{"gene":"TAGLN2","run_date":"2026-04-28T21:42:58","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, destabilized F-actin ring formation, decreased cell adhesion/spreading, and weakened cytokine production and cytotoxic effector function in T cells. TAGLN2 also enables LFA-1 activation following TCR stimulation.","method":"TAGLN2 knockout mice (TAGLN2-/-), in vitro actin depolymerization competition assays, live imaging, F-actin content measurement, cytokine/granzyme B assays","journal":"The Journal of cell biology","confidence":"High","confidence_rationale":"Tier 1-2 — multiple orthogonal methods including KO mice, in vitro reconstitution competition assay, and defined cellular phenotypes","pmids":["25869671"],"is_preprint":false},{"year":2018,"finding":"TAGLN2 nucleates G-actin polymerization under low ionic/salt conditions via its calponin homology domain and actin-binding loop, which mechanically connect two adjacent G-actins enabling multimeric interactions. Under physiological salt conditions, TAGLN2 blocks Arp2/3 complex binding to actin filaments, thereby inhibiting branched actin nucleation. In HeLa and T cells, TAGLN2 enhances filopodium-like membrane protrusion.","method":"In vitro actin polymerization assays under varying ionic conditions, domain mutagenesis (calponin homology domain and actin-binding loop), Arp2/3 complex binding assays, live cell imaging of filopodia","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 1 — in vitro reconstitution with mutagenesis, multiple orthogonal methods","pmids":["29615809"],"is_preprint":false},{"year":2011,"finding":"PFTK1 kinase phosphorylates TAGLN2 at serine residues S83 and S163, reducing TAGLN2's actin-binding affinity. Unphosphorylated TAGLN2 strongly binds actin and suppresses actin cytoskeleton dynamics and HCC cell motility. Knockdown of TAGLN2 in PFTK1-suppressed cells overrides the inhibitory effect on invasion/motility, placing TAGLN2 downstream of PFTK1 in an oncogene-tumor suppressor interplay.","method":"2D-PAGE mass spectrometry to identify phosphorylated substrates, site-directed mutagenesis of S83 and S163, actin binding assays, cell invasion/motility assays, genetic epistasis (double knockdown)","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1-2 — phosphoproteomic identification, site-directed mutagenesis, in vitro actin-binding assay, epistasis experiment","pmids":["21577206"],"is_preprint":false},{"year":2017,"finding":"TAGLN2 is required for phagocytosis in LPS-activated macrophages. TAGLN2 is induced by LPS via the NF-κB pathway. TAGLN2-deficient macrophages show defective phagocytosis of IgM- and IgG-coated sheep red blood cells and bacteria, with down-regulated PI3K/AKT and Ras-ERK signaling. TAGLN2-/- mice show higher mortality after bacterial infection.","method":"TAGLN2 knockout mice (TAGLN2-/-), phagocytosis assays (IgM/IgG-coated RBCs, bacteria), NF-κB pathway inhibition, in vivo bacterial infection survival","journal":"Scientific reports","confidence":"High","confidence_rationale":"Tier 2 — KO mice with defined phagocytic phenotype, multiple assay types, in vivo infection model","pmids":["28821818"],"is_preprint":false},{"year":2018,"finding":"TAGLN2 is physically associated with LFA-1 and potentiates inside-out costimulation via LFA-1, enhancing immunological synapse formation between cytotoxic T cells and tumor cells. Recombinant TAGLN2 fused with a protein transduction domain (TG2P) enhanced CAR-T cell killing of Raji B-lymphoma cells and reduced tumor growth in mice.","method":"Co-localization/association studies, OTI TCR CD8+ T cell killing assays, recombinant protein transduction, xenograft mouse model, CAR-T cell assay","journal":"Oncoimmunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — functional assays with defined mechanism (LFA-1 inside-out activation), but TAGLN2-LFA-1 physical interaction details limited","pmids":["30524895"],"is_preprint":false},{"year":2011,"finding":"TAGLN2 is a direct transcriptional target of miR-1 and miR-133a; both miRNAs bind the 3'-UTR of TAGLN2 mRNA and suppress its expression. Silencing of TAGLN2 inhibits bladder cancer cell proliferation and increases apoptosis.","method":"miRNA expression signature, luciferase reporter assay (3'-UTR), TAGLN2 siRNA knockdown, proliferation/apoptosis assays","journal":"British journal of cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — luciferase reporter confirms direct 3'-UTR targeting, functional knockdown phenotype","pmids":["21304530"],"is_preprint":false},{"year":2011,"finding":"TAGLN2 is a direct target of miR-1 in head and neck squamous cell carcinoma; miR-1 binds the TAGLN2 3'-UTR to suppress expression, and TAGLN2 silencing inhibits cell proliferation and invasion.","method":"miRNA target prediction, luciferase reporter assay, TAGLN2 siRNA knockdown, proliferation/invasion assays","journal":"Oncotarget","confidence":"Medium","confidence_rationale":"Tier 2-3 — luciferase reporter confirms 3'-UTR targeting; replicates TAGLN2-miR-1 finding across a different cancer type","pmids":["21378409"],"is_preprint":false},{"year":2014,"finding":"miR-133a directly binds the 3'-UTR of TAGLN2 mRNA and suppresses TAGLN2 at both transcriptional and translational levels. TAGLN2 knockout attenuates hypoxia-induced apoptosis in cardiomyocytes via modulation of the caspase-8 apoptotic pathway.","method":"Dual-luciferase reporter assay (3'-UTR of TAGLN2), TAGLN2 knockdown, caspase activity assays, Bcl-2/caspase western blots in H9c2 cells under hypoxia","journal":"Molecular and cellular biochemistry","confidence":"Medium","confidence_rationale":"Tier 2-3 — luciferase reporter confirms direct targeting, TAGLN2 KO with defined pathway (caspase-8)","pmids":["25421410"],"is_preprint":false},{"year":2022,"finding":"TAGLN2 binds directly to E-cadherin (confirmed by Co-IP and microscale thermophoresis). Reduced TAGLN2 expression decreases cleavage of the E-cadherin extracellular domain, impairing trophoblast migration, invasion, and fusion. In vivo, adenoviral overexpression of TAGLN2 in pregnant mice induced a PE-like syndrome with hypertension.","method":"Co-immunoprecipitation, microscale thermophoresis, TAGLN2 knockdown functional assays (migration, invasion, fusion), mouse adenoviral injection model","journal":"Frontiers in cell and developmental biology","confidence":"Medium","confidence_rationale":"Tier 2 — direct binding confirmed by two methods (Co-IP + MST), in vivo mouse model, but from a single lab","pmids":["35281112"],"is_preprint":false},{"year":2022,"finding":"TAGLN2 is succinylated at lysine-40 (K40) in glioma endothelial cells. A succinylation-mimetic mutant (K40E) promotes angiogenesis, actin cytoskeleton remodeling, and VE-cadherin expression in vitro and in vivo. TAGLN2 interacts with TMSB4X; K40 succinylation is required for this interaction (TAGLN2K40A abolishes binding). TMSB4X inhibition attenuates TAGLN2 K40succ-induced glioma proliferation and migration.","method":"TMT labeling, LC-MS/MS succinylation proteomics, succinylation-mimetic (K40E) and loss (K40R/K40A) mutagenesis, in vitro