{"gene":"TAGLN","run_date":"2026-06-10T10:51:54","timeline":{"discoveries":[{"year":2000,"finding":"SM22/TAGLN binds actin through multiple regions in its C-terminal domain (residues ~151-201), including a putative actin-binding site (154-KKAQEHKR-161) and residues 170-186. Phosphorylation of Ser-181 by protein kinase C greatly decreases actin binding. A Ser181Asp phosphomimetic mutation also reduced actin binding. Full-length SM22 colocalizes with actin filaments in transfected airway myocytes, while C-terminally truncated SM22-(1-151) does not.","method":"Site-directed mutagenesis, in vitro cosedimentation assay, PKC phosphorylation assay, immunofluorescence of transfected cells","journal":"Journal of applied physiology","confidence":"High","confidence_rationale":"Tier 1 / Strong — reconstitution in vitro with systematic mutagenesis, multiple orthogonal methods (cosedimentation, phosphorylation assay, immunofluorescence), single rigorous study","pmids":["11053353"],"is_preprint":false},{"year":2000,"finding":"SM22/TAGLN is a substrate of protein kinase C (PKC) in vitro. Upon PKC activation in vivo, SM22 dissociates from the actin cytoskeleton and redistributes diffusely in the cytoplasm, indicating that PKC-mediated phosphorylation controls the intracellular localization of SM22.","method":"In vitro PKC kinase assay on tissue lysate fractions, 2D-gel electrophoresis, mass spectrometry, and in vivo PKC activation with subcellular localization assessment","journal":"Electrophoresis","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vitro kinase assay plus in vivo localization experiment, single lab, two orthogonal methods","pmids":["10939458"],"is_preprint":false},{"year":2006,"finding":"SM22/TAGLN represses MMP-9 expression by attenuating ERK/MAPK activation and reducing AP-1 (c-Fos)-dependent transactivation at the proximal MMP-9 promoter. The N-terminal calponin homology domain of SM22 is required for this repressive activity. SM22 overexpression decreased MMP-9 mRNA/protein and reduced in vitro invasion; siRNA knockdown elevated MMP-9; SM22-null mouse uterus showed strong MMP-9 immunoreactivity.","method":"Expression cloning, siRNA knockdown, MMP-9 promoter deletion and mutagenesis, AP-1 reporter assay, nuclear extract c-Fos binding assay, constitutively active MEK construct, SM22-null mouse immunohistochemistry","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (overexpression, siRNA, promoter mutagenesis, AP-1 reporter, in vivo null mouse), single rigorous study with replicated pathway placement","pmids":["16835221"],"is_preprint":false},{"year":2010,"finding":"SM22 deficiency in vascular smooth muscle cells increases reactive oxygen species (ROS) production (via both mitochondrial and NADPH oxidase contributions linked to p47phox activation), which activates NF-κB2 (p52 pathway) and upregulates proinflammatory genes (Vcam1, Icam1, Cx3cl1, Ccl2, Ptgs2). This was demonstrated in Sm22 knockout mice after carotid denudation injury, in primary Sm22-/- VSMCs, and in PAC1 cells after Sm22 knockdown; ROS scavengers blocked NF-κB activation and proinflammatory gene induction.","method":"Sm22 knockout mouse carotid denudation model, primary VSMC culture, siRNA knockdown, ROS scavenger experiments, NF-κB activation assays, qRT-PCR, Western blot","journal":"Circulation research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout plus in vitro knockdown with mechanistic rescue by ROS scavengers, multiple orthogonal methods across multiple experimental systems","pmids":["20224039"],"is_preprint":false},{"year":2010,"finding":"SM22 deficiency alters VSMC actin cytoskeleton (compromised stress fiber formation, increased actin dynamics) and promotes chondrogenic conversion after arterial injury, evidenced by upregulation of SOX9, type II collagen, aggrecan, BMP2, and osteopontin, with concomitant suppression of myocardin and VSMC markers. Enhanced ROS production and NF-κB pathway activation mediate SOX9 upregulation in SM22-deficient VSMCs.","method":"Sm22 knockout mouse carotid denudation model, primary Sm22-/- VSMC culture, VSMC line Sm22 knockdown, actin dynamics assays, gene expression