{"gene":"TAGLN2","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2015,"finding":"TAGLN2 stabilizes cortical F-actin at the immunological synapse (IS) by competing with cofilin to block actin depolymerization, both in vitro and in vivo. TAGLN2 knockout reduced F-actin content and destabilized F-actin ring formation, resulting in decreased LFA-1 activation, cell adhesion, spreading, cytokine production, and cytotoxic effector function in T cells.","method":"TAGLN2 knockout mouse T cells, in vitro actin depolymerization competition assay with cofilin, live-cell imaging of IS F-actin ring, adhesion/spreading/cytokine/cytotoxicity assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal genetic KO with multiple orthogonal functional readouts plus direct in vitro competition assay with cofilin; replicated in subsequent review paper (PMID:26129675)","pmids":["25869671"],"is_preprint":false},{"year":2018,"finding":"TAGLN2 nucleates G-actin polymerization under low-salt conditions through its calponin homology domain and actin-binding loop, which mechanically connect two adjacent G-actin monomers mediating multimeric interactions. Under physiological salt conditions, TAGLN2 blocks Arp2/3 complex binding to actin filaments, thereby inhibiting branched actin nucleation and promoting filopodium-like membrane protrusions in HeLa and T cells.","method":"In vitro actin polymerization assays under low-salt and physiological conditions, domain deletion/mutation analysis (calponin homology domain and actin-binding loop), Arp2/3 complex binding assay, live-cell imaging of filopodia in HeLa and T cells","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro biochemical reconstitution with mutagenesis identifying essential domains, supported by cell-based functional validation; single lab but multiple orthogonal methods","pmids":["29615809"],"is_preprint":false},{"year":2011,"finding":"PFTK1 kinase phosphorylates TAGLN2 at serine residues S83 and S163, reducing its actin-binding affinity. In PFTK1-suppressed hepatocellular carcinoma (HCC) cells, unphosphorylated TAGLN2 shows strong actin-binding and inhibits actin cytoskeleton dynamics, cell invasion, and motility. Knockdown of TAGLN2 in PFTK1-suppressed cells overrides the inhibitory effect on cell invasion/motility, placing TAGLN2 downstream of PFTK1 in an oncogene-tumor suppressor axis.","method":"2D-PAGE mass spectrometry to identify phosphorylated substrates, site-directed mutagenesis of S83 and S163, PFTK1 knockdown/overexpression, actin polymerization assay, cell invasion and motility assays, epistasis (double knockdown)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis of specific phosphorylation sites combined with epistasis experiments and actin-binding assay; single lab but multiple orthogonal methods","pmids":["21577206"],"is_preprint":false},{"year":2017,"finding":"TAGLN2 is induced in macrophages by LPS via the NF-κB pathway. TAGLN2-deficient macrophages show defective phagocytosis of IgM/IgG-opsonized red blood cells and bacteria, with down-regulation of PI3K/AKT and Ras-ERK signaling pathways involved in actin rearrangement. TAGLN2-/- mice show higher mortality after bacterial infection than wild-type littermates.","method":"TAGLN2 knockout macrophages (TAGLN2-/- mice), phagocytosis assays (IgM- and IgG-coated sheep RBCs and bacteria), PI3K/AKT and Ras-ERK pathway analysis, NF-κB pathway inhibition, in vivo bacterial infection survival assay","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genetic knockout with multiple orthogonal functional readouts in vitro and in vivo, pathway analysis; single lab","pmids":["28821818"],"is_preprint":false},{"year":2018,"finding":"TAGLN2 is physically associated with LFA-1 and potentiates 'inside-out' activation of LFA-1 to enhance immunological synapse formation between T cells and tumor cells. A cell-permeable recombinant TAGLN2 (TG2P, fused with protein transduction domain) enhanced cytotoxic T cell killing of ICAM-1-positive tumor cells and reduced tumor growth in mice. The TAGLN2-actin-LFA-1 axis also enhanced CAR-T cell killing of Raji B-lymphoma cells.","method":"Co-immunoprecipitation (TAGLN2-LFA-1 interaction), recombinant protein transduction (TG2P), OTI TCR CD8+ T cell cytotoxicity assays against ICAM-1+/- tumor cells, in vivo tumor growth assay, CAR-T cell killing assay","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for physical interaction with LFA-1, functional assays in multiple cell types and in vivo; single lab","pmids":["30524895"],"is_preprint":false},{"year":2022,"finding":"Lysine-40 succinylation (K40succ) of TAGLN2 promotes glioma angiogenesis and tumor growth. A succinylation-mimetic mutant (TAGLN2-K40E) promotes angiogenesis, VE-cadherin expression, actin cytoskeleton remodeling, and tumor cell adhesion/metastasis in vitro and in vivo. TAGLN2 interacts with TMSB4X (co-localizing in nucleus and cytoplasm), and this interaction is dependent on WT TAGLN2 but not the non-succinylated K40A mutant. Inhibition of TMSB4X attenuates TAGLN2-K40succ-induced proliferation and migration.","method":"TMT labeling and LC-MS/MS to identify K40 succinylation, succinylation-mimetic (K40E) and non-succinylatable (K40R/K40A) mutants, in vitro angiogenesis assays, in vivo xenograft tumors, immunofluorescence co-localization of TAGLN2 and TMSB4X","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — PTM identified by MS with functional mimetic/non-succinylatable mutants and co-localization; single lab","pmids":["36131066"],"is_preprint":false},{"year":2022,"finding":"TAGLN2 binds directly to E-cadherin (shown by co-immunoprecipitation and microscale thermophoresis). Decreased TAGLN2 expression reduces cleavage of the E-cadherin extracellular domain, impairing trophoblast migration, invasion, and fusion, and reducing soluble E-cadherin levels that affect placental blood vessel formation. TAGLN2 overexpression (adenoviral) in pregnant mice induced a PE-like syndrome.","method":"Co-immunoprecipitation and microscale thermophoresis (TAGLN2-E-cadherin binding), TAGLN2 knockdown in trophoblast cell lines, migration/invasion/fusion assays, E-cadherin cleavage analysis, in vivo adenoviral TAGLN2 overexpression in pregnant mice","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct binding confirmed by two orthogonal methods (Co-IP + MST), functional KD and in vivo overexpression; single lab","pmids":["35281112"],"is_preprint":false},{"year":2016,"finding":"TAGLN2 positively regulates hepatitis B virus (HBV) transcription and replication: ectopic TAGLN2 expression in HepG2 cells enhanced HBV transcription and replication, while TAGLN2 knockdown had the opposite effect. The viral protein HBx induced TAGLN2 expression in a dose-dependent manner in a Tet-on HBx