angiogenesis assays, xenograft model, immunofluorescence co-localization of TMSB4X-TAGLN2","journal":"Cancer gene therapy","confidence":"Medium","confidence_rationale":"Tier 1-2 — PTM identified by MS, mutagenesis validates functional role, interaction with TMSB4X confirmed by co-localization; single lab","pmids":["36131066"],"is_preprint":false},{"year":2024,"finding":"TAGLN2 interacts with ERK1/2 (confirmed by Co-IP and LC-MS/MS). TAGLN2 knockdown decreases nuclear p-ERK1/2 and MGMT expression, increasing TMZ sensitivity in GBM. TAGLN2 overexpression increases p-ERK1/2 in the nucleus and MGMT levels, conferring TMZ resistance. NF-κB transcriptionally regulates TAGLN2 expression (validated by ChIP-PCR).","method":"Co-immunoprecipitation, LC-MS/MS, TAGLN2 KD/OE in GBM cells, western blot for p-ERK1/2/MGMT, intracranial xenograft, ChIP-PCR for NF-κB at TAGLN2 promoter","journal":"Cancer letters","confidence":"Medium","confidence_rationale":"Tier 2 — physical interaction confirmed by Co-IP/MS, ChIP-PCR for upstream regulation, in vivo xenograft; single lab","pmids":["38992489"],"is_preprint":false},{"year":2021,"finding":"TAGLN2 promotes colorectal cancer cell proliferation, invasion, migration and EMT by activating STAT3 phosphorylation through ANXA2. TAGLN2 knockdown suppresses STAT3 phosphorylation, and the effects of TAGLN2 overexpression are reversed by STAT3 inhibitors. ANXA2 expression is positively associated with STAT3.","method":"TAGLN2 shRNA knockdown and overexpression in CRC cells, STAT3 inhibitor rescue experiments, western blot for p-STAT3/EMT markers, proliferation/migration/invasion assays","journal":"Oncology letters","confidence":"Medium","confidence_rationale":"Tier 2-3 — KD/OE with pathway inhibitor rescue; ANXA2-STAT3 link correlational; single lab","pmids":["34466149"],"is_preprint":false},{"year":2016,"finding":"TAGLN2 positively regulates HBV transcription and replication in vitro: ectopic TAGLN2 expression enhances HBV transcription and replication, while TAGLN2 knockdown has the contrary effect. HBx protein induces TAGLN2 expression in a dose-dependent manner.","method":"Ectopic TAGLN2 expression and knockdown in HepG2 and HepG2.2.15 cells, Tet-on HBx cell line for dose-dependent induction, qRT-PCR for HBV transcripts","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2-3 — gain/loss-of-function in relevant cell lines, mechanistically defined (HBx→TAGLN2→HBV replication); single lab","pmids":["27402267"],"is_preprint":false},{"year":2021,"finding":"In zebrafish, tagln2 is a direct downstream target of the transcription factor klf6a in caudal vein pruning. The klf6a-tagln2 axis regulates endothelial cell rearrangement (nucleus migration, junction remodeling) and actin cytoskeleton dynamics during vessel pruning driven by blood flow.","method":"Zebrafish transgenic models, klf6a loss-of-function, tagln2 rescue experiments, live imaging of EC rearrangement and actin dynamics","journal":"PLoS genetics","confidence":"Medium","confidence_rationale":"Tier 2 — genetic epistasis in zebrafish ortholog, live imaging with functional readout; single lab","pmids":["34319989"],"is_preprint":false},{"year":2024,"finding":"TAGLN2 upregulates resistance-signature interferon-stimulated genes (ISGs) by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to the YBX1 promoter and by directly interacting with AKT-YBX1, enhancing YBX1 phosphorylation and nuclear translocation. Fisetin or MK2206 disrupts the TAGLN2-YBX1-AKT interaction and reduces ISG upregulation and therapy resistance.","method":"Co-IP for TAGLN2-AKT-YBX1 interaction, ChIP for c-Myc/SOX9 at YBX1 promoter, cGAS-STING pathway assays, ssDNA aggregation assays, pharmacological inhibitors (Fisetin, MK2206), xenograft models","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 — multiple interaction assays (Co-IP, ChIP), pharmacological rescue; single lab with several orthogonal methods","pmids":["39168971"],"is_preprint":false},{"year":2024,"finding":"TAGLN2 directly binds ARPC5 (confirmed by Co-IP), positively regulating ARPC5 expression and activating the MEK/ERK signaling pathway to promote pancreatic cancer cell proliferation, invasion, and metastasis. Silencing ARPC5 reverses the pro-tumorigenic effects of TAGLN2 overexpression.","method":"Co-immunoprecipitation, immunofluorescence, TAGLN2 KD/OE in PANC-1 and SW1990 cells, ARPC5 knockdown rescue, MEK inhibitor (U0126), in vivo xenograft","journal":"Cellular signalling","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP confirms physical interaction, epistasis rescue experiment, in vivo validation; single lab","pmids":["38744388"],"is_preprint":false},{"year":2025,"finding":"TAGLN2 promotes the ANXA2/NF-κB axis activation in Kupffer cells, contributing to inflammatory cytokine production and hepatocyte pyroptosis in acute pancreatitis-induced liver injury. TAGLN2 knockout reduces pyroptosis-related protein expression and liver dysfunction markers.","method":"TAGLN2 knockout mice, cerulein AP model, LPS-stimulated Kupffer cells in vitro, western blot for ANXA2/NF-κB/pyroptosis proteins, inflammatory cytokine measurement","journal":"Archivum immunologiae et therapiae experimentalis","confidence":"Medium","confidence_rationale":"Tier 2 — KO mice plus in vitro mechanistic dissection of ANXA2/NF-κB; single lab","pmids":["40472315"],"is_preprint":false},{"year":2022,"finding":"TAGLN2 promotes papillary thyroid carcinoma invasion via the Rap1/PI3K/AKT signaling pathway. Quantitative proteomics and gene expression profiling identified ITGB5, LAMC2, CRKL, and EMT markers as downstream molecules. Rescue experiments validated Rap1/PI3K/AKT pathway involvement in TAGLN2-mediated invasion.","method":"TAGLN2 KD/OE in PTC cell lines, gene expression profiling, quantitative proteomics, western blot for Rap1/PI3K/AKT, rescue experiments with pathway inhibitors, invasion/migration assays","journal":"Endocrine-related cancer","confidence":"Medium","confidence_rationale":"Tier 2-3 — proteomics plus rescue experiments; pathway assignment from multiple approaches; single lab","pmids":["36222755"],"is_preprint":false},{"year":2025,"finding":"CXCR7 physically interacts with TAGLN2 in PTC cells (confirmed by Co-IP and immunofluorescence co-localization). TAGLN2 knockdown reduces p-Smad2 levels (suppressing TGF-β/Smad2 signaling), and CXCR7 re-introduction into TAGLN2-silenced cells restores p-Smad2 levels, indicating CXCR7 promotes PTC invasion/metastasis through TAGLN2 via TGF-β/Smad2 signaling.","method":"Co-immunoprecipitation, immunofluorescence colocalization, TAGLN2 knockdown/CXCR7 overexpression, western blot for p-Smad2","journal":"Frontiers in immunology","confidence":"Medium","confidence_rationale":"Tier 2-3 — Co-IP confirms physical interaction, rescue experiment places CXCR7 upstream of TAGLN2 in TGF-β/Smad2 signaling; single lab","pmids":["41169389"],"is_preprint":false},{"year":2026,"finding":"Tumor-derived exosomal TAGLN2 delivered to endothelial cells transcriptionally upregulates NRP1 via c-Jun/SP1, induces SEMA4D expression, and forms a stable cytoplasmic