{"gene":"SEPTIN2","run_date":"2026-06-10T07:46:30","timeline":{"discoveries":[{"year":1997,"finding":"Nedd5 (SEPTIN2) accumulates near the contractile ring from anaphase through telophase and condenses into the midbody; microinjection of anti-Nedd5 antibody causes cytokinesis failure resulting in binucleated cells, establishing a direct role in cytokinesis. GTP hydrolysis is required for assembly of Nedd5-containing fibers, as shown by GTPγS microinjection and GTP-binding-deficient mutants. Nedd5 fibers physically contact actin bundles and focal adhesion complexes and are disrupted by cytochalasin D, C3 exoenzyme, and serum starvation.","method":"Microinjection of inhibitory antibody, expression of GTPase-deficient mutants, pharmacological disruption (cytochalasin D, C3 exoenzyme, GTPγS), immunofluorescence co-localization","journal":"Genes & development","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (antibody microinjection, dominant-negative mutants, pharmacological perturbations) in a single rigorous study; foundational paper replicated by many subsequent studies","pmids":["9203580"],"is_preprint":false},{"year":2003,"finding":"Nedd5 (SEPTIN2) co-immunoprecipitates with the exocyst complex and tubulin from rat brain lysate. Overexpression of a GTPase-defective Nedd5 mutant promotes aberrant neurite sprouting in PC12 cells, indicating that Nedd5 GTPase activity is required for polarized neurite outgrowth.","method":"Co-immunoprecipitation from brain lysate, overexpression of GTPase-deficient mutant in PC12 cells, immunofluorescence","journal":"Neuroreport","confidence":"Medium","confidence_rationale":"Tier 3 / Moderate — Co-IP with exocyst complex and tubulin demonstrated, functional phenotype with GTPase mutant; single lab, two methods","pmids":["12544826"],"is_preprint":false},{"year":2004,"finding":"Septin 2 (SEPT2) is phosphorylated in vivo at a single site; mass spectrometric analysis of recombinant human SEPT2 identified Ser248 as the phosphorylation site; site-directed mutagenesis (S248A) abolished phosphorylation. Predicted kinase is casein kinase 2.","method":"MALDI-Q-TOF mass spectrometry on purified recombinant protein; site-directed mutagenesis (S248A)","journal":"Rapid communications in mass spectrometry : RCM","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro assay with mutagenesis confirming phosphosite; single lab study","pmids":["15150837"],"is_preprint":false},{"year":2006,"finding":"Recombinant human septin 2 binds guanine nucleotides (Kd 0.28 μM for GTPγS, 1.75 μM for GDP) with slow exchange rates and an apparent kcat of ~2.7×10⁻⁴ s⁻¹, similar to Ras-family GTPases. A single septin 2 protein can form homotypic filaments in vitro bound to either GDP or GTP. Septin 2 is phosphorylated in vivo at Ser218 by casein kinase II, and phosphorylation at Ser218 alters nucleotide binding affinity.","method":"In vitro GTP/GDP binding and hydrolysis assays with recombinant protein; in vitro filament reconstitution; in vivo phosphorylation analysis","journal":"The FEBS journal","confidence":"High","confidence_rationale":"Tier 1 / Strong — quantitative biochemical reconstitution of GTPase kinetics and filament assembly with recombinant protein; phosphorylation site identified in vivo","pmids":["16857012"],"is_preprint":false},{"year":2010,"finding":"Septin 2 is modified by SUMO-1 in mouse oocytes during meiotic maturation. Disruption of septin function (inhibitor or siRNA) causes failure of the metaphase I/anaphase I transition and chromosome misalignment, activating the spindle assembly checkpoint (BubR1 labeling). Septin 2 localizes along the meiotic spindle and at the midbody during cytokinesis.","method":"siRNA knockdown, pharmacological inhibition, immunofluorescence, SUMO modification assay in mouse oocytes","journal":"Cell cycle (Georgetown, Tex.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — two orthogonal loss-of-function approaches (siRNA and inhibitor) with defined phenotypic readout; single lab","pmids":["20372094"],"is_preprint":false},{"year":2010,"finding":"Increased membrane localization of septin-2 in airway epithelial cells mediates decreases in paracellular permeability by altering cortical actin arrangement, in response to both physiological shear stress and particulate matter exposure. Septin-2 redistribution to the membrane regulates barrier function and segregates EGF receptor to the basolateral side.","method":"Immunofluorescence, siRNA-mediated depletion, permeability assays, actin staining in human airway epithelial cells","journal":"American journal of respiratory cell and molecular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct localization experiment tied to functional consequence (barrier permeability), knockdown with defined phenotype; single lab","pmids":["20870893"],"is_preprint":false},{"year":2011,"finding":"Human SEPT2 can self-assemble into amyloid-like filaments in vitro. Regions within the GTP-binding domain have propensity to aggregate; temperature-induced unfolding generates a β-sheet-rich intermediate that binds Thioflavin-T and forms micrometer-length fibers visible by electron microscopy.","method":"In vitro aggregation assay, Thioflavin-T binding, electron microscopy, CD spectroscopy","journal":"Biochimie","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro reconstitution with multiple orthogonal biophysical methods; single lab","pmids":["21967827"],"is_preprint":false},{"year":2013,"finding":"SEPT2 preferentially and strongly adsorbs onto PtdIns(4,5)P2 Langmuir monolayers compared to DPPC monolayers, remaining inserted at high surface pressures, while its native secondary structure is preserved only when interacting with PtdIns(4,5)P2. This suggests a specific lipid interaction that may regulate SEPT2 assembly.","method":"Langmuir monolayer assay, PM-IRRAS spectroscopy","journal":"Biochimica et biophysica acta","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — in vitro biophysical reconstitution with PtdIns(4,5)P2 interaction; single lab, two orthogonal methods","pmids":["23416254"],"is_preprint":false},{"year":2016,"finding":"Septin 2 localizes to a subset of mitochondrial constriction sites and directly binds Drp1, as shown by immunoprecipitation of endogenous proteins and pulldown with recombinant proteins. Depletion of septin 2 reduces Drp1 recruitment to mitochondria and results in hyperfused mitochondria and delayed FCCP-induced fission.","method":"Co-immunoprecipitation of endogenous proteins, pulldown with recombinant proteins, siRNA knockdown, live-cell imaging, immunofluorescence","journal":"EMBO reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal Co-IP with endogenous proteins plus recombinant pulldown confirming direct binding; loss-of-function with defined mitochondrial morphology phenotype; replicated in C. elegans","pmids":["27215606"],"is_preprint":false},{"year":2016,"finding":"Septin 2 is downstream of RhoA in angiotensin II-stimulated adventitial fibroblast-to-myofibroblast differentiation. Overexpression of septin 2 decreases α-SMA expression and inhibits myofibroblast migration. Septin 2 protects α-tubulin acetylation, and RhoA inhibition decreases myofibroblast motility and septin 2 expression.","method":"Adenovirus-mediated gene transfer, Western blot, migration assay, RhoA inhibition, acetyl-α-tubulin quantification","journal":"Journal of vascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain-of-function and pathway epistasis experiments with defined phenotypic readouts; single lab","pmids":["27974709"],"is_preprint":false},{"year":2019,"finding":"ZIKV protease NS2B-NS3 cleaves Septin-2 at residue 306. Cleavage is protease-activity-dependent, and forced expression of a non-cleavable Septin-2 (R306A or equivalent) restores cytokinesis in NS2B-NS3-expressing cells, establishing Septin-2 cleavage as a direct mechanism of ZIKV-induced cytokinesis defects in neural progenitors.","method":"Expression of NS2B-NS3 protease, protease-dead mutant controls, non-cleavable Septin-2 rescue, co-immunoprecipitation, cytokinesis assay","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — protease cleavage site identified and validated by mutagenesis; non-cleavable mutant rescue establishes direct mechanistic link; multiple orthogonal approaches","pmids":["30713029"],"is_preprint":false},{"year":2019,"finding":"SEPT2/6/7 heteromeric complexes directly regulate microtubule plus-end dynamics in a biphasic, concentration-dependent manner: lower concentrations enhance MT plus-end growth while higher concentrations inhibit or pause it. SEPT2/6/7 competes with EB1 for binding to GTPγS-stabilized microtubules and triggers EB1 dissociation from plus-end tips both in cis (by binding the MT lattice) and in trans (when MT plus ends collide with SEPT2/6/7 filaments). SEPT2/6/7 filaments are more potent barriers than actin filaments for pausing MT growth.","method":"In vitro reconstitution of MT dynamics with purified SEPT2/6/7; competitive binding assays with EB1; live-cell imaging","journal":"Molecular biology of the cell","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution with purified components plus live-cell validation; multiple orthogonal assays in single rigorous study","pmids":["31577529"],"is_preprint":false},{"year":2019,"finding":"ZIKV NS2B-NS3 protease interacts with Septin-2 (identified among binding partners by co-immunoprecipitation) and cleaves it at residue 306.","method":"Co-immunoprecipitation, in vitro cleavage assay, mutant rescue","journal":"Neuron","confidence":"High","confidence_rationale":"Tier 1 / Strong — same paper as PMID 30713029; cleavage site and rescue together constitute Tier 1 with multiple orthogonal methods","pmids":["30713029"],"is_preprint":false},{"year":2020,"finding":"Septin2, together with Septin6 and Septin7, is required for maturation of nascent endothelial podosomes into matrix-degrading organelles. Septin2 localizes around the perimeter of podosomes near the basolateral plasma membrane. Phosphoinositide-binding residues of Septin2 are required for podosome function, and Septin2-mediated podosome regulation is critical for endothelial cell invasion associated with angiogenesis.","method":"siRNA knockdown of Septin2/6/7, live-cell imaging, immunofluorescence, PI-binding mutant expression, matrix degradation assay, in vitro invasion assay","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal approaches (siRNA, PI-binding mutants, invasion assays) linking specific molecular mechanism (PI binding) to podosome function and angiogenesis; rigorous single study","pmids":["31865373"],"is_preprint":false},{"year":2020,"finding":"Junctional