cell line.","method":"Ectopic expression and knockdown of TAGLN2 in HepG2 and HepG2.2.15 cells, HBV transcription/replication assays (qRT-PCR for HBc, HBs, HBx), Tet-on HBx inducible system","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — gain- and loss-of-function in cell lines with viral readouts and upstream inducer identified; single lab, single method per direction","pmids":["27402267"],"is_preprint":false},{"year":2021,"finding":"In zebrafish, klf6a transcription factor directly drives tagln2 expression as a downstream target during caudal vein pruning. The klf6a-tagln2 axis regulates endothelial cell rearrangement (nucleus migration, junction remodeling, actin cytoskeleton dynamics) required for vessel pruning.","method":"Zebrafish genetic loss-of-function (klf6a disruption), epistasis placing tagln2 downstream of klf6a in vessel pruning, live imaging of EC rearrangement, actin cytoskeleton analysis in transgenic embryos","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic epistasis in zebrafish with direct downstream target relationship and multiple cellular readouts; single lab","pmids":["34319989"],"is_preprint":false},{"year":2024,"finding":"TAGLN2 interacts with ERK1/2 (shown by Co-IP and LC-MS/MS). TAGLN2 knockdown decreases p-ERK1/2 nuclear expression, while overexpression increases it. TAGLN2 regulates MGMT expression downstream of ERK, contributing to temozolomide resistance. NF-κB regulates TAGLN2 expression (validated by ChIP-PCR). TAGLN2 also promotes proneural-to-mesenchymal transition in GBM.","method":"Co-immunoprecipitation, LC-MS/MS, TAGLN2 knockdown/overexpression in GBM cells, p-ERK1/2 nuclear localization analysis, MGMT expression assays, chromatin immunoprecipitation (ChIP-PCR) for NF-κB binding to TAGLN2 promoter, intracranial xenograft mouse models","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + LC-MS/MS for ERK interaction plus ChIP-PCR for upstream regulation; single lab, multiple orthogonal methods","pmids":["38992489"],"is_preprint":false},{"year":2021,"finding":"TAGLN2 promotes colorectal cancer cell proliferation, invasion, migration, and EMT by activating STAT3 signaling through ANXA2. TAGLN2 knockdown suppresses STAT3 phosphorylation, and STAT3 inhibitor reverses the pro-tumorigenic effects of TAGLN2 overexpression. ANXA2 expression is positively associated with STAT3.","method":"TAGLN2 shRNA knockdown and overexpression in CRC cell lines, STAT3 phosphorylation western blot, STAT3 inhibitor rescue experiment, ANXA2-STAT3 association by western blot, proliferation/migration/invasion/EMT assays","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — gain/loss-of-function with pharmacological rescue and pathway analysis; single lab","pmids":["34466149"],"is_preprint":false},{"year":2022,"finding":"TAGLN2 promotes invasion of papillary thyroid carcinoma cells via the Rap1/PI3K/AKT signaling pathway. Rescue experiments validated involvement of this pathway in TAGLN2-mediated invasion. Quantitative proteomics identified ITGB5, LAMC2, CRKL, vimentin, N-cadherin, and E-cadherin as downstream molecules.","method":"Gain- and loss-of-function in PTC cell lines (K1, TPC-1, BCPAP), gene expression profiling, quantitative proteomics, western blotting, Rap1/PI3K/AKT pathway rescue experiments, invasion/migration/angiogenesis assays","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — pathway rescue experiments combined with quantitative proteomics; single lab","pmids":["36222755"],"is_preprint":false},{"year":2024,"finding":"TAGLN2 upregulates resistance-signature interferon-stimulated genes (ISGs) in gastric cancer by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to the YBX1 promoter region and by directly interacting with AKT-YBX1, thereby enhancing YBX1 phosphorylation and nuclear translocation.","method":"Co-IP (TAGLN2-AKT-YBX1 interaction), ChIP assays (c-Myc and SOX9 at YBX1 promoter), ssDNA aggregation assays, cGAS-STING pathway analysis, ISG expression profiling, pharmacological inhibition (Fisetin, MK2206), xenograft tumor models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP and ChIP for mechanistic interactions with multiple pathway readouts; single lab","pmids":["39168971"],"is_preprint":false},{"year":2025,"finding":"TAGLN2 promotes activation of the ANXA2/NF-κB axis in Kupffer cells, contributing to inflammatory response and hepatocyte pyroptosis in acute pancreatitis-induced liver injury. TAGLN2 knockout reduced inflammatory cytokine levels, pyroptosis-related protein expression, and liver dysfunction markers.","method":"TAGLN2 knockout mice (cerulein-induced AP model), TAGLN2 knockdown in LPS-stimulated Kupffer cells, ANXA2/NF-κB pathway analysis, pyroptosis-related protein expression, cytokine measurement, liver injury markers (ALT, AST)","journal":"Archivum immunologiae et therapiae experimentalis","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — in vivo KO and in vitro KD with mechanistic pathway analysis; single lab, relatively recent paper","pmids":["40472315"],"is_preprint":false},{"year":2024,"finding":"TAGLN2 binds directly to ARPC5 (actin-related protein 2/3 complex subunit 5) as confirmed by co-immunoprecipitation and immunofluorescence co-localization. TAGLN2 promotes ARPC5 expression and activates the MEK/ERK signaling pathway; silencing ARPC5 reverses TAGLN2-driven proliferation, invasion, and metastasis of pancreatic cancer cells.","method":"Co-immunoprecipitation and immunofluorescence (TAGLN2-ARPC5 interaction), TAGLN2 overexpression/knockdown with ARPC5 silencing epistasis, MEK inhibitor (U0126), in vitro and in vivo tumor assays","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + IF for interaction, epistasis with ARPC5 knockdown and MEK inhibitor; single lab","pmids":["38744388"],"is_preprint":false},{"year":2025,"finding":"CXCR7 physically interacts with TAGLN2 in papillary thyroid carcinoma cells (shown by Co-IP and immunofluorescence co-localization). CXCR7 promotes PTC migration and invasion through TAGLN2 by activating the TGF-β/Smad2 signaling pathway. TAGLN2 knockdown decreases p-Smad2 levels, and CXCR7 re-introduction restores p-Smad2 in TAGLN2-silenced cells.","method":"Co-immunoprecipitation and immunofluorescence co-localization (CXCR7-TAGLN2), lentiviral cotransfection with TAGLN2 silencing and CXCR7 overexpression, p-Smad2/Smad2 western blot, migration assays in TPC-1 and BCPAP cells","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP + IF for protein interaction, epistasis rescue experiment with pathway readout; single lab","pmids":["41169389"],"is_preprint":false},{"year":2026,"finding":"Tumor-derived exosomal TAGLN2 is delivered to endothelial cells where it transcriptionally upregulates NRP1 via c-Jun/SP1 and induces SEMA4D expression. TAGLN2 