analysis, immunofluorescence","journal":"Cardiovascular research","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo knockout model plus in vitro knockdown, multiple chondrogenic markers measured, ROS-NF-κB pathway mechanistically linked, single lab but multiple orthogonal approaches","pmids":["21183509"],"is_preprint":false},{"year":2008,"finding":"The yeast SM22 homologue Scp1 contains two actin-binding domains that allow it to both bind and bundle actin without dimerization. Scp1 localizes to cortical actin patches during endocytosis. Key residues in the actin interface are required for patch localization. Loss of Scp1 impairs patch movement away from the plasma membrane; double deletion of scp1 and fimbrin/sac6 dramatically increases patch lifetime, establishing a redundant role for actin-bundling proteins in endocytosis.","method":"Live cell imaging of GFP-tagged mutants, in vitro actin-bundling assays, genetic epistasis (scp1Δ, sac6Δ, double mutant), site-directed mutagenesis of actin-binding domains","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1 / Strong — in vitro reconstitution of actin bundling plus mutagenesis plus live imaging plus genetic epistasis, yeast ortholog with conserved function","pmids":["18400761"],"is_preprint":false},{"year":2005,"finding":"Fission yeast Stg1, a SM22/transgelin-like protein, crosslinks F-actin in vitro and localizes to actin patches. Overexpression of Stg1 suppresses contractile ring formation and causes abnormal F-actin aggregates, implicating it in cytokinesis control through actin cytoskeleton regulation.","method":"Biochemical F-actin crosslinking assay, microscopic localization, overexpression phenotype analysis in S. pombe","journal":"FEBS letters","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — in vitro crosslinking assay and localization confirmed, but only overexpression phenotype studied in single lab with no mutagenesis; fission yeast ortholog","pmids":["16256112"],"is_preprint":false},{"year":1994,"finding":"A bovine aorta SM22 homolog (25-kDa protein, corresponding to WS3-10) directly binds F-actin at a molar ratio of 1:6 actin monomers with a binding constant of 7.0 × 10^5 M^-1, and associates with the membrane fraction in a Ca2+-sensitive manner (membrane association promoted by Ca2+, dissociated by EGTA).","method":"Protein purification, F-actin cosedimentation/binding assay, membrane fractionation with Ca2+/EGTA treatment, partial sequence analysis","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 1 / Weak — direct in vitro binding assay with quantified binding constant and Ca2+ modulation, single lab, single study","pmids":["8117285"],"is_preprint":false},{"year":2015,"finding":"SM22 phosphorylation by Rho kinase (ROCK), but not by PKC, negatively regulates SM22-actin binding in smooth muscle cells. Higher phospho-SM22 levels and decreased SM22-actin binding were found in internal anal sphincter (IAS) vs. rectal smooth muscle (RSM) cells. SM22 overexpression caused concentration-dependent relaxation of IAS SMCs greater than RSM SMCs; SM22 siRNA caused contraction in both. This links Rho kinase-mediated SM22 phosphorylation to basal smooth muscle tone regulation.","method":"pFLAG-SM22 transfection, SM22 siRNA, SMC length measurement, phospho-SM22 western blot, ROCK inhibitor Y-27632 and PKC inhibitor Gö-6850 treatment, SM22-actin binding assay","journal":"American journal of physiology. Gastrointestinal and liver physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — multiple methods (overexpression, siRNA, kinase inhibitors, binding assay) in single lab, defines ROCK as the relevant kinase for SM22 phosphorylation and functional consequence","pmids":["25617350"],"is_preprint":false},{"year":2013,"finding":"TAGLN upregulation in cancer-associated fibroblasts (CAFs) from gastric carcinoma promotes cancer cell migration and invasion in vitro and in vivo. TAGLN knockdown via siRNA in CAFs significantly reduced MMP-2 expression and decreased tumor metastatic capacity, placing TAGLN upstream of MMP-2 in a stromal pro-metastatic pathway.","method":"siRNA knockdown in CAFs, qRT-PCR, Western blot for MMP-2, transwell migration/invasion