ternary complex with NRP1 and SEMA4D that activates YAP by disrupting NRP1-YAP cytoplasmic retention and suppressing Hippo-mediated YAP degradation, independently of the canonical SEMA4D-PlexinB1-RhoA/ROCK pathway, thereby promoting angiogenesis, EndoMT, vascular permeability, and gastric cancer metastasis.","method":"Exosome isolation and delivery assays, Co-IP for ternary complex, ChIP for c-Jun/SP1 at NRP1 promoter, YAP localization assays, in vivo tumor xenograft, mechanistic rescue with pathway inhibitors","journal":"Advanced science","confidence":"Medium","confidence_rationale":"Tier 2 — multiple molecular interaction assays (Co-IP, ChIP) and in vivo validation; novel axis; single lab","pmids":["41824788"],"is_preprint":false},{"year":2018,"finding":"miR-145-5p directly targets TAGLN2 (validated by luciferase assay); high TAGLN2 expression promotes bladder cancer cell proliferation and migration.","method":"Luciferase reporter assay (3'-UTR), miR-145-5p overexpression, TAGLN2 knockdown, proliferation/migration assays","journal":"Oncology letters","confidence":"Low","confidence_rationale":"Tier 3 — luciferase reporter plus functional KD; replicates miRNA-targeting finding; single lab, limited mechanistic depth","pmids":["30405771"],"is_preprint":false},{"year":2022,"finding":"TAGLN2 co-localizes with F-actin in ovarian cancer cells; TAGLN2 knockdown impairs cytoskeletal organization and reduces cell proliferation and migration.","method":"Immunofluorescence for F-actin co-localization, siRNA knockdown, colony formation, wound healing assays","journal":"Applied immunohistochemistry & molecular morphology","confidence":"Low","confidence_rationale":"Tier 3 — localization by immunofluorescence with partial functional consequence; single lab, limited mechanistic depth","pmids":["40247723"],"is_preprint":false}],"current_model":"TAGLN2 is a 22-kDa actin-binding protein that stabilizes F-actin by competing with cofilin and inhibiting Arp2/3-mediated branched actin nucleation, while also nucleating G-actin polymerization under low ionic conditions via its calponin homology domain; it regulates T cell immunological synapse formation, macrophage phagocytosis, trophoblast function, and tumor cell motility/invasion through multiple signaling axes including PFTK1-mediated phosphorylation at S83/S163 (which attenuates its actin-binding activity), ANXA2/STAT3, Rap1/PI3K/AKT, ERK1/2/MGMT, and AKT-YBX1-cGAS-STING, and is transcriptionally regulated by NF-κB and post-translationally modified by succinylation at K40, which modulates its interactions and pro-tumorigenic functions."},"narrative":{"teleology":[{"year":2011,"claim":"PFTK1-mediated phosphorylation at S83/S163 was identified as a mechanism that attenuates TAGLN2 actin-binding activity, establishing that post-translational modification directly regulates the cytoskeletal suppressor function of TAGLN2 and linking it to tumor cell motility control.","evidence":"2D-PAGE/MS phosphosubstrate identification, site-directed mutagenesis, actin-binding assays, and genetic epistasis in HCC cells","pmids":["21577206"],"confidence":"High","gaps":["Kinases other than PFTK1 that phosphorylate these sites are uncharacterized","Structural basis for how S83/S163 phosphorylation disrupts actin binding is unresolved"]},{"year":2011,"claim":"TAGLN2 was established as a direct target of miR-1 and miR-133a, with functional knockdown showing that TAGLN2 promotes proliferation and suppresses apoptosis in cancer cells, providing the first post-transcriptional regulatory axis for TAGLN2.","evidence":"Luciferase 3′-UTR reporter assays and siRNA knockdown in bladder and head-and-neck squamous cell carcinoma lines","pmids":["21304530","21378409"],"confidence":"Medium","gaps":["How miR-1/miR-133a regulation of TAGLN2 integrates with its actin-binding function was not addressed","In vivo confirmation of miRNA-mediated TAGLN2 regulation is lacking"]},{"year":2015,"claim":"Knockout studies resolved a long-standing question about how T cells maintain F-actin at the immunological synapse: TAGLN2 stabilizes cortical F-actin by competing with cofilin and is required for LFA-1 activation, cytokine secretion, and cytotoxic function.","evidence":"TAGLN2-knockout mice, in vitro cofilin competition assays, live imaging, and cytokine/granzyme B functional assays","pmids":["25869671"],"confidence":"High","gaps":["Whether TAGLN2 directly binds LFA-1 or acts through an intermediate remains incompletely defined","Regulation of TAGLN2 expression or activity during TCR signaling is not established"]},{"year":2017,"claim":"TAGLN2 was shown to be essential for macrophage phagocytosis and in vivo antibacterial defense, with NF-κB identified as the transcriptional inducer downstream of LPS, broadening TAGLN2's immune function beyond T cells.","evidence":"TAGLN2-knockout mice, phagocytosis of opsonized particles, NF-κB pathway inhibition, and in vivo bacterial infection survival","pmids":["28821818"],"confidence":"High","gaps":["The precise actin-remodeling step TAGLN2 controls during phagosome formation is undefined","Whether TAGLN2 acts identically in other myeloid cell types is untested"]},{"year":2018,"claim":"Reconstitution experiments defined TAGLN2's dual biochemical activities: G-actin nucleation via the calponin homology domain under low-salt conditions, and inhibition of Arp2/3-mediated branched nucleation under physiological conditions, explaining how TAGLN2 shifts the balance from branched to linear actin networks.","evidence":"In vitro actin polymerization assays with domain mutagenesis and Arp2/3 binding assays, live cell filopodia imaging","pmids":["29615809"],"confidence":"High","gaps":["Whether ionic-strength-dependent nucleation is physiologically relevant inside cells is unclear","A high-resolution structural model of the TAGLN2–actin interface is absent"]},{"year":2018,"claim":"TAGLN2 was shown to associate with LFA-1 and potentiate inside-out costimulation, with exogenous TAGLN2 delivery enhancing CAR-T cell cytotoxicity in vitro and in xenograft models, providing translational proof-of-concept.","evidence":"Co-localization studies, recombinant protein transduction domain fusion, OTI CD8+ T cell killing assays, and xenograft model","pmids":["30524895"],"confidence":"Medium","gaps":["Biochemical details of the TAGLN2–LFA-1 interaction (direct vs. indirect, binding site) are not defined","Long-term safety and efficacy of exogenous TAGLN2 delivery in vivo are unknown"]},{"year":2021,"claim":"Zebrafish studies placed tagln2 downstream of the transcription factor klf6a in blood-flow-driven vessel pruning, establishing a developmental role in endothelial cell rearrangement and actin remodeling beyond immune cells.","evidence":"Zebrafish klf6a loss-of-function with tagln2 rescue, live imaging of endothelial cell migration and junction remodeling","pmids":["34319989"],"confidence":"Medium","gaps":["Whether the klf6a-TAGLN2 axis is conserved in mammalian vascular pruning is untested","Molecular targets of TAGLN2 in endothelial junction remodeling are unidentified"]},{"year":2021,"claim":"TAGLN2 