then interacts with both NRP1 and SEMA4D to form a stable cytoplasmic ternary complex that dually activates YAP (by disrupting NRP1-YAP binding and suppressing Hippo-mediated degradation), independently of the canonical SEMA4D-PlexinB1-RhoA/ROCK pathway.","method":"Exosome isolation and delivery experiments, ChIP (c-Jun/SP1 at NRP1 promoter), Co-IP (TAGLN2-NRP1-SEMA4D ternary complex), YAP localization/activity assays, in vivo tumor growth and lung metastasis models, combination drug treatment (cisplatin + MK2206)","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP for ternary complex, ChIP for transcriptional regulation, multiple functional readouts; single lab, very recent","pmids":["41824788"],"is_preprint":false},{"year":2014,"finding":"miR-133a directly binds the 3'-UTR of TAGLN2 mRNA (validated by dual-luciferase reporter assay) and suppresses TAGLN2 at both transcriptional and translational levels. TAGLN2 knockout modulates hypoxia-induced apoptosis in cardiomyocytes via the caspase-8 apoptotic pathway.","method":"Dual-luciferase reporter assay (miR-133a binding to TAGLN2 3'-UTR), TAGLN2 knockout in hypoxic H9c2 cells, caspase-8/-9/-3 and Bcl-2 protein expression analysis","journal":"Molecular and cellular biochemistry","confidence":"Low","confidence_rationale":"Tier 3 / Weak — luciferase reporter for miRNA-target validation plus KO phenotype; single lab, limited mechanistic depth on TAGLN2 protein function itself","pmids":["25421410"],"is_preprint":false},{"year":2018,"finding":"TAGLN2 promotes meningioma cell proliferation, invasion, and survival while inhibiting apoptosis. TAGLN2 knockdown inhibited p-PI3K and p-AKT expression, while overexpression increased them, placing TAGLN2 upstream of the PI3K/AKT signaling pathway in meningioma cells.","method":"Lentiviral TAGLN2 knockdown and overexpression in CH157 meningioma cells, CCK8, colony formation, transwell invasion, flow cytometry apoptosis assays, p-PI3K and p-AKT western blot","journal":"European review for medical and pharmacological sciences","confidence":"Low","confidence_rationale":"Tier 3 / Weak — single lab, western blot for pathway activation without direct mechanistic experiments; limited methodological rigor","pmids":["29424888"],"is_preprint":false}],"current_model":"TAGLN2 is a 22-kDa actin-binding protein that stabilizes F-actin by competing with cofilin to block depolymerization, nucleates G-actin polymerization via its calponin homology domain and actin-binding loop under low-ionic conditions, and blocks Arp2/3-mediated branched actin nucleation under physiological conditions; its actin-regulatory activity is modulated by PFTK1 kinase-mediated phosphorylation at S83/S163 and by K40 succinylation, and it acts as a signaling scaffold that physically associates with LFA-1, E-cadherin, ERK1/2, ARPC5, CXCR7, NRP1, SEMA4D, and the AKT-YBX1 complex to regulate T cell immunity, trophoblast function, macrophage phagocytosis, angiogenesis, and cancer cell invasion/metastasis through downstream PI3K/AKT, MEK/ERK, Rap1, TGF-β/Smad2, NF-κB, STAT3/ANXA2, and cGAS-STING/YAP signaling axes."},"narrative":{"mechanistic_narrative":"TAGLN2 is an actin-binding protein that controls cortical actin architecture and acts as a signaling scaffold linking cytoskeletal remodeling to immune, developmental, and oncogenic programs [PMID:25869671, PMID:29615809]. At the immunological synapse it stabilizes F-actin by competing with cofilin to block depolymerization, sustaining LFA-1 activation, T cell adhesion, spreading, and cytotoxic effector function [PMID:25869671]; it physically associates with LFA-1 to potentiate inside-out integrin activation, an axis exploitable to enhance cytotoxic and CAR-T cell killing of tumor cells [PMID:30524895]. Biochemically, TAGLN2 nucleates G-actin polymerization through its calponin homology domain and actin-binding loop under low-salt conditions and, under physiological conditions, blocks Arp2/3 binding to filaments to inhibit branched nucleation and promote filopodium-like protrusions [PMID:29615809]. Its actin-regulatory activity is tuned by post-translational modification: PFTK1-mediated phosphorylation at S83/S163 reduces actin-binding affinity and relieves TAGLN2 suppression of cell invasion and motility [PMID:21577206], while K40 succinylation drives an interaction with TMSB4X that promotes angiogenesis and cytoskeletal remodeling in glioma [PMID:36131066]. TAGLN2 is induced in macrophages by LPS via NF-κB and is required for Fc-receptor phagocytosis and host defense through PI3K/AKT and Ras-ERK signaling [PMID:28821818]. Across multiple cancers, TAGLN2 acts as a pro-tumorigenic scaffold by binding partners including ARPC5 (MEK/ERK) [PMID:38744388], E-cadherin (trophoblast invasion) [PMID:35281112], ERK1/2 (MGMT-driven temozolomide resistance) [PMID:38992489], CXCR7 (TGF-β/Smad2) [PMID:41169389], and the AKT-YBX1 complex (cGAS-STING/ISG resistance) [PMID:39168971], and by promoting EMT and invasion through STAT3/ANXA2 and Rap1/PI3K/AKT axes [PMID:34466149, PMID:36222755].","teleology":[{"year":2011,"claim":"Established TAGLN2 as a phosphoregulated effector downstream of a kinase, showing that its actin-binding activity is switchable and links to cancer cell invasion.","evidence":"Phosphosite mapping by 2D-PAGE/MS, S83/S163 mutagenesis, PFTK1 knockdown/overexpression, and epistasis in HCC cells","pmids":["21577206"],"confidence":"High","gaps":["Structural basis of how phosphorylation reduces actin affinity not resolved","Whether other kinases target the same sites unknown"]},{"year":2014,"claim":"Identified an upstream miRNA brake on TAGLN2 and linked its dosage to cardiomyocyte apoptosis, hinting at non-cancer roles.","evidence":"Dual-luciferase 3'-UTR reporter for miR-133a and TAGLN2 KO in hypoxic H9c2 cells","pmids":["25421410"],"confidence":"Low","gaps":["Limited mechanistic depth on TAGLN2 protein function itself","Caspase-8 axis link is correlative"]},{"year":2015,"claim":"Defined the core molecular mechanism: TAGLN2 stabilizes F-actin by competing with cofilin, connecting it to immunological synapse integrity and T cell function.","evidence":"TAGLN2 KO mouse T cells, in vitro cofilin competition assay, live-cell IS imaging, adhesion/cytotoxicity readouts","pmids":["25869671"],"confidence":"High","gaps":["Stoichiometry of TAGLN2-cofilin competition on filaments not quantified","Regulation of TAGLN2 recruitment to the synapse unclear"]},{"year":2016,"claim":"Extended TAGLN2 function to viral biology, placing it downstream of HBx as a positive regulator of HBV replication.","evidence":"Gain/loss-of-function in HepG2 cells with HBV transcription/replication readouts and Tet-on HBx system","pmids":["27402267"],"confidence":"Medium","gaps":["Direct molecular mechanism