assay, in vivo metastasis model","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotype and identification of MMP-2 as downstream effector, single lab but multiple orthogonal assays","pmids":["23510049"],"is_preprint":false},{"year":2012,"finding":"Depletion of SM22/TAGLN in REF52 fibroblasts disrupts actin organization, increases cell motility, and enables spontaneous podosome formation with increased Matrigel invasion capacity. Conversely, re-expression of SM22 in SM22-negative PC3 prostate cancer cells reduces Matrigel invasion. SM22-depleted cells also show reduced reactive oxygen species levels under serum starvation stress.","method":"SM22 siRNA knockdown in REF52 fibroblasts, SM22 re-expression in PC3 cells, actin organization assays, podosome scoring, Matrigel invasion assay, ROS measurement under stress","journal":"BMC cell biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal loss-of-function and gain-of-function experiments with defined actin and invasion phenotypes, single lab, multiple cell lines","pmids":["22257561"],"is_preprint":false},{"year":2021,"finding":"TRAF6 (an E3 ubiquitin ligase) catalyzes mono-ubiquitination of TAGLN at K89 or K108 residues (with E2 UBE2A/E2A), targeting it for proteasomal degradation. This TRAF6-mediated ubiquitination and degradation of TAGLN leads to activation of NF-κB and Myc signaling pathways. Ablation of TAGLN in prostate cancer cells promoted cell proliferation and suppressed migration.","method":"In vitro ubiquitination assay screening >20 E2-E3 pairs, site-directed mutagenesis of ubiquitination sites (K89/K108), proteasome inhibitor treatment, TRAF6 overexpression/knockdown, NF-κB and Myc pathway activation assays","journal":"Molecular cancer research","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro ubiquitination reconstitution with mutagenesis identifying specific sites, plus functional pathway consequence assays, single lab but multiple orthogonal methods","pmids":["33771884"],"is_preprint":false},{"year":2021,"finding":"TAGLN is expressed in vascular endothelial cells (ECs), where its expression is activated during EC elongation downstream of VEGF-A signaling and PI3K-Akt/mTORC1 pathway inhibition. Genetic disruption of TAGLN (and paralogs TAGLN2, TAGLN3) augmented angiogenic behaviors of HUVECs, identifying TAGLN as a negative regulator of EC elongation and angiogenesis.","method":"Mouse ESC Tagln promoter-driven fluorescence reporter, VEGF-A treatment, PI3K-Akt/mTORC1 inhibition, HUVEC angiogenesis model, TAGLN/TAGLN2/TAGLN3 CRISPR knockout, immunofluorescence in mouse embryo ECs","journal":"Journal of cell science","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic disruption with defined angiogenic phenotype plus promoter reporter and in vivo EC expression confirmation, single lab with multiple orthogonal approaches","pmids":["34338296"],"is_preprint":false},{"year":2021,"finding":"TAGLN acts as a mechanosensitive protein in ovarian cancer cells that responds to extracellular matrix stiffness, forms a regulation loop with Src kinase activation, and mediates stiffness-regulated tumor progression through the RhoA/ROCK pathway.","method":"Atomic force microscopy (AFM) for stiffness measurement, collagen-coated polyacrylamide hydrogel system for stiffness modulation, transwell assay, immunofluorescence, western blot for RhoA/ROCK pathway, in vivo tumor model","journal":"Journal of experimental & clinical cancer research","confidence":"Medium","confidence_rationale":"Tier 2 / Weak — defined mechanosensitive pathway placement with multiple assays but single lab and Src-TAGLN loop characterization is incompletely described in abstract","pmids":["34538264"],"is_preprint":false},{"year":2021,"finding":"ALKBH5, an m6A RNA demethylase, binds to m6A sites in TAGLN mRNA and reduces its m6A methylation level, thereby inhibiting TAGLN mRNA degradation and increasing TAGLN protein expression. Elevated TAGLN then inhibits enteric neural crest cell proliferation and migration, contributing to Hirschsprung's disease pathogenesis.","method":"MeRIP-qPCR for m6A site identification, dual-luciferase reporter, ALKBH5 overexpression/knockdown, cell