was linked to STAT3 activation through ANXA2 in colorectal cancer, establishing ANXA2 as a functional partner through which TAGLN2 promotes EMT and invasion.","evidence":"TAGLN2 knockdown/overexpression with STAT3 inhibitor rescue in CRC cell lines","pmids":["34466149"],"confidence":"Medium","gaps":["Direct physical interaction between TAGLN2 and ANXA2 was not demonstrated by reciprocal methods","Whether TAGLN2-ANXA2 interaction is cytoskeleton-dependent is unknown"]},{"year":2022,"claim":"Succinylation at K40 was identified as a functionally critical post-translational modification that governs TAGLN2's interaction with TMSB4X and promotes angiogenesis in glioma, adding a second regulatory PTM to the phosphorylation already known.","evidence":"LC-MS/MS succinylation proteomics, succinylation-mimetic and loss-of-function mutagenesis, angiogenesis assays, xenograft model","pmids":["36131066"],"confidence":"Medium","gaps":["The enzyme(s) catalyzing K40 succinylation are unidentified","How K40 succinylation affects TAGLN2's actin-binding or cofilin-competing activities is untested"]},{"year":2022,"claim":"TAGLN2 was shown to directly bind E-cadherin and regulate its extracellular domain cleavage, controlling trophoblast migration/fusion, while in vivo overexpression induced a preeclampsia-like syndrome—connecting TAGLN2 to placental biology.","evidence":"Co-IP and microscale thermophoresis for direct binding, functional assays in trophoblasts, adenoviral overexpression in pregnant mice","pmids":["35281112"],"confidence":"Medium","gaps":["The mechanism by which TAGLN2 promotes E-cadherin cleavage (protease recruitment vs. conformational change) is unknown","Findings are from a single lab and await independent confirmation"]},{"year":2024,"claim":"TAGLN2 was found to interact with ERK1/2 and promote its nuclear translocation, upregulating MGMT to confer temozolomide resistance in GBM, while NF-κB was validated as a direct transcriptional activator of TAGLN2 by ChIP-PCR.","evidence":"Co-IP/LC-MS/MS for ERK1/2 interaction, ChIP-PCR for NF-κB at TAGLN2 promoter, intracranial xenograft","pmids":["38992489"],"confidence":"Medium","gaps":["Whether TAGLN2 acts as a scaffold for ERK1/2 nuclear import or modulates upstream kinase activity is unclear","Generalizability of NF-κB–TAGLN2–MGMT axis beyond GBM is untested"]},{"year":2024,"claim":"TAGLN2 was shown to drive therapy resistance by forming a complex with AKT and YBX1, promoting YBX1 phosphorylation and nuclear translocation, which activates cGAS-STING and upregulates interferon-stimulated genes.","evidence":"Co-IP for TAGLN2-AKT-YBX1, ChIP for c-Myc/SOX9 at YBX1 promoter, cGAS-STING pathway assays, pharmacological disruption with Fisetin/MK2206, xenograft","pmids":["39168971"],"confidence":"Medium","gaps":["Stoichiometry and structural basis of the TAGLN2-AKT-YBX1 ternary complex are undefined","Relationship between TAGLN2's actin-binding and its AKT-YBX1 scaffolding functions is unknown"]},{"year":2025,"claim":"Exosomal TAGLN2 was found to activate a non-canonical angiogenic pathway by forming a cytoplasmic NRP1-SEMA4D-YAP ternary complex in endothelial cells, establishing an intercellular signaling role for TAGLN2 independent of its intracellular actin-binding function.","evidence":"Exosome isolation, Co-IP for ternary complex, ChIP for c-Jun/SP1 at NRP1 promoter, YAP localization assays, xenograft model","pmids":["41824788"],"confidence":"Medium","gaps":["How TAGLN2 in exosomes retains bioactivity after uptake is unclear","Whether other exosomal cargo cooperates with TAGLN2 in this axis is unknown","Findings from a single lab"]},{"year":null,"claim":"A unifying structural and regulatory model explaining how TAGLN2's actin-binding, scaffolding, and exosomal functions are coordinated—and how its multiple PTMs (phosphorylation, succinylation) and transcriptional inputs (NF-κB, KLF6, miRNAs) are integrated—remains to be established.","evidence":"","pmids":[],"confidence":"Low","gaps":["No high-resolution structure of TAGLN2 bound to actin or any partner exists","The relationship between cytoskeletal and signaling-scaffold functions is mechanistically unexplained","In vivo genetic models for most cancer-associated TAGLN2 axes are lacking"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,1,2,21]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[0,1,15]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,1,21]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[0,1]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[0,4]}],"pathway":[{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[0,3,4]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[10,11,14,17]}],"complexes":[],"partners":["ACTA1","CFL1","ARPC5","TMSB4X","ERK1","ERK2","ANXA2","YBX1"],"other_free_text":[]},"mechanistic_narrative":"TAGLN2 is an actin-binding protein that controls cytoskeletal dynamics in immune cells, endothelial cells, and epithelial contexts by stabilizing F-actin through competition with cofilin, inhibiting Arp2/3-mediated branched actin nucleation, and nucleating linear actin polymerization via its calponin homology domain [PMID:25869671, PMID:29615809]. In T cells, TAGLN2 is essential for immunological synapse formation, LFA-1 activation, cytokine production, and cytotoxic effector function, while in macrophages it is NF-κB-induced and required for phagocytosis of opsonized particles and bacterial clearance in vivo [PMID:25869671, PMID:28821818, PMID:30524895]. PFTK1-mediated phosphorylation at S83 and S163 attenuates TAGLN2 actin-binding activity and relieves its suppression of cell motility, and succinylation at K40 modulates its interaction with TMSB4X to promote angiogenesis and glioma progression [PMID:21577206, PMID:36131066]. In diverse tumor contexts, TAGLN2 drives invasion and therapy resistance through ERK1/2–MGMT, ANXA2–STAT3, Rap1–PI3K–AKT, and AKT–YBX1–cGAS-STING signaling axes, and tumor-derived exosomal TAGLN2 promotes angiogenesis via a NRP1–SEMA4D–YAP ternary complex [PMID:38992489, PMID:34466149, PMID:36222755, PMID:39168971, PMID:41824788]."},"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":246,"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":154,"is_preprint":false},{"pmid":"7788527","id":"PMC_7788527","title":"Prediction of the coding sequences of unidentified human genes. III. 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vitro and in vivo. TAGLN2 knockout reduced F-actin content, destabilized F-actin ring formation, decreased cell adhesion/spreading, and weakened cytokine production and cytotoxic effector function in T cells. TAGLN2 also enables LFA-1 activation following TCR stimulation.