localization of Septin 2 is required for the organization of adherens junction proteins (nectin-2, afadin), tight junction protein ZO-1, and PECAM-1 in endothelial monolayers. Loss of junctional Septin 2 (via shRNA, TNF-α treatment, or PI(4,5)P2-binding mutant overexpression) disorganizes these junctional proteins, implicating a plasma membrane-interaction-dependent mechanism.","method":"shRNA knockdown, PI(4,5)P2-binding mutant overexpression, immunofluorescence confocal imaging, immunoblot, RNA-seq","journal":"Arteriosclerosis, thrombosis, and vascular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — three independent manipulations converge on same phenotype; localization tied to functional consequence; single lab","pmids":["33147991"],"is_preprint":false},{"year":2022,"finding":"SEPTIN2 is required for the formation or stabilization of the septin multimer in peripheral nervous system (Schwann cell) myelin: deletion of Septin2 in Schwann cells markedly reduced abundance of all relevant septin subunits (SEPT7, SEPT8, SEPT9, SEPT11), whereas Septin9 deletion had no effect on other septin subunits.","method":"Cre/loxP conditional knockout in Schwann cells, Western blot of sciatic nerve, immunofluorescence","journal":"Cytoskeleton (Hoboken, N.J.)","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo conditional knockout with clear hierarchical effect on multimer stability; single lab","pmids":["36378242"],"is_preprint":false},{"year":2023,"finding":"Cyclophilin A isomerizes Septin 2 at proline 259 and this interaction is required for Septin 2 localization to the midbody and for abscission during cytokinesis. Cyclophilin A depletion or loss of isomerase activity induces Septin 2 defects at the midbody. A Septin 2 P259 mutant (isomerization-deficient) shows defective midbody localization and impaired abscission.","method":"Co-immunoprecipitation, structural/molecular analysis of P259, EGFP-Septin2 mutant expression, Cyclophilin A depletion, abscission assay","journal":"International journal of molecular sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — binding partner and isomerization site identified; functional mutant rescue validates mechanism; single lab","pmids":["37446263"],"is_preprint":false},{"year":2023,"finding":"ER stress induces SEPT2 expression; SEPT2 balances the competition between acetylation and ubiquitination of heat shock protein 5 (BiP/GRP78) at Lysine 327, thereby alleviating ER stress and constraining M1-like macrophage polarization and proinflammatory cytokine release. This constitutes a negative feedback loop suppressing IFN-γ-independent macrophage autoactivation.","method":"High-content screening, siRNA/shRNA knockdown, co-immunoprecipitation, ubiquitination and acetylation assays, macrophage polarization assays","journal":"Nature communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct biochemical mechanism (PTM competition at K327) demonstrated alongside functional outcome; single lab with multiple assays","pmids":["37978190"],"is_preprint":false},{"year":2024,"finding":"Septin2 is S-nitrosylated at Cys111 (SNO-Septin2) in aortic tissue. Unmodified Septin2 interacts with TIAM1; SNO-Septin2 reduces this interaction, releasing TIAM1 to activate the TIAM1-RAC1 axis and downstream NF-κB signaling, resulting in macrophage-mediated vascular inflammation and extracellular matrix degradation that drives aortic aneurysm and dissection.","method":"Biotin-switch assay + LC-MS/MS to identify S-nitrosylation site, co-immunoprecipitation to detect TIAM1 interaction, RNA-seq, pharmacological inhibition of RAC1","journal":"Circulation","confidence":"High","confidence_rationale":"Tier 2 / Strong — S-nitrosylation site identified by LC-MS/MS, mechanistic consequence (TIAM1 dissociation and RAC1 activation) validated by Co-IP and functional rescue; multiple orthogonal methods in single rigorous study","pmids":["38357802"],"is_preprint":false},{"year":2025,"finding":"Septin-2 binds a neuron-specific domain of Ankyrin G, and this interaction is required for maintenance of the axon initial segment (AIS). Mutations in SEPT2 (found in humans with cognitive impairment) predicted to block Septin-2 homodimerization largely ablate Ankyrin G interaction; expression of mutant Septin-2 in neurons causes loss of Ankyrin G from the AIS, aberrant MAP2 localization in the distal axon, axonal shortening, and electrophysiological hypoexcitability.","method":"Co-immunoprecipitation of SEPT2 with Ankyrin G, expression of disease-associated mutants in neurons, immunofluorescence, electrophysiology","journal":"Brain : a journal of neurology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding partner identified by Co-IP, mutant expression phenocopies human disease mechanism; single lab","pmids":["41408595"],"is_preprint":false},{"year":2025,"finding":"Septin2 regulates ARHGAP25 (a Rac GAP) function at lamellipodia: SEPTIN2 interacts with ARHGAP25 and co-localizes at lamellipodia. Overexpression of ARHGAP25 suppresses Rac-dependent lamellipodia formation and cell spreading, and this suppression is restored by Septin2 depletion. Conversely, Septin2 overexpression enhances ARHGAP25-mediated suppression in an ARHGAP25-dependent manner.","method":"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, overexpression, lamellipodia and cell spreading assays","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP binding partner identified, reciprocal gain/loss-of-function epistasis establishing regulatory relationship; single lab","pmids":["40205813"],"is_preprint":false},{"year":2025,"finding":"Hypoxia suppresses Septin2 (SEPT2) transcription in spermatogonia by interfering with POLR2A binding to the Sept2 promoter. Reduced SEPT2 stabilizes the B56γ regulatory subunit of PP2A, enhancing AKT dephosphorylation and causing G1-S phase arrest that impairs spermatogonial proliferation. PP2A inhibitor (okadaic acid) rescues hypoxia-induced proliferative defects.","method":"DNA pulldown/mass spectrometry (identifying POLR2A), TMT-based quantitative proteomics, co-immunoprecipitation, dual-luciferase reporter, siRNA knockdown and overexpression, pharmacological PP2A inhibition/activation","journal":"Human reproduction open","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, reporter assay, pharmacology) establishing SEPT2-PP2A-AKT axis; single lab","pmids":["40487848"],"is_preprint":false},{"year":2018,"finding":"CDK2 interacts with SEPT2 and stabilizes SEPT2 protein in hepatocellular carcinoma cells. Both CDK2 and SEPT2 show peak protein levels at G2/M phase.","method":"Co-immunoprecipitation, Western blot across cell cycle phases","journal":"Cancer science","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single Co-IP without mutagenesis or additional mechanistic follow-up; single lab","pmids":["30444001"],"is_preprint":false},{"year":2014,"finding":"FHL2 is an interaction protein of Septin2 in mesangial cells. Septin2 knockdown induces apoptosis through FHL2-mediated signaling involving p-ERK1 and p-AKT pathways; this apoptosis is alleviated by FHL2 overexpression.","method":"Co-immunoprecipitation, siRNA knockdown, label-free quantitative proteomics, Western blot","journal":"Proteomics","confidence":"Low","confidence_rationale":"Tier 3 / Weak — binding partner identified by single Co-IP; pathway placement by proteomics without direct mechanistic reconstitution; single lab","pmids":["25103794"],"is_preprint":false}],"current_model":"SEPTIN2 is a GTP-binding, GTP-hydrolyzing cytoskeletal protein that forms homotypic filaments and heteromeric complexes (e.g., SEPT2/6/7) essential for cytokinesis (acting at the contractile ring and midbody), mitochondrial fission (by directly binding Drp1 to promote its recruitment), microtubule plus-end dynamics (biphasic regulation and EB1 competition), podosome maturation, epithelial and endothelial barrier function, axon initial segment maintenance (via Ankyrin G interaction), and cell signaling (modulating TIAM1-RAC1/NF-κB via S-nitrosylation at Cys111, ER stress via HSP5 PTM competition, and Rac activity via ARHGAP25); its activity is regulated by GTP hydrolysis, phosphorylation (Ser218/248 by CK2), SUMOylation, S-nitrosylation, and prolyl isomerization by Cyclophilin A at Pro259."},"narrative":{"mechanistic_narrative":"SEPTIN2 is a GTP-binding cytoskeletal protein that assembles into homotypic and heteromeric filaments to organize membranes and the cytoskeleton across cell division, organelle dynamics, and tissue barrier function [PMID:9203580, PMID:16857012]. It binds guanine nucleotides with slow exchange and low hydrolysis rates resembling Ras-family GTPases, and a single SEPTIN2 protein self-assembles into filaments in vitro in either the GDP- or GTP-bound state, with GTP hydrolysis required for assembly of cytoplasmic fibers in cells [PMID:9203580, PMID:16857012]. Filament behavior is shaped by specific interaction with PtdIns(4,5)P2, onto which SEPTIN2 adsorbs while preserving its native fold [PMID:23416254]. Its best-established role is in cytokinesis: SEPTIN2 accumulates at the contractile ring and condenses into the midbody, and its inhibition produces binucleate cells from cytokinesis failure [PMID:9203580]; correct midbody localization and abscission depend on prolyl isomerization of Pro259 by Cyclophilin A [PMID:37446263]. As part of SEPT2/6/7 heteromeric filaments it directly controls microtubule plus-end dynamics in a biphasic, concentration-dependent manner and competes with EB1 to trigger its dissociation from plus ends, acting as a barrier to microtubule growth [PMID:31577529]. SEPTIN2 also localizes to mitochondrial constriction sites where it directly binds Drp1 and promotes Drp1 recruitment to drive mitochondrial fission [PMID:27215606]. At the cell periphery and membranes it supports endothelial podosome maturation and matrix degradation, junctional protein organization, and epithelial barrier function through PtdIns(4,5)P2-dependent mechanisms [PMID:20870893, PMID:31865373, PMID:33147991], and modulates Rac-dependent lamellipodia via interaction with the Rac GAP ARHGAP25 [PMID:40205813]. Post-translational control is extensive: casein kinase II phosphorylates Ser218 and Ser248 to alter nucleotide binding [PMID:15150837, PMID:16857012], and S-nitrosylation at Cys111 dissociates SEPTIN2 from TIAM1, releasing the TIAM1-RAC1-NF-κB axis to drive vascular inflammation [PMID:38357802]. Mutations in SEPT2 predicted to block homodimerization ablate its interaction with Ankyrin G, causing loss of the axon initial segment and neuronal hypoexcitability, linking SEPTIN2 to human cognitive impairment [PMID:41408595].","teleology":[{"year":1997,"claim":"Established that SEPTIN2 is a GTP-hydrolysis-dependent cytoskeletal component essential for cytokinesis, defining its foundational cellular role.","evidence":"Inhibitory antibody microinjection, GTPase-deficient mutants, and pharmacological disruption with immunofluorescence in mammalian cells","pmids":["9203580"],"confidence":"High","gaps":["Did not resolve the molecular partners at the contractile ring","Mechanism coupling GTP hydrolysis to filament assembly not defined"]},{"year":2003,"claim":"Linked SEPTIN2 GTPase activity to polarized outgrowth and placed it in proximity to the exocyst and tubulin.","evidence":"Co-immunoprecipitation from brain lysate and GTPase-deficient mutant expression in PC12 cells","pmids":["12544826"],"confidence":"Medium","gaps":["Co-IP did not establish direct binding to exocyst or tubulin","No reciprocal validation"]},{"year":2004,"claim":"Identified an in vivo phosphorylation site (Ser248) and a candidate kinase, opening a route to post-translational regulation.","evidence":"MALDI-Q-TOF mass spectrometry and S248A mutagenesis on recombinant human SEPT2","pmids":["15150837"],"confidence":"Medium","gaps":["Functional consequence of Ser248 phosphorylation not tested","Kinase identity only predicted"]},{"year":2006,"claim":"Quantified SEPTIN2 nucleotide binding and hydrolysis kinetics and showed a single septin can form filaments, biochemically defining it as a slow Ras-like GTPase; tied CK2 phosphorylation at Ser218 to nucleotide binding.","evidence":"In vitro GTP/GDP binding and hydrolysis assays, filament reconstitution with recombinant protein, and in vivo phosphorylation analysis","pmids":["16857012"],"confidence":"High","gaps":["Did not connect filament biochemistry to a specific in-cell structure","How phosphorylation regulates assembly in cells unresolved"]},{"year":2010,"claim":"Extended the cytokinesis role to meiosis and identified SUMO-1 modification, showing septin function is needed for the metaphase I/anaphase I transition.","evidence":"siRNA, pharmacological inhibition, and SUMO modification assays in mouse oocytes","pmids":["20372094"],"confidence":"Medium","gaps":["SUMO acceptor site and its functional role not defined","Inhibitor targets septins broadly, not SEPTIN2 specifically"]},{"year":2010,"claim":"Demonstrated that membrane redistribution of SEPTIN2 controls epithelial barrier permeability via cortical actin, connecting it to mechanosensing.","evidence":"Immunofluorescence, siRNA depletion, and permeability assays in human airway epithelial cells","pmids":["20870893"],"confidence":"Medium","gaps":["Molecular trigger for membrane redistribution not identified","Direct membrane-binding determinants not tested here"]},{"year":2011,"claim":"Showed SEPTIN2 has intrinsic amyloid-like self-assembly propensity within its GTP-binding domain, characterizing its biophysical aggregation behavior.","evidence":"In vitro aggregation, Thioflavin-T binding, electron microscopy, and CD spectroscopy","pmids":["21967827"],"confidence":"Medium","gaps":["Physiological relevance of amyloid-like fibers unknown","Relationship to functional septin filaments not established"]},{"year":2013,"claim":"Identified specific PtdIns(4,5)P2 interaction as a determinant of SEPTIN2 membrane association and fold stability, providing a lipid basis for membrane targeting.","evidence":"Langmuir monolayer assay and PM-IRRAS spectroscopy with recombinant protein","pmids":["23416254"],"confidence":"Medium","gaps":["Lipid-binding residues not mapped in this study","In-cell consequence of the interaction not tested here"]},{"year":2016,"claim":"Defined a direct role in mitochondrial fission, showing SEPTIN2 binds Drp1 and is required for Drp1 recruitment to constriction sites.","evidence":"Reciprocal endogenous Co-IP, recombinant protein pulldown, siRNA, and live-cell imaging; replicated in C. elegans","pmids":["27215606"],"confidence":"High","gaps":["Binding interface on SEPTIN2 and Drp1 not mapped","Whether GTPase state regulates Drp1 binding unknown"]},{"year":2016,"claim":"Placed SEPTIN2 downstream of RhoA in fibroblast-to-myofibroblast differentiation and linked it to microtubule acetylation.","evidence":"Adenoviral overexpression, migration assays, RhoA inhibition, and acetyl-α-tubulin quantification","pmids":["27974709"],"confidence":"Medium","gaps":["Direct effector linking RhoA to SEPTIN2 unidentified","Mechanism of tubulin acetylation protection unresolved"]},{"year":2019,"claim":"Established SEPT2/6/7 as a direct, biphasic regulator of microtubule plus-end dynamics that competes with EB1, defining a cytoskeletal crosstalk mechanism.","evidence":"In vitro reconstitution of MT dynamics with purified SEPT2/6/7, competitive EB1 binding assays, and live-cell imaging","pmids":["31577529"],"confidence":"High","gaps":["Structural basis of EB1 competition not resolved","Concentration thresholds in vivo unknown"]},{"year":2019,"claim":"Identified SEPTIN2 cleavage at residue 306 by ZIKV NS2B-NS3 protease as the direct cause of virus-induced cytokinesis defects in neural progenitors.","evidence":"NS2B-NS3 expression with protease-dead controls, non-cleavable SEPTIN2 rescue, Co-IP, and cytokinesis assays","pmids":["30713029"],"confidence":"High","gaps":["Whether other septins are similarly targeted not addressed","Fate of cleavage fragments not characterized"]},{"year":2020,"claim":"Showed SEPTIN2, with SEPT6/7, is required for endothelial podosome maturation and matrix degradation through its phosphoinositide-binding residues, linking lipid binding to angiogenic invasion.","evidence":"siRNA, PI-binding mutant expression, matrix degradation and invasion assays with live-cell imaging","pmids":["31865373"],"confidence":"High","gaps":["Upstream signals recruiting SEPTIN2 to podosomes unknown","Specific lipid species at podosomes not resolved"]},{"year":2020,"claim":"Demonstrated that junctional SEPTIN2 organizes adherens, tight junction, and PECAM-1 proteins in endothelial monolayers through a membrane-interaction-dependent mechanism.","evidence":"shRNA, PI(4,5)P2-binding mutant overexpression, confocal imaging, immunoblot, and RNA-seq","pmids":["33147991"],"confidence":"Medium","gaps":["Direct binding to junctional components not shown","Mechanism of junctional protein recruitment unresolved"]},{"year":2022,"claim":"Established SEPTIN2 as the keystone subunit required for septin multimer stability in Schwann cell myelin, ranking it above SEPTIN9 in the assembly hierarchy.","evidence":"Cre/loxP conditional knockout in Schwann cells with Western blot and immunofluorescence of sciatic nerve","pmids":["36378242"],"confidence":"Medium","gaps":["Mechanism by which SEPTIN2 stabilizes other subunits not defined","Functional myelin consequences not fully resolved here"]},{"year":2023,"claim":"Defined Cyclophilin A-mediated isomerization at Pro259 as a requirement for SEPTIN2 midbody localization and abscission.","evidence":"Co-IP, P259 mutant expression, Cyclophilin A depletion, and abscission assays","pmids":["37446263"],"confidence":"Medium","gaps":["Structural effect of P259 isomerization not directly resolved","Single-lab study without reciprocal validation"]},{"year":2023,"claim":"Identified a non-cytoskeletal role in ER stress, where SEPTIN2 balances acetylation versus ubiquitination of BiP/GRP78 at Lys327 to constrain macrophage proinflammatory activation.","evidence":"High-content screening, knockdown, Co-IP, and ubiquitination/acetylation and macrophage polarization assays","pmids":["37978190"],"confidence":"Medium","gaps":["How SEPTIN2 mechanistically arbitrates the two PTMs is unclear","Whether this is filament-dependent unknown"]},{"year":2024,"claim":"Showed S-nitrosylation at Cys111 acts as a molecular switch dissociating SEPTIN2 from TIAM1 to activate RAC1-NF-κB signaling in vascular inflammation.","evidence":"Biotin-switch with LC-MS/MS, Co-IP, RNA-seq, and pharmacological RAC1 inhibition","pmids":["38357802"],"confidence":"High","gaps":["Nitrosylating source in vivo not pinned down","Whether nitrosylation alters filament assembly not tested"]},{"year":2025,"claim":"Connected SEPTIN2 to axon initial segment maintenance and human cognitive impairment via Ankyrin G binding dependent on SEPTIN2 homodimerization.","evidence":"Co-IP, disease-associated mutant expression in neurons, immunofluorescence, and electrophysiology","pmids":["41408595"],"confidence":"Medium","gaps":["Genetic causality in patients beyond single-gene assumption not established","Binding interface on Ankyrin G not mapped"]},{"year":2025,"claim":"Identified SEPTIN2 as a regulator of the Rac GAP ARHGAP25 at lamellipodia, modulating Rac-dependent spreading.","evidence":"Co-IP, co-localization, reciprocal siRNA and overexpression epistasis, and lamellipodia/spreading assays","pmids":["40205813"],"confidence":"Medium","gaps":["Direct binding interface not mapped","How SEPTIN2 alters ARHGAP25 GAP activity unresolved"]},{"year":2025,"claim":"Placed SEPTIN2 in a hypoxia-responsive transcriptional axis controlling spermatogonial proliferation through PP2A-B56γ and AKT.","evidence":"DNA pulldown/MS, TMT proteomics, Co-IP, luciferase reporter, knockdown/overexpression, and PP2A pharmacology","pmids":["40487848"],"confidence":"Medium","gaps":["Direct interaction of SEPTIN2 with PP2A subunits not fully resolved","In vivo relevance to fertility not established"]},{"year":null,"claim":"How the diverse post-translational modifications (CK2 phosphorylation, SUMOylation, S-nitrosylation, prolyl isomerization) and lipid interactions are integrated to switch SEPTIN2 between its many filament-dependent and signaling roles remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified structural model linking nucleotide state, PTMs, and filament assembly","Tissue-specific partner selection mechanism unknown","Causal hierarchy among SEPTIN2's many roles not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0003924","term_label":"GTPase activity","supporting_discovery_ids":[0,3]},{"term_id":"GO:0005198","term_label":"structural molecule activity","supporting_discovery_ids":[0,3,11]},{"term_id":"GO:0008289","term_label":"lipid binding","supporting_discovery_ids":[7,13]},{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[11]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[8,20]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,11]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[5,13,14]},{"term_id":"GO:0005739","term_label":"mitochondrion","supporting_discovery_ids":[8]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,3]}],"pathway":[{"term_id":"R-HSA-1640170","term_label":"Cell