proliferation and migration assays, zebrafish ALKBH5 overexpression model","journal":"Life sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-qPCR identifies m6A sites, dual-luciferase validates regulation, functional phenotype confirmed in vitro and in vivo zebrafish model, single lab","pmids":["33961858"],"is_preprint":false},{"year":2020,"finding":"TAGLN physically interacts with HMGA2 (by co-immunoprecipitation), and this complex mediates TGF-β-induced colorectal cancer cell migration and invasion. TGF-β promotes TAGLN protein expression and nuclear translocation. TAGLN knockdown reverses TGF-β-induced EMT (rescues E-cadherin loss, reduces vimentin, fibronectin, MMP9, MMP2); HMGA2 overexpression restores these effects when TAGLN is inhibited, both in vitro and in vivo.","method":"Co-immunoprecipitation, siRNA knockdown, HMGA2 overexpression, EMT marker western blot (E-cadherin, vimentin, fibronectin), MMP2/MMP9 assay, in vivo tumor model","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — Co-IP identifies TAGLN-HMGA2 interaction, functional epistasis with HMGA2 rescue experiments, multiple EMT markers assessed, single lab","pmids":["33116628"],"is_preprint":false},{"year":2007,"finding":"The C-terminal domain of SM22α interacts with F-actin. SM22α colocalizes with F-actin during VSMC re-differentiation (serum withdrawal/restimulation). GST pulldown and co-immunoprecipitation confirmed that SM22α interacts with F-actin via its C-terminal domains to participate in cytoskeleton reorganization.","method":"GST pulldown assay, co-immunoprecipitation, immunofluorescence, F-actin/G-actin fractionation by western blot, prokaryotic expression of GST-SM22α","journal":"Chinese journal of applied physiology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal pulldown and co-IP plus localization, consistent with mutagenesis data from PMID 11053353, single lab","pmids":["21162287"],"is_preprint":false},{"year":2025,"finding":"TAGLN promotes skin fibrosis through a mechano-metabolic axis: TAGLN activates the RhoA/ROCK2 pathway, which in turn upregulates the glucose transporter SLC2A3, thereby promoting glycolysis and enhancing fibroblast motility, contraction, and collagen secretion. Downregulation of TAGLN inhibited fibroblast invasion, migration, contraction, and collagen secretion in vitro, and reduced fibrosis in a bleomycin mouse model.","method":"Transwell assay, wound healing assay, collagen gel contraction assay, immunofluorescence, RNA-seq, RhoA/ROCK2 pathway inhibition, TAGLN knockdown, bleomycin mouse model","journal":"International journal of biological sciences","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — RNA-seq identifies SLC2A3 as downstream target, RhoA/ROCK2 pathway mechanistically placed between TAGLN and SLC2A3, functional assays with in vivo validation, single lab","pmids":["39781462"],"is_preprint":false},{"year":2025,"finding":"NRF2 directly transcriptionally activates TAGLN expression by binding a functional antioxidant response element (ARE) in the TAGLN promoter, as confirmed by dual luciferase and ChIP assays. TAGLN overexpression promotes ovarian cancer cell migration and EMT (increased N-cadherin, decreased E-cadherin); TAGLN siRNA knockdown in NRF2-overexpressing cells reverses these effects, placing TAGLN downstream of NRF2 in a pro-migratory EMT pathway.","method":"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), TAGLN overexpression, siRNA knockdown, wound-healing assay, Transwell assay, EMT marker western blot","journal":"Journal of ovarian research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and dual luciferase confirm direct ARE-mediated transcriptional regulation by NRF2, functional rescue experiments confirm epistasis, single lab","pmids":["41029755"],"is_preprint":false},{"year":1987,"finding":"SM22α from chicken gizzard smooth muscle is a 197-residue single polypeptide chain (Mr ~21,978) that exists as a monomer at physiological ionic strengths and is a moderately asymmetric globular protein. Its complete amino acid sequence was determined; no significant homology to previously known proteins was found at the time of