by which TAGLN2 enhances HBV transcription unknown","Single method per direction"]},{"year":2017,"claim":"Showed TAGLN2 is an LPS/NF-κB-induced effector required for macrophage phagocytosis and host defense, establishing an innate-immune role.","evidence":"TAGLN2 KO macrophages, opsonized-particle phagocytosis assays, PI3K/AKT and Ras-ERK pathway analysis, in vivo infection survival","pmids":["28821818"],"confidence":"High","gaps":["Whether TAGLN2 acts directly at the phagocytic cup or via signaling not separated","Direct effectors linking TAGLN2 to PI3K/AKT not identified"]},{"year":2018,"claim":"Resolved the biochemical mechanism of actin regulation (nucleation vs. Arp2/3 inhibition) and defined a therapeutically actionable TAGLN2-actin-LFA-1 immunotherapy axis.","evidence":"In vitro polymerization assays with domain mutants, Arp2/3 binding assay, filopodia imaging (29615809); Co-IP and cell-permeable TG2P with cytotoxicity/tumor models (30524895)","pmids":["29615809","30524895"],"confidence":"High","gaps":["High-resolution structure of TAGLN2-actin and TAGLN2-LFA-1 interfaces lacking","How salt conditions translate to physiological switching unclear"]},{"year":2021,"claim":"Embedded TAGLN2 in transcriptional networks and tumor signaling, showing both an in vivo developmental driver (klf6a) and a STAT3/ANXA2 oncogenic route.","evidence":"Zebrafish klf6a epistasis with EC rearrangement imaging (34319989); CRC gain/loss-of-function with STAT3 inhibitor rescue (34466149)","pmids":["34319989","34466149"],"confidence":"Medium","gaps":["Direct vs. indirect TAGLN2-STAT3 link not established","Whether klf6a-tagln2 axis is conserved in mammals untested"]},{"year":2022,"claim":"Diversified the partner/PTM repertoire, identifying K40 succinylation (TMSB4X), direct E-cadherin binding, and Rap1/PI3K/AKT-mediated invasion across angiogenesis, trophoblast, and thyroid contexts.","evidence":"MS-identified K40succ with mimetic mutants and TMSB4X co-localization (36131066); Co-IP+MST for E-cadherin with trophoblast assays (35281112); proteomics and Rap1/PI3K/AKT rescue in PTC (36222755)","pmids":["36131066","35281112","36222755"],"confidence":"Medium","gaps":["Enzyme controlling K40 succinylation not identified","Each partner shown by single lab without reciprocal cross-validation"]},{"year":2024,"claim":"Expanded TAGLN2 into a multi-pathway scaffold in cancer, binding ARPC5 (MEK/ERK), ERK1/2 (MGMT/TMZ resistance), and the AKT-YBX1 complex (cGAS-STING/ISG resistance).","evidence":"Co-IP/IF and ARPC5 epistasis with MEK inhibitor in pancreatic cancer (38744388); Co-IP/LC-MS/MS, ChIP-PCR and xenografts in GBM (38992489); Co-IP, ChIP and cGAS-STING readouts in gastric cancer (39168971)","pmids":["38744388","38992489","39168971"],"confidence":"Medium","gaps":["Whether these interactions are direct or scaffolded via actin not dissected","Context-specificity of partner selection unexplained"]},{"year":2025,"claim":"Demonstrated TAGLN2 drives intercellular signaling (exosomal transfer, CXCR7/TGF-β/Smad2) and inflammatory ANXA2/NF-κB injury, broadening it from cell-autonomous to niche-level functions.","evidence":"Exosome delivery, ChIP and Co-IP for NRP1-SEMA4D-YAP (41824788); Co-IP/IF and CXCR7 rescue with p-Smad2 readout (41169389); TAGLN2 KO AP-liver injury model (40472315)","pmids":["41824788","41169389","40472315"],"confidence":"Medium","gaps":["Mechanism of TAGLN2 sorting into exosomes unknown","Stoichiometry and structure of NRP1-SEMA4D ternary complex undefined"]},{"year":null,"claim":"How TAGLN2 selects among its many signaling partners in a given cell type, and whether its scaffolding functions depend on or are separable from its actin-regulatory activity, remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unifying model connecting actin regulation to partner-specific signaling","No structural data on the multiple interaction interfaces","Endogenous physiological vs. pathological context of each axis not delineated"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,2]},{"term_id":"GO:0060090","term_label":"molecular adaptor activity","supporting_discovery_ids":[4,14,16]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[5,16]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[5,9]}],"pathway":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1]}],"complexes":[],"partners":["LFA-1","E-CADHERIN","ERK1/2","ARPC5","CXCR7","NRP1","SEMA4D","YBX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P37802","full_name":"Transgelin-2","aliases":["Epididymis tissue protein Li 7e","SM22-alpha homolog"],"length_aa":199,"mass_kda":22.4,"function":"","subcellular_location":"","url":"https://www.uniprot.org/uniprotkb/P37802/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAGLN2","classification":"Not Classified","n_dependent_lines":11,"n_total_lines":1208,"dependency_fraction":0.009105960264900662},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[{"gene":"ELOVL1","stoichiometry":0.2}],"url":"https://opencell.sf.czbiohub.org/search/TAGLN2","total_profiled":1310},"omim":[{"mim_id":"605168","title":"FATTY ACID-BINDING PROTEIN 5; FABP5","url":"https://www.omim.org/entry/605168"},{"mim_id":"604634","title":"TRANSGELIN 2; TAGLN2","url":"https://www.omim.org/entry/604634"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Cytosol","reliability":"Approved"},{"location":"Vesicles","reliability":"Additional"},{"location":"Actin filaments","reliability":"Additional"},{"location":"Basal body","reliability":"Additional"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/TAGLN2"},"hgnc":{"alias_symbol":["KIAA0120","HA1756"],"prev_symbol":[]},"alphafold":{"accession":"P37802","domains":[{"cath_id":"1.10.418.10","chopping":"9-149","consensus_level":"high","plddt":93.7182,"start":9,"end":149}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P37802","model_url":"https://alphafold.ebi.ac.uk/files/AF-P37802-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P37802-F1-predicted_aligned_error_v6.png","plddt_mean":88.12},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAGLN2","jax_strain_url":"https://www.jax.org/strain/search?query=TAGLN2"},"sequence":{"accession":"P37802","fasta_url":"https://rest.uniprot.org/uniprotkb/P37802.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P37802/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P37802"}},"corpus_meta":[{"pmid":"21304530","id":"PMC_21304530","title":"The tumour-suppressive function of miR-1 and miR-133a targeting TAGLN2 in bladder cancer.","date":"2011","source":"British journal of cancer","url":"https://pubmed.ncbi.nlm.nih.gov/21304530","citation_count":247,"is_preprint":false},{"pmid":"21378409","id":"PMC_21378409","title":"miR-1 as a tumor suppressive microRNA targeting TAGLN2 in head and neck squamous cell carcinoma.","date":"2011","source":"Oncotarget","url":"https://pubmed.ncbi.nlm.nih.gov/21378409","citation_count":155,"is_preprint":false},{"pmid":"7788527","id":"PMC_7788527","title":"Prediction of the coding sequences of unidentified human genes. 