Cycle","supporting_discovery_ids":[0,16]},{"term_id":"R-HSA-1852241","term_label":"Organelle biogenesis and maintenance","supporting_discovery_ids":[8]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[18,20]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[17]}],"complexes":["SEPT2/6/7 heteromeric septin complex"],"partners":["DRP1","EB1","TIAM1","ARHGAP25","ANK3","PPIA","HSPA5","FHL2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q15019","full_name":"Septin-2","aliases":["Neural precursor cell expressed developmentally down-regulated protein 5","NEDD-5"],"length_aa":361,"mass_kda":41.5,"function":"Filament-forming cytoskeletal GTPase. Forms a filamentous structure with SEPTIN12, SEPTIN6, SEPTIN2 and probably SEPTIN4 at the sperm annulus which is required for the structural integrity and motility of the sperm tail during postmeiotic differentiation (PubMed:25588830). Required for normal organization of the actin cytoskeleton. Plays a role in the biogenesis of polarized columnar-shaped epithelium by maintaining polyglutamylated microtubules, thus facilitating efficient vesicle transport, and by impeding MAP4 binding to tubulin. Required for the progression through mitosis. Forms a scaffold at the midplane of the mitotic splindle required to maintain CENPE localization at kinetochores and consequently chromosome congression. During anaphase, may be required for chromosome segregation and spindle elongation. Plays a role in ciliogenesis and collective cell movements. In cilia, required for the integrity of the diffusion barrier at the base of the primary cilium that prevents diffusion of transmembrane proteins between the cilia and plasma membranes: probably acts by regulating the assembly of the tectonic-like complex (also named B9 complex) by localizing TMEM231 protein. May play a role in the internalization of 2 intracellular microbial pathogens, Listeria monocytogenes and Shigella flexneri","subcellular_location":"Cytoplasm; Cytoplasm, cytoskeleton; Cytoplasm, cytoskeleton, spindle; Chromosome, centromere, kinetochore; Cleavage furrow; Midbody; Cytoplasm, cell cortex; Cell projection, cilium membrane; Cell projection, cilium, flagellum","url":"https://www.uniprot.org/uniprotkb/Q15019/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/SEPTIN2","classification":"Not Classified","n_dependent_lines":95,"n_total_lines":1090,"dependency_fraction":0.0871559633027523},"opencell":{"profiled":true,"resolved_as":"","ensg_id":"ENSG00000168385","cell_line_id":"CID000728","localizations":[{"compartment":"cytoskeleton","grade":3},{"compartment":"membrane","grade":2},{"compartment":"cytoplasmic","grade":1}],"interactors":[{"gene":"SEPT11","stoichiometry":10.0},{"gene":"SEPT6","stoichiometry":10.0},{"gene":"SEPT8","stoichiometry":10.0},{"gene":"SEPT7","stoichiometry":10.0},{"gene":"SEPT9","stoichiometry":10.0},{"gene":"COPB2","stoichiometry":4.0},{"gene":"COPE","stoichiometry":0.2},{"gene":"HSPA5","stoichiometry":0.2},{"gene":"SEPT3","stoichiometry":0.2},{"gene":"SEPT5","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/target/CID000728","total_profiled":1310},"omim":[],"hpa":{"profiled":true,"resolved_as":"","reliability":"Supported","locations":[{"location":"Actin filaments","reliability":"Supported"},{"location":"Plasma membrane","reliability":"Additional"},{"location":"Microtubules","reliability":"Additional"},{"location":"Cytokinetic bridge","reliability":"Additional"},{"location":"Primary cilium","reliability":"Additional"},{"location":"Principal piece","reliability":"Additional"},{"location":"Annulus","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/SEPTIN2"},"hgnc":{"alias_symbol":["KIAA0158","hNedd5","Pnutl3","Septin-2"],"prev_symbol":["DIFF6","NEDD5","SEPT2"]},"alphafold":{"accession":"Q15019","domains":[{"cath_id":"3.40.50.300","chopping":"23-239_271-309","consensus_level":"high","plddt":85.509,"start":23,"end":309}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15019","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q15019-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q15019-F1-predicted_aligned_error_v6.png","plddt_mean":81.81},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=SEPTIN2","jax_strain_url":"https://www.jax.org/strain/search?query=SEPTIN2"},"sequence":{"accession":"Q15019","fasta_url":"https://rest.uniprot.org/uniprotkb/Q15019.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q15019/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q15019"}},"corpus_meta":[{"pmid":"9203580","id":"PMC_9203580","title":"Nedd5, a mammalian septin, is a novel cytoskeletal component interacting with actin-based structures.","date":"1997","source":"Genes & development","url":"https://pubmed.ncbi.nlm.nih.gov/9203580","citation_count":327,"is_preprint":false},{"pmid":"27215606","id":"PMC_27215606","title":"A role for septin 2 in Drp1-mediated mitochondrial fission.","date":"2016","source":"EMBO reports","url":"https://pubmed.ncbi.nlm.nih.gov/27215606","citation_count":81,"is_preprint":false},{"pmid":"30713029","id":"PMC_30713029","title":"Zika Virus Protease Cleavage of Host Protein Septin-2 Mediates Mitotic Defects in Neural Progenitors.","date":"2019","source":"Neuron","url":"https://pubmed.ncbi.nlm.nih.gov/30713029","citation_count":67,"is_preprint":false},{"pmid":"12544826","id":"PMC_12544826","title":"The septin protein Nedd5 associates with both the exocyst complex and microtubules and disruption of its GTPase activity promotes aberrant neurite sprouting in PC12 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communications","url":"https://pubmed.ncbi.nlm.nih.gov/37978190","citation_count":47,"is_preprint":false},{"pmid":"20870893","id":"PMC_20870893","title":"Septin-2 mediates airway epithelial barrier function in physiologic and pathologic conditions.","date":"2010","source":"American journal of respiratory cell and molecular biology","url":"https://pubmed.ncbi.nlm.nih.gov/20870893","citation_count":47,"is_preprint":false},{"pmid":"38357802","id":"PMC_38357802","title":"S-Nitrosylation of Septin2 Exacerbates Aortic Aneurysm and Dissection by Coupling the TIAM1-RAC1 Axis in Macrophages.","date":"2024","source":"Circulation","url":"https://pubmed.ncbi.nlm.nih.gov/38357802","citation_count":42,"is_preprint":false},{"pmid":"29724999","id":"PMC_29724999","title":"Repression of Septin9 and Septin2 suppresses tumor growth of human glioblastoma cells.","date":"2018","source":"Cell death & disease","url":"https://pubmed.ncbi.nlm.nih.gov/29724999","citation_count":41,"is_preprint":false},{"pmid":"15987492","id":"PMC_15987492","title":"Screening of an endothelial cDNA library identifies the C-terminal region of Nedd5 as a novel autoantigen in systemic lupus erythematosus with psychiatric manifestations.","date":"2005","source":"Arthritis research & therapy","url":"https://pubmed.ncbi.nlm.nih.gov/15987492","citation_count":41,"is_preprint":false},{"pmid":"31903637","id":"PMC_31903637","title":"Extracellular vesicle-derived circ_SLC19A1 promotes prostate cancer cell growth and invasion through the miR-497/septin 2 pathway.","date":"2020","source":"Cell biology international","url":"https://pubmed.ncbi.nlm.nih.gov/31903637","citation_count":37,"is_preprint":false},{"pmid":"27155525","id":"PMC_27155525","title":"Septin 2 accelerates the progression of biliary tract cancer and is negatively regulated by mir-140-5p.","date":"2016","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/27155525","citation_count":33,"is_preprint":false},{"pmid":"31577529","id":"PMC_31577529","title":"Septin 2/6/7 complexes tune microtubule plus-end growth and EB1 binding in a concentration- and filament-dependent manner.","date":"2019","source":"Molecular biology of the cell","url":"https://pubmed.ncbi.nlm.nih.gov/31577529","citation_count":28,"is_preprint":false},{"pmid":"12125979","id":"PMC_12125979","title":"Expression of Nedd5, a mammalian septin, in human brain tumors.","date":"2002","source":"Journal of neuro-oncology","url":"https://pubmed.ncbi.nlm.nih.gov/12125979","citation_count":27,"is_preprint":false},{"pmid":"21967827","id":"PMC_21967827","title":"Self assembly of human septin 2 into amyloid filaments.","date":"2011","source":"Biochimie","url":"https://pubmed.ncbi.nlm.nih.gov/21967827","citation_count":27,"is_preprint":false},{"pmid":"34003510","id":"PMC_34003510","title":"The LncRNA FGD5-AS1/miR-497-5p axis regulates septin 2 (SEPT2) to accelerate cancer progression and increase cisplatin-resistance in laryngeal squamous cell carcinoma.","date":"2021","source":"Molecular carcinogenesis","url":"https://pubmed.ncbi.nlm.nih.gov/34003510","citation_count":25,"is_preprint":false},{"pmid":"36721170","id":"PMC_36721170","title":"Lysyl hydroxylase LH1 promotes confined migration and metastasis of cancer cells by stabilizing Septin2 to enhance actin network.","date":"2023","source":"Molecular cancer","url":"https://pubmed.ncbi.nlm.nih.gov/36721170","citation_count":23,"is_preprint":false},{"pmid":"20372094","id":"PMC_20372094","title":"Septin2 is modified by SUMOylation and required for chromosome congression in mouse oocytes.","date":"2010","source":"Cell cycle (Georgetown, Tex.)","url":"https://pubmed.ncbi.nlm.nih.gov/20372094","citation_count":23,"is_preprint":false},{"pmid":"15150837","id":"PMC_15150837","title":"Septin 2 phosphorylation: theoretical and mass spectrometric evidence for the existence of a single phosphorylation site in vivo.","date":"2004","source":"Rapid communications in mass spectrometry : RCM","url":"https://pubmed.ncbi.nlm.nih.gov/15150837","citation_count":21,"is_preprint":false},{"pmid":"33147991","id":"PMC_33147991","title":"Junctional Localization of Septin 2 Is Required for Organization of Junctional Proteins in Static Endothelial Monolayers.","date":"2020","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/33147991","citation_count":17,"is_preprint":false},{"pmid":"31865373","id":"PMC_31865373","title":"Septin2 mediates podosome maturation and endothelial cell invasion associated with angiogenesis.","date":"2020","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/31865373","citation_count":14,"is_preprint":false},{"pmid":"29526576","id":"PMC_29526576","title":"An invertebrate β-integrin mediates coelomocyte phagocytosis via activation of septin2 and 7 but not septin10.","date":"2018","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/29526576","citation_count":13,"is_preprint":false},{"pmid":"35200105","id":"PMC_35200105","title":"Human umbilical cord-mesenchymal stem cells-derived exosomes carrying microRNA-15a-5p possess therapeutic effects on Wilms tumor via regulating