publication.","method":"Automated and manual Edman degradation sequencing, sedimentation equilibrium, CD spectroscopy, Stokes radius determination","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 1 / Moderate — direct biochemical characterization of purified protein by multiple physical methods; primary structural determination","pmids":["3571244"],"is_preprint":false}],"current_model":"TAGLN (SM22/transgelin) is an actin-binding and actin-bundling protein that binds F-actin through multiple regions in its C-terminal domain; PKC-mediated phosphorylation at Ser-181 (and Rho kinase-mediated phosphorylation) reduces actin binding and redistributes the protein from the cytoskeleton to the cytoplasm. TAGLN suppresses MMP-9 expression by attenuating ERK/MAPK signaling and AP-1-dependent transcription; it is degraded via TRAF6-catalyzed mono-ubiquitination at K89/K108 followed by proteasomal degradation, leading to NF-κB/Myc activation; SM22 deficiency promotes inflammatory signaling in VSMCs through ROS-mediated NF-κB2 activation; TAGLN mediates mechanosensitive signaling through RhoA/ROCK2, regulates glycolysis via SLC2A3 in fibroblasts, and is a direct transcriptional target of NRF2 through an ARE in its promoter, collectively placing it as a multifunctional cytoskeletal regulator that integrates mechanical, metabolic, and inflammatory signals."},"narrative":{"mechanistic_narrative":"TAGLN (SM22/transgelin) is an actin-binding and actin-bundling cytoskeletal protein that integrates mechanical, metabolic, and inflammatory signals to control cell shape, motility, and invasion [PMID:11053353, PMID:22257561, PMID:39781462]. It binds F-actin through multiple regions in its C-terminal domain (residues ~151-201, including a 154-KKAQEHKR-161 site and residues 170-186) and colocalizes with actin filaments, whereas C-terminally truncated protein fails to associate [PMID:11053353, PMID:21162287]; phosphorylation at Ser-181 by protein kinase C, and phosphorylation by Rho kinase (ROCK), reduces actin binding and redistributes the protein from the cytoskeleton to the cytoplasm, thereby tuning smooth muscle tone [PMID:11053353, PMID:10939458, PMID:25617350]. Loss of TAGLN destabilizes the actin cytoskeleton, compromises stress fibers, increases motility, and permits podosome formation and matrix invasion, while re-expression suppresses invasion [PMID:22257561, PMID:21183509]. Through its N-terminal calponin homology domain, TAGLN represses MMP-9 expression by attenuating ERK/MAPK and AP-1 (c-Fos)-dependent transcription [PMID:16835221], and SM22 deficiency in vascular smooth muscle elevates ROS that drive NF-κB2 activation, proinflammatory gene induction, and chondrogenic conversion after arterial injury [PMID:20224039, PMID:21183509]. TAGLN protein levels are set by multiple regulatory inputs: TRAF6-catalyzed mono-ubiquitination at K89/K108 targets it for proteasomal degradation and de-represses NF-κB and Myc signaling [PMID:33771884]; ALKBH5-mediated m6A demethylation stabilizes TAGLN mRNA [PMID:33961858]; and NRF2 directly transactivates TAGLN through an ARE in its promoter [PMID:41029755]. In disease contexts TAGLN functions as a mechanosensor responding to matrix stiffness via RhoA/ROCK, drives a mechano-metabolic fibrotic axis that upregulates the glucose transporter SLC2A3 to fuel glycolysis, and acts in stromal and tumor cells to promote migration, EMT, and metastasis [PMID:34538264, PMID:39781462, PMID:23510049, PMID:33116628]. Conserved orthologs in budding and fission yeast bundle and crosslink actin and localize to actin patches and the contractile ring, underscoring an ancient role in actin organization [PMID:18400761, PMID:16256112].","teleology":[{"year":1987,"claim":"Establishing the primary structure and physical state of SM22α was the foundation for all later mechanistic work; the question was simply what this abundant smooth-muscle protein is.","evidence":"Edman sequencing, sedimentation equilibrium, and CD spectroscopy of chicken gizzard SM22α","pmids":["3571244"],"confidence":"Medium","gaps":["No binding partner or function assigned at this stage","No homology to known proteins identified at the