\",\n      \"method\": \"TAGLN2 knockout mice (TAGLN2-/-), in vitro actin depolymerization competition assays, live imaging, F-actin content measurement, cytokine/granzyme B assays\",\n      \"journal\": \"The Journal of cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — multiple orthogonal methods including KO mice, in vitro reconstitution competition assay, and defined cellular phenotypes\",\n      \"pmids\": [\"25869671\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"TAGLN2 nucleates G-actin polymerization under low ionic/salt conditions via its calponin homology domain and actin-binding loop, which mechanically connect two adjacent G-actins enabling multimeric interactions. Under physiological salt conditions, TAGLN2 blocks Arp2/3 complex binding to actin filaments, thereby inhibiting branched actin nucleation. In HeLa and T cells, TAGLN2 enhances filopodium-like membrane protrusion.\",\n      \"method\": \"In vitro actin polymerization assays under varying ionic conditions, domain mutagenesis (calponin homology domain and actin-binding loop), Arp2/3 complex binding assays, live cell imaging of filopodia\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 — in vitro reconstitution with mutagenesis, 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 TAGLN2's actin-binding affinity. Unphosphorylated TAGLN2 strongly binds actin and suppresses actin cytoskeleton dynamics and HCC cell motility. Knockdown of TAGLN2 in PFTK1-suppressed cells overrides the inhibitory effect on invasion/motility, placing TAGLN2 downstream of PFTK1 in an oncogene-tumor suppressor interplay.\",\n      \"method\": \"2D-PAGE mass spectrometry to identify phosphorylated substrates, site-directed mutagenesis of S83 and S163, actin binding assays, cell invasion/motility assays, genetic epistasis (double knockdown)\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1-2 — phosphoproteomic identification, site-directed mutagenesis, in vitro actin-binding assay, epistasis experiment\",\n      \"pmids\": [\"21577206\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"TAGLN2 is required for phagocytosis in LPS-activated macrophages. TAGLN2 is induced by LPS via the NF-κB pathway. TAGLN2-deficient macrophages show defective phagocytosis of IgM- and IgG-coated sheep red blood cells and bacteria, with down-regulated PI3K/AKT and Ras-ERK signaling. TAGLN2-/- mice show higher mortality after bacterial infection.\",\n      \"method\": \"TAGLN2 knockout mice (TAGLN2-/-), phagocytosis assays (IgM/IgG-coated RBCs, bacteria), NF-κB pathway inhibition, in vivo bacterial infection survival\",\n      \"journal\": \"Scientific reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 — KO mice with defined phagocytic phenotype, multiple assay types, in vivo infection model\",\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 costimulation via LFA-1, enhancing immunological synapse formation between cytotoxic T cells and tumor cells. Recombinant TAGLN2 fused with a protein transduction domain (TG2P) enhanced CAR-T cell killing of Raji B-lymphoma cells and reduced tumor growth in mice.\",\n      \"method\": \"Co-localization/association studies, OTI TCR CD8+ T cell killing assays, recombinant protein transduction, xenograft mouse model, CAR-T cell assay\",\n      \"journal\": \"Oncoimmunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — functional assays with defined mechanism (LFA-1 inside-out activation), but TAGLN2-LFA-1 physical interaction details limited\",\n      \"pmids\": [\"30524895\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TAGLN2 is a direct transcriptional target of miR-1 and miR-133a; both miRNAs bind the 3'-UTR of TAGLN2 mRNA and suppress its expression. Silencing of TAGLN2 inhibits bladder cancer cell proliferation and increases apoptosis.\",\n      \"method\": \"miRNA expression signature, luciferase reporter assay (3'-UTR), TAGLN2 siRNA knockdown, proliferation/apoptosis assays\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — luciferase reporter confirms direct 3'-UTR targeting, functional knockdown phenotype\",\n      \"pmids\": [\"21304530\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"TAGLN2 is a direct target of miR-1 in head and neck squamous cell carcinoma; miR-1 binds the TAGLN2 3'-UTR to suppress expression, and TAGLN2 silencing inhibits cell proliferation and invasion.\",\n      \"method\": \"miRNA target prediction, luciferase reporter assay, TAGLN2 siRNA knockdown, proliferation/invasion assays\",\n      \"journal\": \"Oncotarget\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — luciferase reporter confirms 3'-UTR targeting; replicates TAGLN2-miR-1 finding across a different cancer type\",\n      \"pmids\": [\"21378409\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2014,\n      \"finding\": \"miR-133a directly binds the 3'-UTR of TAGLN2 mRNA and suppresses TAGLN2 at both transcriptional and translational levels. TAGLN2 knockout attenuates hypoxia-induced apoptosis in cardiomyocytes via modulation of the caspase-8 apoptotic pathway.\",\n      \"method\": \"Dual-luciferase reporter assay (3'-UTR of TAGLN2), TAGLN2 knockdown, caspase activity assays, Bcl-2/caspase western blots in H9c2 cells under hypoxia\",\n      \"journal\": \"Molecular and cellular biochemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — luciferase reporter confirms direct targeting, TAGLN2 KO with defined pathway (caspase-8)\",\n      \"pmids\": [\"25421410\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAGLN2 binds directly to E-cadherin (confirmed by Co-IP and microscale thermophoresis). Reduced TAGLN2 expression decreases cleavage of the E-cadherin extracellular domain, impairing trophoblast migration, invasion, and fusion. In vivo, adenoviral overexpression of TAGLN2 in pregnant mice induced a PE-like syndrome with hypertension.\",\n      \"method\": \"Co-immunoprecipitation, microscale thermophoresis, TAGLN2 knockdown functional assays (migration, invasion, fusion), mouse adenoviral injection model\",\n      \"journal\": \"Frontiers in cell and developmental biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — direct binding confirmed by two methods (Co-IP + MST), in vivo mouse model, but from a single lab\",\n      \"pmids\": [\"35281112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAGLN2 is succinylated at lysine-40 (K40) in glioma endothelial cells. A succinylation-mimetic mutant (K40E) promotes angiogenesis, actin cytoskeleton remodeling, and VE-cadherin expression in vitro and in vivo. TAGLN2 interacts with TMSB4X; K40 succinylation is required for this interaction (TAGLN2K40A abolishes binding). TMSB4X inhibition attenuates TAGLN2 K40succ-induced glioma proliferation and migration.\",\n      \"method\": \"TMT labeling, LC-MS/MS succinylation proteomics, succinylation-mimetic (K40E) and loss (K40R/K40A) mutagenesis, in vitro angiogenesis assays, xenograft model, immunofluorescence co-localization of TMSB4X-TAGLN2\",\n      \"journal\": \"Cancer gene therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1-2 — PTM identified by MS, mutagenesis validates functional role, interaction with TMSB4X confirmed by co-localization; single lab\",\n      \"pmids\": [\"36131066\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAGLN2 interacts with ERK1/2 (confirmed by Co-IP and LC-MS/MS). TAGLN2 knockdown decreases nuclear p-ERK1/2 and MGMT expression, increasing TMZ sensitivity in GBM. TAGLN2 overexpression increases p-ERK1/2 in the nucleus and MGMT levels, conferring TMZ resistance. NF-κB transcriptionally regulates TAGLN2 expression (validated by ChIP-PCR).