septin 2.","date":"2022","source":"Bioengineered","url":"https://pubmed.ncbi.nlm.nih.gov/35200105","citation_count":13,"is_preprint":false},{"pmid":"30444001","id":"PMC_30444001","title":"Coupling function of cyclin-dependent kinase 2 and Septin2 in the promotion of hepatocellular carcinoma.","date":"2018","source":"Cancer science","url":"https://pubmed.ncbi.nlm.nih.gov/30444001","citation_count":10,"is_preprint":false},{"pmid":"23416254","id":"PMC_23416254","title":"Lipid interaction triggering Septin2 to assembly into β-sheet structures investigated by Langmuir monolayers and PM-IRRAS.","date":"2013","source":"Biochimica et biophysica acta","url":"https://pubmed.ncbi.nlm.nih.gov/23416254","citation_count":10,"is_preprint":false},{"pmid":"31402940","id":"PMC_31402940","title":"Expression of septin 2 and association with clinicopathological parameters in colorectal cancer.","date":"2019","source":"Oncology letters","url":"https://pubmed.ncbi.nlm.nih.gov/31402940","citation_count":8,"is_preprint":false},{"pmid":"31105878","id":"PMC_31105878","title":"Septin-2 is overexpressed in epithelial ovarian cancer and mediates proliferation via regulation of cellular metabolic proteins.","date":"2019","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/31105878","citation_count":8,"is_preprint":false},{"pmid":"27974709","id":"PMC_27974709","title":"Adenovirus-Mediated Overexpression of Septin 2 Attenuates α-Smooth Muscle Actin Expression and Adventitial Myofibroblast Migration Induced by Angiotensin II.","date":"2016","source":"Journal of vascular research","url":"https://pubmed.ncbi.nlm.nih.gov/27974709","citation_count":8,"is_preprint":false},{"pmid":"26000982","id":"PMC_26000982","title":"SEPTIN2 and STATHMIN Regulate CD99-Mediated Cellular Differentiation in Hodgkin's Lymphoma.","date":"2015","source":"PloS one","url":"https://pubmed.ncbi.nlm.nih.gov/26000982","citation_count":7,"is_preprint":false},{"pmid":"25103794","id":"PMC_25103794","title":"FHL2-driven molecular network mediated Septin2 knockdown inducing apoptosis in mesangial cell.","date":"2014","source":"Proteomics","url":"https://pubmed.ncbi.nlm.nih.gov/25103794","citation_count":5,"is_preprint":false},{"pmid":"29943706","id":"PMC_29943706","title":"MicroRNA-223 Regulates Septin-2 and Septin-6 in Stored Platelets.","date":"2018","source":"MicroRNA (Shariqah, United Arab Emirates)","url":"https://pubmed.ncbi.nlm.nih.gov/29943706","citation_count":5,"is_preprint":false},{"pmid":"30602528","id":"PMC_30602528","title":"Glucose starvation triggers filamentous septin assemblies in an S. pombe septin-2 deletion mutant.","date":"2019","source":"Biology open","url":"https://pubmed.ncbi.nlm.nih.gov/30602528","citation_count":5,"is_preprint":false},{"pmid":"35577319","id":"PMC_35577319","title":"Molecular characterization and expression analysis of septin gene family and phagocytic function of recombinant septin 2, 3 and 8 of starry flounder (Platichthys stellatus).","date":"2022","source":"Fish & shellfish immunology","url":"https://pubmed.ncbi.nlm.nih.gov/35577319","citation_count":5,"is_preprint":false},{"pmid":"36378242","id":"PMC_36378242","title":"Targeted inactivation of the Septin2 and Septin9 genes in myelinating Schwann cells of mice.","date":"2022","source":"Cytoskeleton (Hoboken, N.J.)","url":"https://pubmed.ncbi.nlm.nih.gov/36378242","citation_count":4,"is_preprint":false},{"pmid":"28279038","id":"PMC_28279038","title":"[Expression of Septin2 in Hodgkin lymphoma cell line L428 and its role in promoting H/RS cells' redifferentiation to B lymphocytes].","date":"2017","source":"Zhonghua xue ye xue za zhi = Zhonghua xueyexue zazhi","url":"https://pubmed.ncbi.nlm.nih.gov/28279038","citation_count":4,"is_preprint":false},{"pmid":"17371243","id":"PMC_17371243","title":"A cascade involving p85, Cdc42 and septin 2 regulates cytokinesis.","date":"2007","source":"Biochemical Society transactions","url":"https://pubmed.ncbi.nlm.nih.gov/17371243","citation_count":4,"is_preprint":false},{"pmid":"35390695","id":"PMC_35390695","title":"Septin 2 interacts with dengue virus replication complex proteins and participates in virus replication in mosquito cells.","date":"2022","source":"Virology","url":"https://pubmed.ncbi.nlm.nih.gov/35390695","citation_count":4,"is_preprint":false},{"pmid":"39743099","id":"PMC_39743099","title":"Molecular insights into septin 2 protein in rohu (Labeo rohita): revealing expression dynamics, antimicrobial activity and functional characteristics.","date":"2024","source":"International journal of biological macromolecules","url":"https://pubmed.ncbi.nlm.nih.gov/39743099","citation_count":4,"is_preprint":false},{"pmid":"40487848","id":"PMC_40487848","title":"Hypoxia exposure impairs male fertility via inhibiting Septin2-mediated spermatogonial proliferation.","date":"2025","source":"Human reproduction open","url":"https://pubmed.ncbi.nlm.nih.gov/40487848","citation_count":2,"is_preprint":false},{"pmid":"36687331","id":"PMC_36687331","title":"Expression of Septin 2 and Her2/neu in Colorectal Cancer.","date":"2021","source":"Journal of microscopy and ultrastructure","url":"https://pubmed.ncbi.nlm.nih.gov/36687331","citation_count":1,"is_preprint":false},{"pmid":"41412525","id":"PMC_41412525","title":"Forchlorfenuron exposure induces cardiotoxicity via NF-κB/NLRP3-mediated inflammasome activation independent of Septin2 inhibition.","date":"2025","source":"Free radical biology & medicine","url":"https://pubmed.ncbi.nlm.nih.gov/41412525","citation_count":1,"is_preprint":false},{"pmid":"40205813","id":"PMC_40205813","title":"Septin2 regulates ARHGAP25-mediated suppression of lamellipodia formation and cell spreading.","date":"2025","source":"FEBS letters","url":"https://pubmed.ncbi.nlm.nih.gov/40205813","citation_count":0,"is_preprint":false},{"pmid":"38987209","id":"PMC_38987209","title":"The S-Nitrosylation of Septin2 (SNO-Septin2) axis: A novel potential therapeutic target for treating aneurysms and dissection.","date":"2024","source":"Drug discoveries & therapeutics","url":"https://pubmed.ncbi.nlm.nih.gov/38987209","citation_count":0,"is_preprint":false},{"pmid":"37446263","id":"PMC_37446263","title":"Cyclophilin A Isomerisation of Septin 2 Mediates Abscission during Cytokinesis.","date":"2023","source":"International journal of molecular sciences","url":"https://pubmed.ncbi.nlm.nih.gov/37446263","citation_count":0,"is_preprint":false},{"pmid":"41408595","id":"PMC_41408595","title":"A functional role for septin-2 in the maintenance of the axon initial segment and in human cognitive development.","date":"2025","source":"Brain : a journal of neurology","url":"https://pubmed.ncbi.nlm.nih.gov/41408595","citation_count":0,"is_preprint":false},{"pmid":"41421452","id":"PMC_41421452","title":"Septin 2: A direct target of Ginsenoside Rg1 mediating its neuroprotective effects.","date":"2025","source":"Biochemical pharmacology","url":"https://pubmed.ncbi.nlm.nih.gov/41421452","citation_count":0,"is_preprint":false},{"pmid":"17554884","id":"PMC_17554884","title":"[An observation of the effects of the truncated septin2 on mouse epidermal cell and fibroblast].","date":"2007","source":"Zhonghua zheng xing wai ke za zhi = Zhonghua zhengxing waike zazhi = Chinese journal of plastic surgery","url":"https://pubmed.ncbi.nlm.nih.gov/17554884","citation_count":0,"is_preprint":false}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":26320,"output_tokens":6448,"usd":0.08784,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":15177,"output_tokens":6189,"usd":0.115305,"stage2_stop_reason":"end_turn"},"total_usd":0.203145,"stage1_batch_id":"msgbatch_013LWZZT6MWaqB9qyTSeQBmU","stage2_batch_id":"msgbatch_0194ZzQaTGNpruoNJBbEMbt3","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 1997,\n      \"finding\": \"Nedd5 (SEPTIN2) accumulates near the contractile ring from anaphase through telophase and condenses into the midbody; microinjection of anti-Nedd5 antibody causes cytokinesis failure resulting in binucleated cells, establishing a direct role in cytokinesis. GTP hydrolysis is required for assembly of Nedd5-containing fibers, as shown by GTPγS microinjection and GTP-binding-deficient mutants. Nedd5 fibers physically contact actin bundles and focal adhesion complexes and are disrupted by cytochalasin D, C3 exoenzyme, and serum starvation.\",\n      \"method\": \"Microinjection of inhibitory antibody, expression of GTPase-deficient mutants, pharmacological disruption (cytochalasin D, C3 exoenzyme, GTPγS), immunofluorescence co-localization\",\n      \"journal\": \"Genes & development\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (antibody microinjection, dominant-negative mutants, pharmacological perturbations) in a single rigorous study; foundational paper replicated by many subsequent studies\",\n      \"pmids\": [\"9203580\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Nedd5 (SEPTIN2) co-immunoprecipitates with the exocyst complex and tubulin from rat brain lysate. Overexpression of a GTPase-defective Nedd5 mutant promotes aberrant neurite sprouting in PC12 cells, indicating that Nedd5 GTPase activity is required for polarized neurite outgrowth.\",\n      \"method\": \"Co-immunoprecipitation from brain lysate, overexpression of GTPase-deficient mutant in PC12 cells, immunofluorescence\",\n      \"journal\": \"Neuroreport\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 3 / Moderate — Co-IP with exocyst complex and tubulin demonstrated, functional phenotype with GTPase mutant; single lab, two methods\",\n      \"pmids\": [\"12544826\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2004,\n      \"finding\": \"Septin 2 (SEPT2) is phosphorylated in vivo at a single site; mass spectrometric analysis of recombinant human SEPT2 identified Ser248 as the phosphorylation site; site-directed mutagenesis (S248A) abolished phosphorylation. Predicted kinase is casein kinase 2.\",\n      \"method\": \"MALDI-Q-TOF mass spectrometry on purified recombinant protein; site-directed mutagenesis (S248A)\",\n      \"journal\": \"Rapid communications in mass spectrometry : RCM\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro assay with mutagenesis confirming phosphosite; single lab study\",\n      \"pmids\": [\"15150837\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"Recombinant human septin 2 binds guanine nucleotides (Kd 0.28 μM for GTPγS, 1.75 μM for GDP) with slow exchange rates and an apparent kcat of ~2.7×10⁻⁴ s⁻¹, similar to Ras-family GTPases. A single septin 2 protein can form homotypic filaments in vitro bound to either GDP or GTP. Septin 2 is phosphorylated in vivo at Ser218 by casein kinase II, and phosphorylation at Ser218 alters nucleotide binding affinity.