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The coding sequences of 40 new genes (KIAA0081-KIAA0120) deduced by analysis of cDNA clones from human cell line KG-1.","date":"1995","source":"DNA research : an international journal for rapid publication of reports on genes and genomes","url":"https://pubmed.ncbi.nlm.nih.gov/7788527","citation_count":92,"is_preprint":false},{"pmid":"25869671","id":"PMC_25869671","title":"TAGLN2 regulates T cell activation by stabilizing the actin cytoskeleton at the immunological synapse.","date":"2015","source":"The Journal of cell biology","url":"https://pubmed.ncbi.nlm.nih.gov/25869671","citation_count":82,"is_preprint":false},{"pmid":"21577206","id":"PMC_21577206","title":"A novel interplay between oncogenic PFTK1 protein kinase and tumor suppressor TAGLN2 in the control of liver cancer cell motility.","date":"2011","source":"Oncogene","url":"https://pubmed.ncbi.nlm.nih.gov/21577206","citation_count":78,"is_preprint":false},{"pmid":"30405771","id":"PMC_30405771","title":"miR-145-5p inhibits the 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TAGLN2 knockout reduced F-actin content and destabilized F-actin ring formation, resulting in decreased LFA-1 activation, cell adhesion, spreading, cytokine production, and cytotoxic effector function in T cells.\",\n      \"method\": \"TAGLN2 knockout mouse T cells, in vitro actin depolymerization competition assay with cofilin, live-cell imaging of IS F-actin ring, adhesion/spreading/cytokine/cytotoxicity assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — reciprocal genetic KO with multiple orthogonal functional readouts plus direct in vitro competition assay with cofilin; replicated in subsequent review paper (PMID:26129675)\",\n      \"pmids\": [\"25869671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TAGLN2 nucleates G-actin polymerization under low-salt conditions through its calponin homology domain and actin-binding loop, which mechanically connect two adjacent G-actin monomers mediating multimeric interactions. Under physiological salt conditions, TAGLN2 blocks Arp2/3 complex binding to actin filaments, thereby inhibiting branched actin nucleation and promoting filopodium-like membrane protrusions in HeLa and T cells.\",\n      \"method\": \"In vitro actin polymerization assays under low-salt and physiological conditions, domain deletion/mutation analysis (calponin homology domain and actin-binding loop), Arp2/3 complex binding assay, live-cell imaging of filopodia in HeLa and T cells\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro biochemical reconstitution with mutagenesis identifying essential domains, supported by cell-based functional validation; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"29615809\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"PFTK1 kinase phosphorylates TAGLN2 at serine residues S83 and S163, reducing its actin-binding affinity. In PFTK1-suppressed hepatocellular carcinoma (HCC) cells, unphosphorylated TAGLN2 shows strong actin-binding and inhibits actin cytoskeleton dynamics, cell invasion, and motility. Knockdown of TAGLN2 in PFTK1-suppressed cells overrides the inhibitory effect on cell invasion/motility, placing TAGLN2 downstream of PFTK1 in an oncogene-tumor suppressor axis.\",\n      \"method\": \"2D-PAGE mass spectrometry to identify phosphorylated substrates, site-directed mutagenesis of S83 and S163, PFTK1 knockdown/overexpression, actin polymerization assay, cell invasion and motility assays, epistasis (double knockdown)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis of specific phosphorylation sites combined with epistasis experiments and actin-binding assay; single lab but multiple orthogonal methods\",\n      \"pmids\": [\"21577206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TAGLN2 is induced in macrophages by LPS via the NF-κB pathway. TAGLN2-deficient macrophages show defective phagocytosis of IgM/IgG-opsonized red blood cells and bacteria, with down-regulation of PI3K/AKT and Ras-ERK signaling pathways involved in actin rearrangement. TAGLN2-/- mice show higher mortality after bacterial infection than wild-type littermates.\",\n      \"method\": \"TAGLN2 knockout macrophages (TAGLN2-/- mice), phagocytosis assays (IgM- and IgG-coated sheep RBCs and bacteria), PI3K/AKT and Ras-ERK pathway analysis, NF-κB pathway inhibition, in vivo bacterial infection survival assay\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic knockout with multiple orthogonal functional readouts in vitro and in vivo, pathway analysis; single lab\",\n      \"pmids\": [\"28821818\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TAGLN2 is physically associated with LFA-1 and potentiates 'inside-out' activation of LFA-1 to enhance immunological synapse formation between T cells and tumor cells. A cell-permeable recombinant TAGLN2 (TG2P, fused with protein transduction domain) enhanced cytotoxic T cell killing of ICAM-1-positive tumor cells and reduced tumor growth in mice. The TAGLN2-actin-LFA-1 axis also enhanced CAR-T cell killing of Raji B-lymphoma cells.\",\n      \"method\": \"Co-immunoprecipitation (TAGLN2-LFA-1 interaction), recombinant protein transduction (TG2P), OTI TCR CD8+ T cell cytotoxicity assays against ICAM-1+/- tumor cells, in vivo tumor growth assay, CAR-T cell killing assay\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for physical interaction with LFA-1, functional assays in multiple cell types and in vivo; single lab\",\n      \"pmids\": [\"30524895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"Lysine-40 succinylation (K40succ) of TAGLN2 promotes glioma angiogenesis and tumor growth. A succinylation-mimetic mutant (TAGLN2-K40E) promotes angiogenesis, VE-cadherin expression, actin cytoskeleton remodeling, and tumor cell adhesion/metastasis in vitro and in vivo. TAGLN2 interacts with TMSB4X (co-localizing in nucleus and cytoplasm), and this interaction is dependent on WT TAGLN2 but not the non-succinylated K40A mutant. Inhibition of TMSB4X attenuates TAGLN2-K40succ-induced proliferation and migration.