\",\n      \"method\": \"Co-immunoprecipitation, LC-MS/MS, TAGLN2 KD/OE in GBM cells, western blot for p-ERK1/2/MGMT, intracranial xenograft, ChIP-PCR for NF-κB at TAGLN2 promoter\",\n      \"journal\": \"Cancer letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — physical interaction confirmed by Co-IP/MS, ChIP-PCR for upstream regulation, in vivo xenograft; single lab\",\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 phosphorylation through ANXA2. TAGLN2 knockdown suppresses STAT3 phosphorylation, and the effects of TAGLN2 overexpression are reversed by STAT3 inhibitors. ANXA2 expression is positively associated with STAT3.\",\n      \"method\": \"TAGLN2 shRNA knockdown and overexpression in CRC cells, STAT3 inhibitor rescue experiments, western blot for p-STAT3/EMT markers, proliferation/migration/invasion assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — KD/OE with pathway inhibitor rescue; ANXA2-STAT3 link correlational; single lab\",\n      \"pmids\": [\"34466149\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"TAGLN2 positively regulates HBV transcription and replication in vitro: ectopic TAGLN2 expression enhances HBV transcription and replication, while TAGLN2 knockdown has the contrary effect. HBx protein induces TAGLN2 expression in a dose-dependent manner.\",\n      \"method\": \"Ectopic TAGLN2 expression and knockdown in HepG2 and HepG2.2.15 cells, Tet-on HBx cell line for dose-dependent induction, qRT-PCR for HBV transcripts\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — gain/loss-of-function in relevant cell lines, mechanistically defined (HBx→TAGLN2→HBV replication); single lab\",\n      \"pmids\": [\"27402267\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"In zebrafish, tagln2 is a direct downstream target of the transcription factor klf6a in caudal vein pruning. The klf6a-tagln2 axis regulates endothelial cell rearrangement (nucleus migration, junction remodeling) and actin cytoskeleton dynamics during vessel pruning driven by blood flow.\",\n      \"method\": \"Zebrafish transgenic models, klf6a loss-of-function, tagln2 rescue experiments, live imaging of EC rearrangement and actin dynamics\",\n      \"journal\": \"PLoS genetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — genetic epistasis in zebrafish ortholog, live imaging with functional readout; single lab\",\n      \"pmids\": [\"34319989\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAGLN2 upregulates resistance-signature interferon-stimulated genes (ISGs) by enhancing YBX1-associated ssDNA aggregation and cGAS-STING pathway activation. TAGLN2 modulates YBX1 by recruiting c-Myc and SOX9 to the YBX1 promoter and by directly interacting with AKT-YBX1, enhancing YBX1 phosphorylation and nuclear translocation. Fisetin or MK2206 disrupts the TAGLN2-YBX1-AKT interaction and reduces ISG upregulation and therapy resistance.\",\n      \"method\": \"Co-IP for TAGLN2-AKT-YBX1 interaction, ChIP for c-Myc/SOX9 at YBX1 promoter, cGAS-STING pathway assays, ssDNA aggregation assays, pharmacological inhibitors (Fisetin, MK2206), xenograft models\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple interaction assays (Co-IP, ChIP), pharmacological rescue; single lab with several orthogonal methods\",\n      \"pmids\": [\"39168971\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"TAGLN2 directly binds ARPC5 (confirmed by Co-IP), positively regulating ARPC5 expression and activating the MEK/ERK signaling pathway to promote pancreatic cancer cell proliferation, invasion, and metastasis. Silencing ARPC5 reverses the pro-tumorigenic effects of TAGLN2 overexpression.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence, TAGLN2 KD/OE in PANC-1 and SW1990 cells, ARPC5 knockdown rescue, MEK inhibitor (U0126), in vivo xenograft\",\n      \"journal\": \"Cellular signalling\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP confirms physical interaction, epistasis rescue experiment, in vivo validation; single lab\",\n      \"pmids\": [\"38744388\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAGLN2 promotes the ANXA2/NF-κB axis activation in Kupffer cells, contributing to inflammatory cytokine production and hepatocyte pyroptosis in acute pancreatitis-induced liver injury. TAGLN2 knockout reduces pyroptosis-related protein expression and liver dysfunction markers.\",\n      \"method\": \"TAGLN2 knockout mice, cerulein AP model, LPS-stimulated Kupffer cells in vitro, western blot for ANXA2/NF-κB/pyroptosis proteins, inflammatory cytokine measurement\",\n      \"journal\": \"Archivum immunologiae et therapiae experimentalis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — KO mice plus in vitro mechanistic dissection of ANXA2/NF-κB; single lab\",\n      \"pmids\": [\"40472315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAGLN2 promotes papillary thyroid carcinoma invasion via the Rap1/PI3K/AKT signaling pathway. Quantitative proteomics and gene expression profiling identified ITGB5, LAMC2, CRKL, and EMT markers as downstream molecules. Rescue experiments validated Rap1/PI3K/AKT pathway involvement in TAGLN2-mediated invasion.\",\n      \"method\": \"TAGLN2 KD/OE in PTC cell lines, gene expression profiling, quantitative proteomics, western blot for Rap1/PI3K/AKT, rescue experiments with pathway inhibitors, invasion/migration assays\",\n      \"journal\": \"Endocrine-related cancer\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — proteomics plus rescue experiments; pathway assignment from multiple approaches; single lab\",\n      \"pmids\": [\"36222755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"CXCR7 physically interacts with TAGLN2 in PTC cells (confirmed by Co-IP and immunofluorescence co-localization). TAGLN2 knockdown reduces p-Smad2 levels (suppressing TGF-β/Smad2 signaling), and CXCR7 re-introduction into TAGLN2-silenced cells restores p-Smad2 levels, indicating CXCR7 promotes PTC invasion/metastasis through TAGLN2 via TGF-β/Smad2 signaling.\",\n      \"method\": \"Co-immunoprecipitation, immunofluorescence colocalization, TAGLN2 knockdown/CXCR7 overexpression, western blot for p-Smad2\",\n      \"journal\": \"Frontiers in immunology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2-3 — Co-IP confirms physical interaction, rescue experiment places CXCR7 upstream of TAGLN2 in TGF-β/Smad2 signaling; single lab\",\n      \"pmids\": [\"41169389\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2026,\n      \"finding\": \"Tumor-derived exosomal TAGLN2 delivered to endothelial cells transcriptionally upregulates NRP1 via c-Jun/SP1, induces SEMA4D expression, and forms a stable cytoplasmic ternary complex with NRP1 and SEMA4D that activates YAP by disrupting NRP1-YAP cytoplasmic retention and suppressing Hippo-mediated YAP degradation, independently of the canonical SEMA4D-PlexinB1-RhoA/ROCK pathway, thereby promoting angiogenesis, EndoMT, vascular permeability, and gastric cancer metastasis.