time"]},{"year":1994,"claim":"Whether SM22 has a cytoskeletal function was answered by showing it directly binds F-actin with measurable stoichiometry and affinity and associates with membranes in a Ca2+-sensitive manner.","evidence":"Protein purification and F-actin cosedimentation with quantified binding constant, plus membrane fractionation under Ca2+/EGTA","pmids":["8117285"],"confidence":"Medium","gaps":["Actin-binding region not mapped","Functional consequence of binding not defined","Physiological role of Ca2+-sensitive membrane association unclear"]},{"year":2000,"claim":"These studies localized the actin-binding determinants to the C-terminal domain and identified PKC phosphorylation of Ser-181 as a switch that releases SM22 from the cytoskeleton, defining how its localization is regulated.","evidence":"Site-directed mutagenesis with in vitro cosedimentation, PKC kinase assay, and immunofluorescence of transfected myocytes; in vivo PKC activation with subcellular localization","pmids":["11053353","10939458"],"confidence":"High","gaps":["Physiological signal triggering PKC phosphorylation in vivo not defined","Whether other kinases regulate binding not addressed"]},{"year":2005,"claim":"Ortholog work tested whether actin regulation is a conserved property; the fission yeast Stg1 crosslinks F-actin and influences cytokinesis, generalizing the actin-organizing role beyond vertebrate smooth muscle.","evidence":"In vitro F-actin crosslinking, localization, and overexpression phenotype in S. pombe","pmids":["16256112"],"confidence":"Medium","gaps":["Only overexpression studied, no loss-of-function mutagenesis","Direct relevance to mammalian TAGLN function inferred from homology"]},{"year":2006,"claim":"Beyond a structural actin role, this work established TAGLN as a transcriptional/signaling regulator, showing its calponin homology domain represses MMP-9 by dampening ERK/MAPK and AP-1 activity.","evidence":"Overexpression, siRNA, MMP-9 promoter mutagenesis, AP-1 reporter, constitutively active MEK, and SM22-null mouse immunohistochemistry","pmids":["16835221"],"confidence":"High","gaps":["Mechanism linking cytoplasmic actin-binding protein to ERK/AP-1 suppression not resolved","Direct versus indirect effect on the pathway unclear"]},{"year":2008,"claim":"The budding yeast ortholog Scp1 clarified the biochemical mode of action, showing two actin-binding domains permit bundling without dimerization and a redundant role with fimbrin in endocytic patch dynamics.","evidence":"Live imaging of GFP mutants, in vitro bundling assays, site-directed mutagenesis, and scp1Δ/sac6Δ genetic epistasis","pmids":["18400761"],"confidence":"High","gaps":["Mammalian TAGLN bundling stoichiometry not directly compared","Endocytic role in mammalian cells not established"]},{"year":2010,"claim":"Knockout studies linked SM22 loss to inflammatory and phenotypic conversion of VSMCs, defining a ROS–NF-κB2 axis and chondrogenic transdifferentiation after vascular injury.","evidence":"Sm22 knockout mouse carotid denudation, primary VSMC culture, knockdown, ROS scavengers, and gene/marker expression analysis","pmids":["20224039","21183509"],"confidence":"High","gaps":["How cytoskeletal disruption mechanistically elevates ROS not fully resolved","Direct target of SM22 in the NADPH oxidase/NF-κB pathway not identified"]},{"year":2012,"claim":"Reciprocal gain- and loss-of-function in fibroblasts and prostate cancer cells established TAGLN as a suppressor of motility, podosome formation, and matrix invasion through actin organization.","evidence":"siRNA in REF52 fibroblasts and re-expression in PC3 cells with actin, podosome, invasion, and ROS assays","pmids":["22257561"],"confidence":"Medium","gaps":["Molecular link between actin organization and podosome suppression not defined","ROS reduction under starvation mechanistically unexplained"]},{"year":2013,"claim":"TAGLN was found to act non-cell-autonomously, with stromal CAF expression promoting metastasis upstream of MMP-2, expanding its role to the tumor microenvironment.","evidence":"siRNA knockdown in gastric carcinoma CAFs, MMP-2 readouts, migration/invasion assays, and in vivo metastasis