\",\n      \"method\": \"TMT labeling and LC-MS/MS to identify K40 succinylation, succinylation-mimetic (K40E) and non-succinylatable (K40R/K40A) mutants, in vitro angiogenesis assays, in vivo xenograft tumors, immunofluorescence co-localization of TAGLN2 and TMSB4X\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — PTM identified by MS with functional mimetic/non-succinylatable mutants and co-localization; single lab\",\n      \"pmids\": [\"36131066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAGLN2 binds directly to E-cadherin (shown by co-immunoprecipitation and microscale thermophoresis). Decreased TAGLN2 expression reduces cleavage of the E-cadherin extracellular domain, impairing trophoblast migration, invasion, and fusion, and reducing soluble E-cadherin levels that affect placental blood vessel formation. TAGLN2 overexpression (adenoviral) in pregnant mice induced a PE-like syndrome.\",\n      \"method\": \"Co-immunoprecipitation and microscale thermophoresis (TAGLN2-E-cadherin binding), TAGLN2 knockdown in trophoblast cell lines, migration/invasion/fusion assays, E-cadherin cleavage analysis, in vivo adenoviral TAGLN2 overexpression in pregnant mice\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct binding confirmed by two orthogonal methods (Co-IP + MST), functional KD and in vivo overexpression; single lab\",\n      \"pmids\": [\"35281112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TAGLN2 positively regulates hepatitis B virus (HBV) transcription and replication: ectopic TAGLN2 expression in HepG2 cells enhanced HBV transcription and replication, while TAGLN2 knockdown had the opposite effect. The viral protein HBx induced TAGLN2 expression in a dose-dependent manner in a Tet-on HBx cell line.\",\n      \"method\": \"Ectopic expression and knockdown of TAGLN2 in HepG2 and HepG2.2.15 cells, HBV transcription/replication assays (qRT-PCR for HBc, HBs, HBx), Tet-on HBx inducible system\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — gain- and loss-of-function in cell lines with viral readouts and upstream inducer identified; single lab, single method per direction\",\n      \"pmids\": [\"27402267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish, klf6a transcription factor directly drives tagln2 expression as a downstream target during caudal vein pruning. The klf6a-tagln2 axis regulates endothelial cell rearrangement (nucleus migration, junction remodeling, actin cytoskeleton dynamics) required for vessel pruning.\",\n      \"method\": \"Zebrafish genetic loss-of-function (klf6a disruption), epistasis placing tagln2 downstream of klf6a in vessel pruning, live imaging of EC rearrangement, actin cytoskeleton analysis in transgenic embryos\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic epistasis in zebrafish with direct downstream target relationship and multiple cellular readouts; single lab\",\n      \"pmids\": [\"34319989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAGLN2 interacts with ERK1/2 (shown by Co-IP and LC-MS/MS). TAGLN2 knockdown decreases p-ERK1/2 nuclear expression, while overexpression increases it. TAGLN2 regulates MGMT expression downstream of ERK, contributing to temozolomide resistance. NF-κB regulates TAGLN2 expression (validated by ChIP-PCR). TAGLN2 also promotes proneural-to-mesenchymal transition in GBM.\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, TAGLN2 knockdown/overexpression in GBM cells, p-ERK1/2 nuclear localization analysis, MGMT expression assays, chromatin immunoprecipitation (ChIP-PCR) for NF-κB binding to TAGLN2 promoter, intracranial xenograft mouse models\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + LC-MS/MS for ERK interaction plus ChIP-PCR for upstream regulation; single lab, multiple orthogonal methods\",\n      \"pmids\": [\"38992489\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TAGLN2 promotes colorectal cancer cell proliferation, invasion, migration, and EMT by activating STAT3 signaling through ANXA2. TAGLN2 knockdown suppresses STAT3 phosphorylation, and STAT3 inhibitor reverses the pro-tumorigenic effects of TAGLN2 overexpression. ANXA2 expression is positively associated with STAT3.\",\n      \"method\": \"TAGLN2 shRNA knockdown and overexpression in CRC cell lines, STAT3 phosphorylation western blot, STAT3 inhibitor rescue experiment, ANXA2-STAT3 association by western blot, proliferation/migration/invasion/EMT assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — gain/loss-of-function with pharmacological rescue and pathway analysis; single lab\",\n      \"pmids\": [\"34466149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAGLN2 promotes invasion of papillary thyroid carcinoma cells via the Rap1/PI3K/AKT signaling pathway. Rescue experiments validated involvement of this pathway in TAGLN2-mediated invasion. Quantitative proteomics identified ITGB5, LAMC2, CRKL, vimentin, N-cadherin, and E-cadherin as downstream molecules.\",\n      \"method\": \"Gain- and loss-of-function in PTC cell lines (K1, TPC-1, BCPAP), gene expression profiling, quantitative proteomics, western blotting, Rap1/PI3K/AKT pathway rescue experiments, invasion/migration/angiogenesis assays\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — pathway rescue experiments combined with quantitative proteomics; single lab\",\n      \"pmids\": [\"36222755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAGLN2 upregulates resistance-signature interferon-stimulated genes (ISGs) in gastric cancer by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to the YBX1 promoter region and by directly interacting with AKT-YBX1, thereby enhancing YBX1 phosphorylation and nuclear translocation.\",\n      \"method\": \"Co-IP (TAGLN2-AKT-YBX1 interaction), ChIP assays (c-Myc and SOX9 at YBX1 promoter), ssDNA aggregation assays, cGAS-STING pathway analysis, ISG expression profiling, pharmacological inhibition (Fisetin, MK2206), xenograft tumor models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP and ChIP for mechanistic interactions with multiple pathway readouts; single lab\",\n      \"pmids\": [\"39168971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAGLN2 promotes activation of the ANXA2/NF-κB axis in Kupffer cells, contributing to inflammatory response and hepatocyte pyroptosis in acute pancreatitis-induced liver injury. TAGLN2 knockout reduced inflammatory cytokine levels, pyroptosis-related protein expression, and liver dysfunction markers.\",\n      \"method\": \"TAGLN2 knockout mice (cerulein-induced AP model), TAGLN2 knockdown in LPS-stimulated Kupffer cells, ANXA2/NF-κB pathway analysis, pyroptosis-related protein expression, cytokine measurement, liver injury markers (ALT, AST)\",\n      \"journal\": \"Archivum immunologiae et therapiae experimentalis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — in vivo KO and in vitro KD with mechanistic pathway analysis; single lab, relatively recent paper\",\n      \"pmids\": [\"40472315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAGLN2 binds directly to ARPC5 (actin-related protein 2/3 complex subunit 5) as confirmed by co-immunoprecipitation and immunofluorescence co-localization. TAGLN2 promotes ARPC5 expression and activates the MEK/ERK signaling pathway; silencing ARPC5 reverses TAGLN2-driven proliferation, invasion, and metastasis of pancreatic cancer cells.