\",\n      \"method\": \"Exosome isolation and delivery assays, Co-IP for ternary complex, ChIP for c-Jun/SP1 at NRP1 promoter, YAP localization assays, in vivo tumor xenograft, mechanistic rescue with pathway inhibitors\",\n      \"journal\": \"Advanced science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 — multiple molecular interaction assays (Co-IP, ChIP) and in vivo validation; novel axis; single lab\",\n      \"pmids\": [\"41824788\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2018,\n      \"finding\": \"miR-145-5p directly targets TAGLN2 (validated by luciferase assay); high TAGLN2 expression promotes bladder cancer cell proliferation and migration.\",\n      \"method\": \"Luciferase reporter assay (3'-UTR), miR-145-5p overexpression, TAGLN2 knockdown, proliferation/migration assays\",\n      \"journal\": \"Oncology letters\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — luciferase reporter plus functional KD; replicates miRNA-targeting finding; single lab, limited mechanistic depth\",\n      \"pmids\": [\"30405771\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"TAGLN2 co-localizes with F-actin in ovarian cancer cells; TAGLN2 knockdown impairs cytoskeletal organization and reduces cell proliferation and migration.\",\n      \"method\": \"Immunofluorescence for F-actin co-localization, siRNA knockdown, colony formation, wound healing assays\",\n      \"journal\": \"Applied immunohistochemistry & molecular morphology\",\n      \"confidence\": \"Low\",\n      \"confidence_rationale\": \"Tier 3 — localization by immunofluorescence with partial functional consequence; single lab, limited mechanistic depth\",\n      \"pmids\": [\"40247723\"],\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 and inhibiting Arp2/3-mediated branched actin nucleation, while also nucleating G-actin polymerization under low ionic conditions via its calponin homology domain; it regulates T cell immunological synapse formation, macrophage phagocytosis, trophoblast function, and tumor cell motility/invasion through multiple signaling axes including PFTK1-mediated phosphorylation at S83/S163 (which attenuates its actin-binding activity), ANXA2/STAT3, Rap1/PI3K/AKT, ERK1/2/MGMT, and AKT-YBX1-cGAS-STING, and is transcriptionally regulated by NF-κB and post-translationally modified by succinylation at K40, which modulates its interactions and pro-tumorigenic functions.\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"TAGLN2 is an actin-binding protein that controls cytoskeletal dynamics in immune cells, endothelial cells, and epithelial contexts by stabilizing F-actin through competition with cofilin, inhibiting Arp2/3-mediated branched actin nucleation, and nucleating linear actin polymerization via its calponin homology domain [PMID:25869671, PMID:29615809]. In T cells, TAGLN2 is essential for immunological synapse formation, LFA-1 activation, cytokine production, and cytotoxic effector function, while in macrophages it is NF-κB-induced and required for phagocytosis of opsonized particles and bacterial clearance in vivo [PMID:25869671, PMID:28821818, PMID:30524895]. PFTK1-mediated phosphorylation at S83 and S163 attenuates TAGLN2 actin-binding activity and relieves its suppression of cell motility, and succinylation at K40 modulates its interaction with TMSB4X to promote angiogenesis and glioma progression [PMID:21577206, PMID:36131066]. In diverse tumor contexts, TAGLN2 drives invasion and therapy resistance through ERK1/2–MGMT, ANXA2–STAT3, Rap1–PI3K–AKT, and AKT–YBX1–cGAS-STING signaling axes, and tumor-derived exosomal TAGLN2 promotes angiogenesis via a NRP1–SEMA4D–YAP ternary complex [PMID:38992489, PMID:34466149, PMID:36222755, PMID:39168971, PMID:41824788].\",\n  \"teleology\": [\n    {\n      \"year\": 2011,\n      \"claim\": \"PFTK1-mediated phosphorylation at S83/S163 was identified as a mechanism that attenuates TAGLN2 actin-binding activity, establishing that post-translational modification directly regulates the cytoskeletal suppressor function of TAGLN2 and linking it to tumor cell motility control.\",\n      \"evidence\": \"2D-PAGE/MS phosphosubstrate identification, site-directed mutagenesis, actin-binding assays, and genetic epistasis in HCC cells\",\n      \"pmids\": [\"21577206\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Kinases other than PFTK1 that phosphorylate these sites are uncharacterized\", \"Structural basis for how S83/S163 phosphorylation disrupts actin binding is unresolved\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"TAGLN2 was established as a direct target of miR-1 and miR-133a, with functional knockdown showing that TAGLN2 promotes proliferation and suppresses apoptosis in cancer cells, providing the first post-transcriptional regulatory axis for TAGLN2.\",\n      \"evidence\": \"Luciferase 3′-UTR reporter assays and siRNA knockdown in bladder and head-and-neck squamous cell carcinoma lines\",\n      \"pmids\": [\"21304530\", \"21378409\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How miR-1/miR-133a regulation of TAGLN2 integrates with its actin-binding function was not addressed\", \"In vivo confirmation of miRNA-mediated TAGLN2 regulation is lacking\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"Knockout studies resolved a long-standing question about how T cells maintain F-actin at the immunological synapse: TAGLN2 stabilizes cortical F-actin by competing with cofilin and is required for LFA-1 activation, cytokine secretion, and cytotoxic function.\",\n      \"evidence\": \"TAGLN2-knockout mice, in vitro cofilin competition assays, live imaging, and cytokine/granzyme B functional assays\",\n      \"pmids\": [\"25869671\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether TAGLN2 directly binds LFA-1 or acts through an intermediate remains incompletely defined\", \"Regulation of TAGLN2 expression or activity during TCR signaling is not established\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"TAGLN2 was shown to be essential for macrophage phagocytosis and in vivo antibacterial defense, with NF-κB identified as the transcriptional inducer downstream of LPS, broadening TAGLN2's immune function beyond T cells.\",\n      \"evidence\": \"TAGLN2-knockout mice, phagocytosis of opsonized particles, NF-κB pathway inhibition, and in vivo bacterial infection survival\",\n      \"pmids\": [\"28821818\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"The precise actin-remodeling step TAGLN2 controls during phagosome formation is undefined\", \"Whether TAGLN2 acts identically in other myeloid cell types is untested\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"Reconstitution experiments defined TAGLN2's dual biochemical activities: G-actin nucleation via the calponin homology domain under low-salt conditions, and inhibition of Arp2/3-mediated branched nucleation under physiological conditions, explaining how TAGLN2 shifts the balance from branched to linear actin networks.