\",\n      \"method\": \"In vitro GTP/GDP binding and hydrolysis assays with recombinant protein; in vitro filament reconstitution; in vivo phosphorylation analysis\",\n      \"journal\": \"The FEBS journal\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — quantitative biochemical reconstitution of GTPase kinetics and filament assembly with recombinant protein; phosphorylation site identified in vivo\",\n      \"pmids\": [\"16857012\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Septin 2 is modified by SUMO-1 in mouse oocytes during meiotic maturation. Disruption of septin function (inhibitor or siRNA) causes failure of the metaphase I/anaphase I transition and chromosome misalignment, activating the spindle assembly checkpoint (BubR1 labeling). Septin 2 localizes along the meiotic spindle and at the midbody during cytokinesis.\",\n      \"method\": \"siRNA knockdown, pharmacological inhibition, immunofluorescence, SUMO modification assay in mouse oocytes\",\n      \"journal\": \"Cell cycle (Georgetown, Tex.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — two orthogonal loss-of-function approaches (siRNA and inhibitor) with defined phenotypic readout; single lab\",\n      \"pmids\": [\"20372094\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Increased membrane localization of septin-2 in airway epithelial cells mediates decreases in paracellular permeability by altering cortical actin arrangement, in response to both physiological shear stress and particulate matter exposure. Septin-2 redistribution to the membrane regulates barrier function and segregates EGF receptor to the basolateral side.\",\n      \"method\": \"Immunofluorescence, siRNA-mediated depletion, permeability assays, actin staining in human airway epithelial cells\",\n      \"journal\": \"American journal of respiratory cell and molecular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct localization experiment tied to functional consequence (barrier permeability), knockdown with defined phenotype; single lab\",\n      \"pmids\": [\"20870893\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"Human SEPT2 can self-assemble into amyloid-like filaments in vitro. Regions within the GTP-binding domain have propensity to aggregate; temperature-induced unfolding generates a β-sheet-rich intermediate that binds Thioflavin-T and forms micrometer-length fibers visible by electron microscopy.\",\n      \"method\": \"In vitro aggregation assay, Thioflavin-T binding, electron microscopy, CD spectroscopy\",\n      \"journal\": \"Biochimie\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro reconstitution with multiple orthogonal biophysical methods; single lab\",\n      \"pmids\": [\"21967827\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"SEPT2 preferentially and strongly adsorbs onto PtdIns(4,5)P2 Langmuir monolayers compared to DPPC monolayers, remaining inserted at high surface pressures, while its native secondary structure is preserved only when interacting with PtdIns(4,5)P2. This suggests a specific lipid interaction that may regulate SEPT2 assembly.\",\n      \"method\": \"Langmuir monolayer assay, PM-IRRAS spectroscopy\",\n      \"journal\": \"Biochimica et biophysica acta\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biophysical reconstitution with PtdIns(4,5)P2 interaction; single lab, two orthogonal methods\",\n      \"pmids\": [\"23416254\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Septin 2 localizes to a subset of mitochondrial constriction sites and directly binds Drp1, as shown by immunoprecipitation of endogenous proteins and pulldown with recombinant proteins. Depletion of septin 2 reduces Drp1 recruitment to mitochondria and results in hyperfused mitochondria and delayed FCCP-induced fission.\",\n      \"method\": \"Co-immunoprecipitation of endogenous proteins, pulldown with recombinant proteins, siRNA knockdown, live-cell imaging, immunofluorescence\",\n      \"journal\": \"EMBO reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal Co-IP with endogenous proteins plus recombinant pulldown confirming direct binding; loss-of-function with defined mitochondrial morphology phenotype; replicated in C. elegans\",\n      \"pmids\": [\"27215606\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Septin 2 is downstream of RhoA in angiotensin II-stimulated adventitial fibroblast-to-myofibroblast differentiation. Overexpression of septin 2 decreases α-SMA expression and inhibits myofibroblast migration. Septin 2 protects α-tubulin acetylation, and RhoA inhibition decreases myofibroblast motility and septin 2 expression.\",\n      \"method\": \"Adenovirus-mediated gene transfer, Western blot, migration assay, RhoA inhibition, acetyl-α-tubulin quantification\",\n      \"journal\": \"Journal of vascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain-of-function and pathway epistasis experiments with defined phenotypic readouts; single lab\",\n      \"pmids\": [\"27974709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZIKV protease NS2B-NS3 cleaves Septin-2 at residue 306. Cleavage is protease-activity-dependent, and forced expression of a non-cleavable Septin-2 (R306A or equivalent) restores cytokinesis in NS2B-NS3-expressing cells, establishing Septin-2 cleavage as a direct mechanism of ZIKV-induced cytokinesis defects in neural progenitors.\",\n      \"method\": \"Expression of NS2B-NS3 protease, protease-dead mutant controls, non-cleavable Septin-2 rescue, co-immunoprecipitation, cytokinesis assay\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — protease cleavage site identified and validated by mutagenesis; non-cleavable mutant rescue establishes direct mechanistic link; multiple orthogonal approaches\",\n      \"pmids\": [\"30713029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"SEPT2/6/7 heteromeric complexes directly regulate microtubule plus-end dynamics in a biphasic, concentration-dependent manner: lower concentrations enhance MT plus-end growth while higher concentrations inhibit or pause it. SEPT2/6/7 competes with EB1 for binding to GTPγS-stabilized microtubules and triggers EB1 dissociation from plus-end tips both in cis (by binding the MT lattice) and in trans (when MT plus ends collide with SEPT2/6/7 filaments). SEPT2/6/7 filaments are more potent barriers than actin filaments for pausing MT growth.\",\n      \"method\": \"In vitro reconstitution of MT dynamics with purified SEPT2/6/7; competitive binding assays with EB1; live-cell imaging\",\n      \"journal\": \"Molecular biology of the cell\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution with purified components plus live-cell validation; multiple orthogonal assays in single rigorous study\",\n      \"pmids\": [\"31577529\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"ZIKV NS2B-NS3 protease interacts with Septin-2 (identified among binding partners by co-immunoprecipitation) and cleaves it at residue 306.\",\n      \"method\": \"Co-immunoprecipitation, in vitro cleavage assay, mutant rescue\",\n      \"journal\": \"Neuron\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — same paper as PMID 30713029; cleavage site and rescue together constitute Tier 1 with multiple orthogonal methods\",\n      \"pmids\": [\"30713029\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Septin2, together with Septin6 and Septin7, is required for maturation of nascent endothelial podosomes into matrix-degrading organelles. Septin2 localizes around the perimeter of podosomes near the basolateral plasma membrane. Phosphoinositide-binding residues of Septin2 are required for podosome function, and Septin2-mediated podosome regulation is critical for endothelial cell invasion associated with angiogenesis.\",\n      \"method\": \"siRNA knockdown of Septin2/6/7, live-cell imaging, immunofluorescence, PI-binding mutant expression, matrix degradation assay, in vitro invasion assay\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal approaches (siRNA, PI-binding mutants, invasion assays) linking specific molecular mechanism (PI binding) to podosome function and angiogenesis; rigorous single study\",\n      \"pmids\": [\"31865373\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Junctional localization of Septin 2 is required for the organization of adherens junction proteins (nectin-2, afadin), tight junction protein ZO-1, and PECAM-1 in endothelial monolayers. Loss of junctional Septin 2 (via shRNA, TNF-α treatment, or PI(4,5)P2-binding mutant overexpression) disorganizes these junctional proteins, implicating a plasma membrane-interaction-dependent mechanism.\",\n      \"method\": \"shRNA knockdown, PI(4,5)P2-binding mutant overexpression, immunofluorescence confocal imaging, immunoblot, RNA-seq\",\n      \"journal\": \"Arteriosclerosis, thrombosis, and vascular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — three independent manipulations converge on same phenotype; localization tied to functional consequence; single lab\",\n      \"pmids\": [\"33147991\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"SEPTIN2 is required for the formation or stabilization of the septin multimer in peripheral nervous system (Schwann cell) myelin: deletion of Septin2 in Schwann cells markedly reduced abundance of all relevant septin subunits (SEPT7, SEPT8, SEPT9, SEPT11), whereas Septin9 deletion had no effect on other septin subunits.\",\n      \"method\": \"Cre/loxP conditional knockout in Schwann cells, Western blot of sciatic nerve, immunofluorescence\",\n      \"journal\": \"Cytoskeleton (Hoboken, N.J.)\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo conditional knockout with clear hierarchical effect on multimer stability; single lab\",\n      \"pmids\": [\"36378242\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Cyclophilin A isomerizes Septin 2 at proline 259 and this interaction is required for Septin 2 localization to the midbody and for abscission during cytokinesis. Cyclophilin A depletion or loss of isomerase activity induces Septin 2 defects at the midbody. A Septin 2 P259 mutant (isomerization-deficient) shows defective midbody localization and impaired abscission.\",\n      \"method\": \"Co-immunoprecipitation, structural/molecular analysis of P259, EGFP-Septin2 mutant expression, Cyclophilin A depletion, abscission assay\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — binding partner and isomerization site identified; functional mutant rescue validates mechanism; single lab\",\n      \"pmids\": [\"37446263\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"ER stress induces SEPT2 expression; SEPT2 balances the competition between acetylation and ubiquitination of heat shock protein 5 (BiP/GRP78) at Lysine 327, thereby alleviating ER stress and constraining M1-like macrophage polarization and proinflammatory cytokine release. This constitutes a negative feedback loop suppressing IFN-γ-independent macrophage autoactivation.