\",\n      \"method\": \"Co-immunoprecipitation and immunofluorescence (TAGLN2-ARPC5 interaction), TAGLN2 overexpression/knockdown with ARPC5 silencing epistasis, MEK inhibitor (U0126), in vitro and in vivo tumor assays\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + IF for interaction, epistasis with ARPC5 knockdown and MEK inhibitor; single lab\",\n      \"pmids\": [\"38744388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CXCR7 physically interacts with TAGLN2 in papillary thyroid carcinoma cells (shown by Co-IP and immunofluorescence co-localization). CXCR7 promotes PTC migration and invasion through TAGLN2 by activating the TGF-β/Smad2 signaling pathway. TAGLN2 knockdown decreases p-Smad2 levels, and CXCR7 re-introduction restores p-Smad2 in TAGLN2-silenced cells.\",\n      \"method\": \"Co-immunoprecipitation and immunofluorescence co-localization (CXCR7-TAGLN2), lentiviral cotransfection with TAGLN2 silencing and CXCR7 overexpression, p-Smad2/Smad2 western blot, migration assays in TPC-1 and BCPAP cells\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP + IF for protein interaction, epistasis rescue experiment with pathway readout; single lab\",\n      \"pmids\": [\"41169389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Tumor-derived exosomal TAGLN2 is delivered to endothelial cells where it transcriptionally upregulates NRP1 via c-Jun/SP1 and induces SEMA4D expression. TAGLN2 then interacts with both NRP1 and SEMA4D to form a stable cytoplasmic ternary complex that dually activates YAP (by disrupting NRP1-YAP binding and suppressing Hippo-mediated degradation), independently of the canonical SEMA4D-PlexinB1-RhoA/ROCK pathway.\",\n      \"method\": \"Exosome isolation and delivery experiments, ChIP (c-Jun/SP1 at NRP1 promoter), Co-IP (TAGLN2-NRP1-SEMA4D ternary complex), YAP localization/activity assays, in vivo tumor growth and lung metastasis models, combination drug treatment (cisplatin + MK2206)\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP for ternary complex, ChIP for transcriptional regulation, multiple functional readouts; single lab, very recent\",\n      \"pmids\": [\"41824788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-133a directly binds the 3'-UTR of TAGLN2 mRNA (validated by dual-luciferase reporter assay) and suppresses TAGLN2 at both transcriptional and translational levels. TAGLN2 knockout modulates hypoxia-induced apoptosis in cardiomyocytes via the caspase-8 apoptotic pathway.\",\n      \"method\": \"Dual-luciferase reporter assay (miR-133a binding to TAGLN2 3'-UTR), TAGLN2 knockout in hypoxic H9c2 cells, caspase-8/-9/-3 and Bcl-2 protein expression analysis\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — luciferase reporter for miRNA-target validation plus KO phenotype; single lab, limited mechanistic depth on TAGLN2 protein function itself\",\n      \"pmids\": [\"25421410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TAGLN2 promotes meningioma cell proliferation, invasion, and survival while inhibiting apoptosis. TAGLN2 knockdown inhibited p-PI3K and p-AKT expression, while overexpression increased them, placing TAGLN2 upstream of the PI3K/AKT signaling pathway in meningioma cells.\",\n      \"method\": \"Lentiviral TAGLN2 knockdown and overexpression in CH157 meningioma cells, CCK8, colony formation, transwell invasion, flow cytometry apoptosis assays, p-PI3K and p-AKT western blot\",\n      \"journal\": \"European review for medical and pharmacological sciences\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 / Weak — single lab, western blot for pathway activation without direct mechanistic experiments; limited methodological rigor\",\n      \"pmids\": [\"29424888\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TAGLN2 is a 22-kDa actin-binding protein that stabilizes F-actin by competing with cofilin to block depolymerization, nucleates G-actin polymerization via its calponin homology domain and actin-binding loop under low-ionic conditions, and blocks Arp2/3-mediated branched actin nucleation under physiological conditions; its actin-regulatory activity is modulated by PFTK1 kinase-mediated phosphorylation at S83/S163 and by K40 succinylation, and it acts as a signaling scaffold that physically associates with LFA-1, E-cadherin, ERK1/2, ARPC5, CXCR7, NRP1, SEMA4D, and the AKT-YBX1 complex to regulate T cell immunity, trophoblast function, macrophage phagocytosis, angiogenesis, and cancer cell invasion/metastasis through downstream PI3K/AKT, MEK/ERK, Rap1, TGF-β/Smad2, NF-κB, STAT3/ANXA2, and cGAS-STING/YAP signaling axes.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TAGLN2 is an actin-binding protein that controls cortical actin architecture and acts as a signaling scaffold linking cytoskeletal remodeling to immune, developmental, and oncogenic programs [#0, #1]. At the immunological synapse it stabilizes F-actin by competing with cofilin to block depolymerization, sustaining LFA-1 activation, T cell adhesion, spreading, and cytotoxic effector function [#0]; it physically associates with LFA-1 to potentiate inside-out integrin activation, an axis exploitable to enhance cytotoxic and CAR-T cell killing of tumor cells [#4]. Biochemically, TAGLN2 nucleates G-actin polymerization through its calponin homology domain and actin-binding loop under low-salt conditions and, under physiological conditions, blocks Arp2/3 binding to filaments to inhibit branched nucleation and promote filopodium-like protrusions [#1]. Its actin-regulatory activity is tuned by post-translational modification: PFTK1-mediated phosphorylation at S83/S163 reduces actin-binding affinity and relieves TAGLN2 suppression of cell invasion and motility [#2], while K40 succinylation drives an interaction with TMSB4X that promotes angiogenesis and cytoskeletal remodeling in glioma [#5]. TAGLN2 is induced in macrophages by LPS via NF-\\u03baB and is required for Fc-receptor phagocytosis and host defense through PI3K/AKT and Ras-ERK signaling [#3]. Across multiple cancers, TAGLN2 acts as a pro-tumorigenic scaffold by binding partners including ARPC5 (MEK/ERK) [#14], E-cadherin (trophoblast invasion) [#6], ERK1/2 (MGMT-driven temozolomide resistance) [#9], CXCR7 (TGF-\\u03b2/Smad2) [#15], and the AKT-YBX1 complex (cGAS-STING/ISG resistance) [#12], and by promoting EMT and invasion through STAT3/ANXA2 and Rap1/PI3K/AKT axes [#10, #11].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"Established TAGLN2 as a phosphoregulated effector downstream of a kinase, showing that its actin-binding activity is switchable and links to cancer cell invasion.