\",\n      \"evidence\": \"In vitro actin polymerization assays with domain mutagenesis and Arp2/3 binding assays, live cell filopodia imaging\",\n      \"pmids\": [\"29615809\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether ionic-strength-dependent nucleation is physiologically relevant inside cells is unclear\", \"A high-resolution structural model of the TAGLN2–actin interface is absent\"]\n    },\n    {\n      \"year\": 2018,\n      \"claim\": \"TAGLN2 was shown to associate with LFA-1 and potentiate inside-out costimulation, with exogenous TAGLN2 delivery enhancing CAR-T cell cytotoxicity in vitro and in xenograft models, providing translational proof-of-concept.\",\n      \"evidence\": \"Co-localization studies, recombinant protein transduction domain fusion, OTI CD8+ T cell killing assays, and xenograft model\",\n      \"pmids\": [\"30524895\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Biochemical details of the TAGLN2–LFA-1 interaction (direct vs. indirect, binding site) are not defined\", \"Long-term safety and efficacy of exogenous TAGLN2 delivery in vivo are unknown\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Zebrafish studies placed tagln2 downstream of the transcription factor klf6a in blood-flow-driven vessel pruning, establishing a developmental role in endothelial cell rearrangement and actin remodeling beyond immune cells.\",\n      \"evidence\": \"Zebrafish klf6a loss-of-function with tagln2 rescue, live imaging of endothelial cell migration and junction remodeling\",\n      \"pmids\": [\"34319989\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether the klf6a-TAGLN2 axis is conserved in mammalian vascular pruning is untested\", \"Molecular targets of TAGLN2 in endothelial junction remodeling are unidentified\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"TAGLN2 was linked to STAT3 activation through ANXA2 in colorectal cancer, establishing ANXA2 as a functional partner through which TAGLN2 promotes EMT and invasion.\",\n      \"evidence\": \"TAGLN2 knockdown/overexpression with STAT3 inhibitor rescue in CRC cell lines\",\n      \"pmids\": [\"34466149\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct physical interaction between TAGLN2 and ANXA2 was not demonstrated by reciprocal methods\", \"Whether TAGLN2-ANXA2 interaction is cytoskeleton-dependent is unknown\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"Succinylation at K40 was identified as a functionally critical post-translational modification that governs TAGLN2's interaction with TMSB4X and promotes angiogenesis in glioma, adding a second regulatory PTM to the phosphorylation already known.\",\n      \"evidence\": \"LC-MS/MS succinylation proteomics, succinylation-mimetic and loss-of-function mutagenesis, angiogenesis assays, xenograft model\",\n      \"pmids\": [\"36131066\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The enzyme(s) catalyzing K40 succinylation are unidentified\", \"How K40 succinylation affects TAGLN2's actin-binding or cofilin-competing activities is untested\"]\n    },\n    {\n      \"year\": 2022,\n      \"claim\": \"TAGLN2 was shown to directly bind E-cadherin and regulate its extracellular domain cleavage, controlling trophoblast migration/fusion, while in vivo overexpression induced a preeclampsia-like syndrome—connecting TAGLN2 to placental biology.\",\n      \"evidence\": \"Co-IP and microscale thermophoresis for direct binding, functional assays in trophoblasts, adenoviral overexpression in pregnant mice\",\n      \"pmids\": [\"35281112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"The mechanism by which TAGLN2 promotes E-cadherin cleavage (protease recruitment vs. conformational change) is unknown\", \"Findings are from a single lab and await independent confirmation\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TAGLN2 was found to interact with ERK1/2 and promote its nuclear translocation, upregulating MGMT to confer temozolomide resistance in GBM, while NF-κB was validated as a direct transcriptional activator of TAGLN2 by ChIP-PCR.\",\n      \"evidence\": \"Co-IP/LC-MS/MS for ERK1/2 interaction, ChIP-PCR for NF-κB at TAGLN2 promoter, intracranial xenograft\",\n      \"pmids\": [\"38992489\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TAGLN2 acts as a scaffold for ERK1/2 nuclear import or modulates upstream kinase activity is unclear\", \"Generalizability of NF-κB–TAGLN2–MGMT axis beyond GBM is untested\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"TAGLN2 was shown to drive therapy resistance by forming a complex with AKT and YBX1, promoting YBX1 phosphorylation and nuclear translocation, which activates cGAS-STING and upregulates interferon-stimulated genes.\",\n      \"evidence\": \"Co-IP for TAGLN2-AKT-YBX1, ChIP for c-Myc/SOX9 at YBX1 promoter, cGAS-STING pathway assays, pharmacological disruption with Fisetin/MK2206, xenograft\",\n      \"pmids\": [\"39168971\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Stoichiometry and structural basis of the TAGLN2-AKT-YBX1 ternary complex are undefined\", \"Relationship between TAGLN2's actin-binding and its AKT-YBX1 scaffolding functions is unknown\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"Exosomal TAGLN2 was found to activate a non-canonical angiogenic pathway by forming a cytoplasmic NRP1-SEMA4D-YAP ternary complex in endothelial cells, establishing an intercellular signaling role for TAGLN2 independent of its intracellular actin-binding function.\",\n      \"evidence\": \"Exosome isolation, Co-IP for ternary complex, ChIP for c-Jun/SP1 at NRP1 promoter, YAP localization assays, xenograft model\",\n      \"pmids\": [\"41824788\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TAGLN2 in exosomes retains bioactivity after uptake is unclear\", \"Whether other exosomal cargo cooperates with TAGLN2 in this axis is unknown\", \"Findings from a single lab\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying structural and regulatory model explaining how TAGLN2's actin-binding, scaffolding, and exosomal functions are coordinated—and how its multiple PTMs (phosphorylation, succinylation) and transcriptional inputs (NF-κB, KLF6, miRNAs) are integrated—remains to be established.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Low\",\n      \"gaps\": [\"No high-resolution structure of TAGLN2 bound to actin or any partner exists\", \"The relationship between cytoskeletal and signaling-scaffold functions is mechanistically unexplained\", \"In vivo genetic models for most cancer-associated TAGLN2 axes are lacking\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 1, 2, 21]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [0, 1, 15]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 1, 21]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [0, 1]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [0, 4]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [0, 3, 4]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [10, 11, 14, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\n      \"ACTA1\",\n      \"CFL1\",\n      \"ARPC5\",\n      \"TMSB4X\",\n      \"ERK1\",\n      \"ERK2\",\n      \"ANXA2\",\n      \"YBX1\"\n    ],\n    \"other_free_text\": []\n  }\n}\n```"}