17 regulation not separated\", \"Single lab without reciprocal validation\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Defined IQGAP3 as an in vivo stem-cell regulator, marking and maintaining proliferating gastric isthmus stem cells via the Ras pathway.\",\n      \"evidence\": \"Iqgap3 reporter mouse, lineage tracing, transcriptomics, and in vivo depletion; gastric cancer Co-IP/localization for GTPase and E-cadherin/β-catenin partners\",\n      \"pmids\": [\"33293280\", \"32824461\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How IQGAP3 reduces cell-cell adhesion mechanistically not detailed\", \"Damage-induced induction signal upstream of IQGAP3 unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Linked IQGAP3 to mitotic fidelity and the cell cycle through MMS19/XPD/CAK, with YAP as a transcriptional driver.\",\n      \"evidence\": \"YAP reporter assays, knockdown cell-cycle/spindle analysis, Co-IP (IQGAP3-MMS19), and XPD-knockdown epistasis rescue\",\n      \"pmids\": [\"34183451\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of MMS19 stabilization by IQGAP3 unresolved\", \"Aneuploidy phenotype not mechanistically connected to MMS19/XPD\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Identified post-transcriptional and additional transcriptional control of IQGAP3, including m6A-reader stabilization and competing PKCδ/PKCα scaffolding.\",\n      \"evidence\": \"RIP and m6A assays (IGF2BP1, SRF, FOXM1), Co-IP competitive binding (PKCδ/PKCα), hnRNPC Co-IP stabilization, and E2F1 transactivation assays\",\n      \"pmids\": [\"36217548\", \"30906629\", \"35355828\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"hnRNPC stabilization mechanism not biochemically defined (Low confidence)\", \"Layered regulators tested largely in single cancer contexts\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Positioned IQGAP3 downstream of CDC42 in a feedback loop driving Ras/ERK proliferation and survival.\",\n      \"evidence\": \"Knockdown, overexpression rescue, and Ras/ERK pathway readouts in bladder cancer\",\n      \"pmids\": [\"35412170\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How CDC42 induces IQGAP3 expression unknown\", \"Single study\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Connected transcriptional induction of IQGAP3 to calcium signaling, with FOXD2 directly activating the promoter.\",\n      \"evidence\": \"ChIP, luciferase reporter, intracellular Ca2+ imaging, and knockdown in gastric adenocarcinoma\",\n      \"pmids\": [\"37724892\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which IQGAP3 raises Ca2+ not defined\", \"Single lab\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Defined a PAK6-IQGAP3-RhoA contractility axis controlling actomyosin tension, invadopodia, and migration, and resolved its regulation by ubiquitination and Rac1-driven invasion.\",\n      \"evidence\": \"Co-IP (PAK6, PRKN), epistasis rescue, RhoA/Rac1 activity assays, contractility/invadopodia/migration assays, ubiquitination assays, and orthotopic HCC models\",\n      \"pmids\": [\"38763182\", \"39343867\", \"38470497\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether PAK6 acts upstream or in complex with IQGAP3 not fully separated\", \"PRKN ubiquitination sites on IQGAP3 unmapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Revealed IQGAP3 as a node coupling Wnt/β-catenin, macrophage polarization, hearing development, and m6A regulation, with IFFO1 as a competitive inhibitor of its Cdc42 interaction.\",\n      \"evidence\": \"TurboID and Co-IP (Axin1/CK1α), IGF2BP2 sequestration with FYN/STAT1 readouts, zebrafish/KO CDC42-activity and Wnt assays, IFFO1 domain mapping and competitive binding, and WTAP/KLF2 promoter regulation with stress-fiber assays\",\n      \"pmids\": [\"40830657\", \"41467907\", \"40239295\", \"40634295\", \"41317937\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Each mechanism rests on a single lab\", \"How one scaffold coordinates these divergent pathways in vivo unresolved\"]\n    },\n    {\n      \"year\": 2026,\n      \"claim\": \"Established mechanotransduction-driven IQGAP3 control of stemness via direct SOX2 stabilization, and a role in Marburg virus nucleocapsid transport.\",\n      \"evidence\": \"YAP1/TEAD reporters, Co-IP (IQGAP3-SOX2), SOX2 stability assays, structure-function drug screening (trimetrexate), and CRISPR IQGAP-isoform knockouts with viral transport imaging\",\n      \"pmids\": [\"42251046\", \"41661241\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"SOX2 stabilization mechanism (degradation pathway) not fully defined\", \"Viral phenotype attributed to actin modulation but not directly demonstrated\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How a single scaffold selects among its many GTPase, signaling, and transcription-factor partners in a given cell context remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model of full-length IQGAP3 or its partner-binding interfaces\", \"Rules governing context-specific partner selection unknown\", \"Most signaling links derive from single-lab cancer studies\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [1, 9, 13, 18, 22, 28]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 11, 25]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 8, 11, 26]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [11, 24]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 11]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [0, 1, 18, 22]},\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [8, 13]},\n      {\"term_id\": \"R-HSA-73894\", \"supporting_discovery_ids\": [10, 21]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [6, 12, 23]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"RAC1\", \"CDC42\", \"HRAS\", \"ERK1\", \"RAD17\", \"MMS19\", \"PAK6\", \"IGF2BP2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":8,"faith_total":8,"faith_pct":100.0}}