\",\n      \"evidence\": \"Phosphosite mapping by 2D-PAGE/MS, S83/S163 mutagenesis, PFTK1 knockdown/overexpression, and epistasis in HCC cells\",\n      \"pmids\": [\"21577206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Structural basis of how phosphorylation reduces actin affinity not resolved\", \"Whether other kinases target the same sites unknown\"]\n    },\n    {\n      \"year\": 2014,\n      \"claim\": \"Identified an upstream miRNA brake on TAGLN2 and linked its dosage to cardiomyocyte apoptosis, hinting at non-cancer roles.\",\n      \"evidence\": \"Dual-luciferase 3'-UTR reporter for miR-133a and TAGLN2 KO in hypoxic H9c2 cells\",\n      \"pmids\": [\"25421410\"],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"Limited mechanistic depth on TAGLN2 protein function itself\", \"Caspase-8 axis link is correlative\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Defined the core molecular mechanism: TAGLN2 stabilizes F-actin by competing with cofilin, connecting it to immunological synapse integrity and T cell function.\",\n      \"evidence\": \"TAGLN2 KO mouse T cells, in vitro cofilin competition assay, live-cell IS imaging, adhesion/cytotoxicity readouts\",\n      \"pmids\": [\"25869671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Stoichiometry of TAGLN2-cofilin competition on filaments not quantified\", \"Regulation of TAGLN2 recruitment to the synapse unclear\"]\n    },\n    {\n      \"year\": 2016,\n      \"claim\": \"Extended TAGLN2 function to viral biology, placing it downstream of HBx as a positive regulator of HBV replication.\",\n      \"evidence\": \"Gain/loss-of-function in HepG2 cells with HBV transcription/replication readouts and Tet-on HBx system\",\n      \"pmids\": [\"27402267\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct molecular mechanism by which TAGLN2 enhances HBV transcription unknown\", \"Single method per direction\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Showed TAGLN2 is an LPS/NF-\\u03baB-induced effector required for macrophage phagocytosis and host defense, establishing an innate-immune role.\",\n      \"evidence\": \"TAGLN2 KO macrophages, opsonized-particle phagocytosis assays, PI3K/AKT and Ras-ERK pathway analysis, in vivo infection survival\",\n      \"pmids\": [\"28821818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TAGLN2 acts directly at the phagocytic cup or via signaling not separated\", \"Direct effectors linking TAGLN2 to PI3K/AKT not identified\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Resolved the biochemical mechanism of actin regulation (nucleation vs. Arp2/3 inhibition) and defined a therapeutically actionable TAGLN2-actin-LFA-1 immunotherapy axis.\",\n      \"evidence\": \"In vitro polymerization assays with domain mutants, Arp2/3 binding assay, filopodia imaging (29615809); Co-IP and cell-permeable TG2P with cytotoxicity/tumor models (30524895)\",\n      \"pmids\": [\"29615809\", \"30524895\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"High-resolution structure of TAGLN2-actin and TAGLN2-LFA-1 interfaces lacking\", \"How salt conditions translate to physiological switching unclear\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Embedded TAGLN2 in transcriptional networks and tumor signaling, showing both an in vivo developmental driver (klf6a) and a STAT3/ANXA2 oncogenic route.\",\n      \"evidence\": \"Zebrafish klf6a epistasis with EC rearrangement imaging (34319989); CRC gain/loss-of-function with STAT3 inhibitor rescue (34466149)\",\n      \"pmids\": [\"34319989\", \"34466149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct vs. indirect TAGLN2-STAT3 link not established\", \"Whether klf6a-tagln2 axis is conserved in mammals untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Diversified the partner/PTM repertoire, identifying K40 succinylation (TMSB4X), direct E-cadherin binding, and Rap1/PI3K/AKT-mediated invasion across angiogenesis, trophoblast, and thyroid contexts.\",\n      \"evidence\": \"MS-identified K40succ with mimetic mutants and TMSB4X co-localization (36131066); Co-IP+MST for E-cadherin with trophoblast assays (35281112); proteomics and Rap1/PI3K/AKT rescue in PTC (36222755)\",\n      \"pmids\": [\"36131066\", \"35281112\", \"36222755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Enzyme controlling K40 succinylation not identified\", \"Each partner shown by single lab without reciprocal cross-validation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Expanded TAGLN2 into a multi-pathway scaffold in cancer, binding ARPC5 (MEK/ERK), ERK1/2 (MGMT/TMZ resistance), and the AKT-YBX1 complex (cGAS-STING/ISG resistance).\",\n      \"evidence\": \"Co-IP/IF and ARPC5 epistasis with MEK inhibitor in pancreatic cancer (38744388); Co-IP/LC-MS/MS, ChIP-PCR and xenografts in GBM (38992489); Co-IP, ChIP and cGAS-STING readouts in gastric cancer (39168971)\",\n      \"pmids\": [\"38744388\", \"38992489\", \"39168971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether these interactions are direct or scaffolded via actin not dissected\", \"Context-specificity of partner selection unexplained\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Demonstrated TAGLN2 drives intercellular signaling (exosomal transfer, CXCR7/TGF-\\u03b2/Smad2) and inflammatory ANXA2/NF-\\u03baB injury, broadening it from cell-autonomous to niche-level functions.\",\n      \"evidence\": \"Exosome delivery, ChIP and Co-IP for NRP1-SEMA4D-YAP (41824788); Co-IP/IF and CXCR7 rescue with p-Smad2 readout (41169389); TAGLN2 KO AP-liver injury model (40472315)\",\n      \"pmids\": [\"41824788\", \"41169389\", \"40472315\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Mechanism of TAGLN2 sorting into exosomes unknown\", \"Stoichiometry and structure of NRP1-SEMA4D ternary complex undefined\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How TAGLN2 selects among its many signaling partners in a given cell type, and whether its scaffolding functions depend on or are separable from its actin-regulatory activity, remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unifying model connecting actin regulation to partner-specific signaling\", \"No structural data on the multiple interaction interfaces\", \"Endogenous physiological vs. pathological context of each axis not delineated\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2]},\n      {\"term_id\": \"GO:0060090\", \"supporting_discovery_ids\": [4, 14, 16]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [5, 16]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [5, 9]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"LFA-1\", \"E-cadherin\", \"ERK1/2\", \"ARPC5\", \"CXCR7\", \"NRP1\", \"SEMA4D\", \"YBX1\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"faith_supported":6,"faith_total":6,"faith_pct":100.0}}