model","pmids":["23510049"],"confidence":"Medium","gaps":["Whether TAGLN regulates MMP-2 transcriptionally or via cytoskeleton unclear","Context dependence versus its MMP-9 suppressive role unresolved"]},{"year":2015,"claim":"This work identified ROCK, rather than PKC, as the kinase regulating SM22-actin binding in specific smooth muscle and tied SM22 phosphorylation to basal tone.","evidence":"pFLAG-SM22 transfection, siRNA, ROCK (Y-27632) and PKC (Gö6850) inhibitors, phospho-SM22 westerns, SMC length, and binding assays","pmids":["25617350"],"confidence":"Medium","gaps":["Reconciliation with earlier PKC/Ser-181 model not addressed","Phosphosite targeted by ROCK not mapped"]},{"year":2020,"claim":"Identification of a TAGLN-HMGA2 complex showed TAGLN can act in TGF-β-driven EMT, with nuclear translocation linking it to a pro-invasive transcriptional program.","evidence":"Co-immunoprecipitation, siRNA, HMGA2 overexpression rescue, EMT marker westerns, and in vivo tumor model","pmids":["33116628"],"confidence":"Medium","gaps":["Single Co-IP without reciprocal structural validation of the interaction","Functional role of nuclear TAGLN not mechanistically defined"]},{"year":2021,"claim":"A cluster of studies defined the regulatory inputs and outputs that set TAGLN levels and signaling: TRAF6 ubiquitination/degradation, m6A control by ALKBH5, mechanosensing via RhoA/ROCK, and negative regulation of angiogenesis.","evidence":"In vitro ubiquitination with E2-E3 screening and K89/K108 mutagenesis; MeRIP-qPCR and luciferase; AFM/stiffness hydrogels with RhoA/ROCK readouts; ESC reporter and TAGLN/TAGLN2/TAGLN3 CRISPR knockout in HUVECs","pmids":["33771884","33961858","34538264","34338296"],"confidence":"High","gaps":["How ubiquitination-coupled degradation integrates with kinase regulation unknown","Mechanism by which TAGLN feeds back on Src and RhoA/ROCK incompletely described","Redundancy with TAGLN2/TAGLN3 in non-angiogenic contexts unexplored"]},{"year":2025,"claim":"The most recent work placed TAGLN at the center of a mechano-metabolic fibrotic axis and as a direct NRF2 target, connecting matrix stiffness, RhoA/ROCK2, SLC2A3-driven glycolysis, and antioxidant transcriptional control.","evidence":"RNA-seq, RhoA/ROCK2 inhibition, knockdown, bleomycin fibrosis model; dual luciferase and ChIP for NRF2 ARE binding with EMT rescue assays","pmids":["39781462","41029755"],"confidence":"Medium","gaps":["How TAGLN activates RhoA/ROCK2 mechanistically not defined","Whether NRF2-driven TAGLN connects to its antioxidant/ROS roles in VSMCs unresolved"]},{"year":null,"claim":"A unifying mechanism for how a single C-terminal actin-binding protein switches between cytoskeletal, transcriptional, and signaling outputs remains undefined.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No structural model explaining context-dependent nuclear versus cytoskeletal function","Direct molecular link from actin binding to ERK/AP-1, NF-κB, and RhoA/ROCK signaling not established","Integration of competing PKC and ROCK phosphorylation regulation unresolved"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0008092","term_label":"cytoskeletal protein binding","supporting_discovery_ids":[0,5,6,7,16]},{"term_id":"GO:0098772","term_label":"molecular function regulator activity","supporting_discovery_ids":[2,3,11]}],"localization":[{"term_id":"GO:0005856","term_label":"cytoskeleton","supporting_discovery_ids":[0,5,16]},{"term_id":"GO:0005829","term_label":"cytosol","supporting_discovery_ids":[1]},{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[15]},{"term_id":"GO:0005886","term_label":"plasma membrane","supporting_discovery_ids":[7]}],"pathway":[{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[3,11,13,17]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[9,14,17,18]},{"term_id":"R-HSA-8953897","term_label":"Cellular responses to stimuli","supporting_discovery_ids":[3,13,17]}],"complexes":[],"partners":["ACTB","TRAF6","UBE2A","HMGA2"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"Q01995","full_name":"Transgelin","aliases":["22 kDa actin-binding protein","Protein WS3-10","Smooth muscle protein 