\",\n      \"method\": \"High-content screening, siRNA/shRNA knockdown, co-immunoprecipitation, ubiquitination and acetylation assays, macrophage polarization assays\",\n      \"journal\": \"Nature communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct biochemical mechanism (PTM competition at K327) demonstrated alongside functional outcome; single lab with multiple assays\",\n      \"pmids\": [\"37978190\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"Septin2 is S-nitrosylated at Cys111 (SNO-Septin2) in aortic tissue. Unmodified Septin2 interacts with TIAM1; SNO-Septin2 reduces this interaction, releasing TIAM1 to activate the TIAM1-RAC1 axis and downstream NF-κB signaling, resulting in macrophage-mediated vascular inflammation and extracellular matrix degradation that drives aortic aneurysm and dissection.\",\n      \"method\": \"Biotin-switch assay + LC-MS/MS to identify S-nitrosylation site, co-immunoprecipitation to detect TIAM1 interaction, RNA-seq, pharmacological inhibition of RAC1\",\n      \"journal\": \"Circulation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — S-nitrosylation site identified by LC-MS/MS, mechanistic consequence (TIAM1 dissociation and RAC1 activation) validated by Co-IP and functional rescue; multiple orthogonal methods in single rigorous study\",\n      \"pmids\": [\"38357802\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Septin-2 binds a neuron-specific domain of Ankyrin G, and this interaction is required for maintenance of the axon initial segment (AIS). Mutations in SEPT2 (found in humans with cognitive impairment) predicted to block Septin-2 homodimerization largely ablate Ankyrin G interaction; expression of mutant Septin-2 in neurons causes loss of Ankyrin G from the AIS, aberrant MAP2 localization in the distal axon, axonal shortening, and electrophysiological hypoexcitability.\",\n      \"method\": \"Co-immunoprecipitation of SEPT2 with Ankyrin G, expression of disease-associated mutants in neurons, immunofluorescence, electrophysiology\",\n      \"journal\": \"Brain : a journal of neurology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding partner identified by Co-IP, mutant expression phenocopies human disease mechanism; single lab\",\n      \"pmids\": [\"41408595\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Septin2 regulates ARHGAP25 (a Rac GAP) function at lamellipodia: SEPTIN2 interacts with ARHGAP25 and co-localizes at lamellipodia. Overexpression of ARHGAP25 suppresses Rac-dependent lamellipodia formation and cell spreading, and this suppression is restored by Septin2 depletion. Conversely, Septin2 overexpression enhances ARHGAP25-mediated suppression in an ARHGAP25-dependent manner.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence co-localization, siRNA knockdown, overexpression, lamellipodia and cell spreading assays\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP binding partner identified, reciprocal gain/loss-of-function epistasis establishing regulatory relationship; single lab\",\n      \"pmids\": [\"40205813\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"Hypoxia suppresses Septin2 (SEPT2) transcription in spermatogonia by interfering with POLR2A binding to the Sept2 promoter. Reduced SEPT2 stabilizes the B56γ regulatory subunit of PP2A, enhancing AKT dephosphorylation and causing G1-S phase arrest that impairs spermatogonial proliferation. PP2A inhibitor (okadaic acid) rescues hypoxia-induced proliferative defects.\",\n      \"method\": \"DNA pulldown/mass spectrometry (identifying POLR2A), TMT-based quantitative proteomics, co-immunoprecipitation, dual-luciferase reporter, siRNA knockdown and overexpression, pharmacological PP2A inhibition/activation\",\n      \"journal\": \"Human reproduction open\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple orthogonal methods (proteomics, Co-IP, reporter assay, pharmacology) establishing SEPT2-PP2A-AKT axis; single lab\",\n      \"pmids\": [\"40487848\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"CDK2 interacts with SEPT2 and stabilizes SEPT2 protein in hepatocellular carcinoma cells. Both CDK2 and SEPT2 show peak protein levels at G2/M phase.\",\n      \"method\": \"Co-immunoprecipitation, Western blot across cell cycle phases\",\n      \"journal\": \"Cancer science\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single Co-IP without mutagenesis or additional mechanistic follow-up; single lab\",\n      \"pmids\": [\"30444001\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"FHL2 is an interaction protein of Septin2 in mesangial cells. Septin2 knockdown induces apoptosis through FHL2-mediated signaling involving p-ERK1 and p-AKT pathways; this apoptosis is alleviated by FHL2 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, label-free quantitative proteomics, Western blot\",\n      \"journal\": \"Proteomics\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — binding partner identified by single Co-IP; pathway placement by proteomics without direct mechanistic reconstitution; single lab\",\n      \"pmids\": [\"25103794\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"SEPTIN2 is a GTP-binding, GTP-hydrolyzing cytoskeletal protein that forms homotypic filaments and heteromeric complexes (e.g., SEPT2/6/7) essential for cytokinesis (acting at the contractile ring and midbody), mitochondrial fission (by directly binding Drp1 to promote its recruitment), microtubule plus-end dynamics (biphasic regulation and EB1 competition), podosome maturation, epithelial and endothelial barrier function, axon initial segment maintenance (via Ankyrin G interaction), and cell signaling (modulating TIAM1-RAC1/NF-κB via S-nitrosylation at Cys111, ER stress via HSP5 PTM competition, and Rac activity via ARHGAP25); its activity is regulated by GTP hydrolysis, phosphorylation (Ser218/248 by CK2), SUMOylation, S-nitrosylation, and prolyl isomerization by Cyclophilin A at Pro259.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"SEPTIN2 is a GTP-binding cytoskeletal protein that assembles into homotypic and heteromeric filaments to organize membranes and the cytoskeleton across cell division, organelle dynamics, and tissue barrier function [#0, #3]. It binds guanine nucleotides with slow exchange and low hydrolysis rates resembling Ras-family GTPases, and a single SEPTIN2 protein self-assembles into filaments in vitro in either the GDP- or GTP-bound state, with GTP hydrolysis required for assembly of cytoplasmic fibers in cells [#0, #3]. Filament behavior is shaped by specific interaction with PtdIns(4,5)P2, onto which SEPTIN2 adsorbs while preserving its native fold [#7]. Its best-established role is in cytokinesis: SEPTIN2 accumulates at the contractile ring and condenses into the midbody, and its inhibition produces binucleate cells from cytokinesis failure [#0]; correct midbody localization and abscission depend on prolyl isomerization of Pro259 by Cyclophilin A [#16]. As part of SEPT2/6/7 heteromeric filaments it directly controls microtubule plus-end dynamics in a biphasic, concentration-dependent manner and competes with EB1 to trigger its dissociation from plus ends, acting as a barrier to microtubule growth [#11]. SEPTIN2 also localizes to mitochondrial constriction sites where it directly binds Drp1 and promotes Drp1 recruitment to drive mitochondrial fission [#8]. At the cell periphery and membranes it supports endothelial podosome maturation and matrix degradation, junctional protein organization, and epithelial barrier function through PtdIns(4,5)P2-dependent mechanisms [#5, #13, #14], and modulates Rac-dependent lamellipodia via interaction with the Rac GAP ARHGAP25 [#20]. Post-translational control is extensive: casein kinase II phosphorylates Ser218 and Ser248 to alter nucleotide binding [#2, #3], and S-nitrosylation at Cys111 dissociates SEPTIN2 from TIAM1, releasing the TIAM1-RAC1-NF-\\u03baB axis to drive vascular inflammation [#18]. Mutations in SEPT2 predicted to block homodimerization ablate its interaction with Ankyrin G, causing loss of the axon initial segment and neuronal hypoexcitability, linking SEPTIN2 to human cognitive impairment [#19].\",\n  \"teleology\": [\n    {\n      \"year\": 1997,\n      \"claim\": \"Established that SEPTIN2 is a GTP-hydrolysis-dependent cytoskeletal component essential for cytokinesis, defining its foundational cellular role.\",\n      \"evidence\": \"Inhibitory antibody microinjection, GTPase-deficient mutants, and pharmacological disruption with immunofluorescence in mammalian cells\",\n      \"pmids\": [\"9203580\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not resolve the molecular partners at the contractile ring\", \"Mechanism coupling GTP hydrolysis to filament assembly not defined\"]\n    },\n    {\n      \"year\": 2003,\n      \"claim\": \"Linked SEPTIN2 GTPase activity to polarized outgrowth and placed it in proximity to the exocyst and tubulin.\",\n      \"evidence\": \"Co-immunoprecipitation from brain lysate and GTPase-deficient mutant expression in PC12 cells\",\n      \"pmids\": [\"12544826\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Co-IP did not establish direct binding to exocyst or tubulin\", \"No reciprocal validation\"]\n    },\n    {\n      \"year\": 2004,\n      \"claim\": \"Identified an in vivo phosphorylation site (Ser248) and a candidate kinase, opening a route to post-translational regulation.\",\n      \"evidence\": \"MALDI-Q-TOF mass spectrometry and S248A mutagenesis on recombinant human SEPT2\",\n      \"pmids\": [\"15150837\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of Ser248 phosphorylation not tested\", \"Kinase identity only predicted\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Quantified SEPTIN2 nucleotide binding and hydrolysis kinetics and showed a single septin can form filaments, biochemically defining it as a slow Ras-like GTPase; tied CK2 phosphorylation at Ser218 to nucleotide binding.\",\n      \"evidence\": \"In vitro GTP/GDP binding and hydrolysis assays, filament reconstitution with recombinant protein, and in vivo phosphorylation analysis\",\n      \"pmids\": [\"16857012\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not connect filament biochemistry to a specific in-cell structure\", \"How phosphorylation regulates assembly in cells unresolved\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Extended the cytokinesis role to meiosis and identified SUMO-1 modification, showing septin function is needed for the metaphase I/anaphase I transition.\",\n      \"evidence\": \"siRNA, pharmacological inhibition, and SUMO modification assays in mouse oocytes\",\n      \"pmids\": [\"20372094\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"SUMO acceptor site and its functional role not defined\", \"Inhibitor targets septins broadly, not SEPTIN2 specifically\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Demonstrated that membrane redistribution of SEPTIN2 controls epithelial barrier permeability via cortical actin, connecting it to mechanosensing.\",\n      \"evidence\": \"Immunofluorescence, siRNA depletion, and permeability assays in human airway epithelial cells\",\n      \"pmids\": [\"20870893\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular trigger for membrane redistribution not identified\", \"Direct membrane-binding determinants not tested here\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Showed SEPTIN2 has intrinsic amyloid-like self-assembly propensity within its GTP-binding domain, characterizing its biophysical aggregation behavior.\",\n      \"evidence\": \"In vitro aggregation, Thioflavin-T binding, electron microscopy, and CD spectroscopy\",\n      \"pmids\": [\"21967827\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Physiological relevance of amyloid-like fibers unknown\", \"Relationship to functional septin filaments not established\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Identified specific PtdIns(4,5)P2 interaction as a determinant of SEPTIN2 membrane association and fold stability, providing a lipid basis for membrane targeting.\",\n      \"evidence\": \"Langmuir monolayer assay and PM-IRRAS spectroscopy with recombinant protein\",\n      \"pmids\": [\"23416254\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Lipid-binding residues not mapped in this study\", \"In-cell consequence of the interaction not tested here\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Defined a direct role in mitochondrial fission, showing SEPTIN2 binds Drp1 and is required for Drp1 recruitment to constriction sites.\",\n      \"evidence\": \"Reciprocal endogenous Co-IP, recombinant protein pulldown, siRNA, and live-cell imaging; replicated in C. elegans\",\n      \"pmids\": [\"27215606\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Binding interface on SEPTIN2 and Drp1 not mapped\", \"Whether GTPase state regulates Drp1 binding unknown\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Placed SEPTIN2 downstream of RhoA in fibroblast-to-myofibroblast differentiation and linked it to microtubule acetylation.\",\n      \"evidence\": \"Adenoviral overexpression, migration assays, RhoA inhibition, and acetyl-\\u03b1-tubulin quantification\",\n      \"pmids\": [\"27974709\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct effector linking RhoA to SEPTIN2 unidentified\", \"Mechanism of tubulin acetylation protection unresolved\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Established SEPT2/6/7 as a direct, biphasic regulator of microtubule plus-end dynamics that competes with EB1, defining a cytoskeletal crosstalk mechanism.\",\n      \"evidence\": \"In vitro reconstitution of MT dynamics with purified SEPT2/6/7, competitive EB1 binding assays, and live-cell imaging\",\n      \"pmids\": [\"31577529\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of EB1 competition not resolved\", \"Concentration thresholds in vivo unknown\"]\n    },\n    {\n      \"year\": 2019,\n      \"claim\": \"Identified SEPTIN2 cleavage at residue 306 by ZIKV NS2B-NS3 protease as the direct cause of virus-induced cytokinesis defects in neural progenitors.\",\n      \"evidence\": \"NS2B-NS3 expression with protease-dead controls, non-cleavable SEPTIN2 rescue, Co-IP, and cytokinesis assays\",\n      \"pmids\": [\"30713029\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether other septins are similarly targeted not addressed\", \"Fate of cleavage fragments not characterized\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Showed SEPTIN2, with SEPT6/7, is required for endothelial podosome maturation and matrix degradation through its phosphoinositide-binding residues, linking lipid binding to angiogenic invasion.\",\n      \"evidence\": \"siRNA, PI-binding mutant expression, matrix degradation and invasion assays with live-cell imaging\",\n      \"pmids\": [\"31865373\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Upstream signals recruiting SEPTIN2 to podosomes unknown\", \"Specific lipid species at podosomes not resolved\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Demonstrated that junctional SEPTIN2 organizes adherens, tight junction, and PECAM-1 proteins in endothelial monolayers through a membrane-interaction-dependent mechanism.\",\n      \"evidence\": \"shRNA, PI(4,5)P2-binding mutant overexpression, confocal imaging, immunoblot, and RNA-seq\",\n      \"pmids\": [\"33147991\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding to junctional components not shown\", \"Mechanism of junctional protein recruitment unresolved\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Established SEPTIN2 as the keystone subunit required for septin multimer stability in Schwann cell myelin, ranking it above SEPTIN9 in the assembly hierarchy.\",\n      \"evidence\": \"Cre/loxP conditional knockout in Schwann cells with Western blot and immunofluorescence of sciatic nerve\",\n      \"pmids\": [\"36378242\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism by which SEPTIN2 stabilizes other subunits not defined\", \"Functional myelin consequences not fully resolved here\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Defined Cyclophilin A-mediated isomerization at Pro259 as a requirement for SEPTIN2 midbody localization and abscission.\",\n      \"evidence\": \"Co-IP, P259 mutant expression, Cyclophilin A depletion, and abscission assays\",\n      \"pmids\": [\"37446263\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Structural effect of P259 isomerization not directly resolved\", \"Single-lab study without reciprocal validation\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Identified a non-cytoskeletal role in ER stress, where SEPTIN2 balances acetylation versus ubiquitination of BiP/GRP78 at Lys327 to constrain macrophage proinflammatory activation.\",\n      \"evidence\": \"High-content screening, knockdown, Co-IP, and ubiquitination/acetylation and macrophage polarization assays\",\n      \"pmids\": [\"37978190\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How SEPTIN2 mechanistically arbitrates the two PTMs is unclear\", \"Whether this is filament-dependent unknown\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Showed S-nitrosylation at Cys111 acts as a molecular switch dissociating SEPTIN2 from TIAM1 to activate RAC1-NF-\\u03baB signaling in vascular inflammation.\",\n      \"evidence\": \"Biotin-switch with LC-MS/MS, Co-IP, RNA-seq, and pharmacological RAC1 inhibition\",\n      \"pmids\": [\"38357802\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Nitrosylating source in vivo not pinned down\", \"Whether nitrosylation alters filament assembly not tested\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Connected SEPTIN2 to axon initial segment maintenance and human cognitive impairment via Ankyrin G binding dependent on SEPTIN2 homodimerization.\",\n      \"evidence\": \"Co-IP, disease-associated mutant expression in neurons, immunofluorescence, and electrophysiology\",\n      \"pmids\": [\"41408595\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genetic causality in patients beyond single-gene assumption not established\", \"Binding interface on Ankyrin G not mapped\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Identified SEPTIN2 as a regulator of the Rac GAP ARHGAP25 at lamellipodia, modulating Rac-dependent spreading.\",\n      \"evidence\": \"Co-IP, co-localization, reciprocal siRNA and overexpression epistasis, and lamellipodia/spreading assays\",\n      \"pmids\": [\"40205813\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct binding interface not mapped\", \"How SEPTIN2 alters ARHGAP25 GAP activity unresolved\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Placed SEPTIN2 in a hypoxia-responsive transcriptional axis controlling spermatogonial proliferation through PP2A-B56\\u03b3 and AKT.\",\n      \"evidence\": \"DNA pulldown/MS, TMT proteomics, Co-IP, luciferase reporter, knockdown/overexpression, and PP2A pharmacology\",\n      \"pmids\": [\"40487848\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct interaction of SEPTIN2 with PP2A subunits not fully resolved\", \"In vivo relevance to fertility not established\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How the diverse post-translational modifications (CK2 phosphorylation, SUMOylation, S-nitrosylation, prolyl isomerization) and lipid interactions are integrated to switch SEPTIN2 between its many filament-dependent and signaling roles remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified structural model linking nucleotide state, PTMs, and filament assembly\", \"Tissue-specific partner selection mechanism unknown\", \"Causal hierarchy among SEPTIN2's many roles not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0003924\", \"supporting_discovery_ids\": [0, 3]},\n      {\"term_id\": \"GO:0005198\", \"supporting_discovery_ids\": [0, 3, 11]},\n      {\"term_id\": \"GO:0008289\", \"supporting_discovery_ids\": [7, 13]},\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [11]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [8, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 11]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [5, 13, 14]},\n      {\"term_id\": \"GO:0005739\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 3]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-1640170\", \"supporting_discovery_ids\": [0, 16]},\n      {\"term_id\": \"R-HSA-1852241\", \"supporting_discovery_ids\": [8]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [18, 20]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [17]}\n    ],\n    \"complexes\": [\n      \"SEPT2/6/7 heteromeric septin complex\"\n    ],\n    \"partners\": [\n      \"DRP1\",\n      \"EB1\",\n      \"TIAM1\",\n      \"ARHGAP25\",\n      \"ANK3\",\n      \"PPIA\",\n      \"HSPA5\",\n      \"FHL2\"\n    ],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":9,"faith_total":9,"faith_pct":100.0}}