22-alpha","SM22-alpha"],"length_aa":201,"mass_kda":22.6,"function":"Actin cross-linking/gelling protein (By similarity). Involved in calcium interactions and contractile properties of the cell that may contribute to replicative senescence","subcellular_location":"Cytoplasm","url":"https://www.uniprot.org/uniprotkb/Q01995/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/TAGLN","classification":"Not Classified","n_dependent_lines":21,"n_total_lines":1208,"dependency_fraction":0.0173841059602649},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/TAGLN","total_profiled":1310},"omim":[{"mim_id":"617492","title":"OLFACTOMEDIN 2; OLFM2","url":"https://www.omim.org/entry/617492"},{"mim_id":"611795","title":"MICRO RNA 145; MIR145","url":"https://www.omim.org/entry/611795"},{"mim_id":"610077","title":"REGULATOR OF CELL CYCLE; RGCC","url":"https://www.omim.org/entry/610077"},{"mim_id":"606127","title":"MYOCARDIN; MYOCD","url":"https://www.omim.org/entry/606127"},{"mim_id":"604634","title":"TRANSGELIN 2; TAGLN2","url":"https://www.omim.org/entry/604634"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Approved","locations":[{"location":"Mitochondria","reliability":"Approved"},{"location":"Cytosol","reliability":"Approved"},{"location":"Nucleoplasm","reliability":"Additional"},{"location":"Microtubules","reliability":"Additional"}],"tissue_specificity":"Tissue enhanced","tissue_distribution":"Detected in all","driving_tissues":[{"tissue":"blood vessel","ntpm":13587.8},{"tissue":"intestine","ntpm":8800.4}],"url":"https://www.proteinatlas.org/search/TAGLN"},"hgnc":{"alias_symbol":["SM22","WS3-10","TAGLN1","SMCC","DKFZp686P11128","TGLN"],"prev_symbol":[]},"alphafold":{"accession":"Q01995","domains":[{"cath_id":"1.10.418.10","chopping":"10-150","consensus_level":"high","plddt":94.2757,"start":10,"end":150}],"viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01995","model_url":"https://alphafold.ebi.ac.uk/files/AF-Q01995-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-Q01995-F1-predicted_aligned_error_v6.png","plddt_mean":88.19},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=TAGLN","jax_strain_url":"https://www.jax.org/strain/search?query=TAGLN"},"sequence":{"accession":"Q01995","fasta_url":"https://rest.uniprot.org/uniprotkb/Q01995.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/Q01995/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/Q01995"}},"corpus_meta":[{"pmid":"8575061","id":"PMC_8575061","title":"SM22 alpha, a marker of adult smooth muscle, is expressed in multiple myogenic lineages during embryogenesis.","date":"1996","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/8575061","citation_count":372,"is_preprint":false},{"pmid":"7768949","id":"PMC_7768949","title":"Structure and expression of a smooth muscle cell-specific gene, SM22 alpha.","date":"1995","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/7768949","citation_count":233,"is_preprint":false},{"pmid":"11053353","id":"PMC_11053353","title":"Mutagenesis analysis of human SM22: characterization of actin binding.","date":"2000","source":"Journal of applied physiology (Bethesda, Md. : 1985)","url":"https://pubmed.ncbi.nlm.nih.gov/11053353","citation_count":105,"is_preprint":false},{"pmid":"16835221","id":"PMC_16835221","title":"Expression cloning identifies transgelin (SM22) as a novel repressor of 92-kDa type IV collagenase (MMP-9) expression.","date":"2006","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/16835221","citation_count":101,"is_preprint":false},{"pmid":"3818630","id":"PMC_3818630","title":"Isolation and characterization of an abundant and novel 22-kDa protein (SM22) from chicken gizzard smooth muscle.","date":"1987","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/3818630","citation_count":99,"is_preprint":false},{"pmid":"3446186","id":"PMC_3446186","title":"An abundant and novel protein of 22 kDa (SM22) is widely distributed in smooth muscles. Purification from bovine aorta.","date":"1987","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/3446186","citation_count":98,"is_preprint":false},{"pmid":"20224039","id":"PMC_20224039","title":"Disruption of SM22 promotes inflammation after artery injury via nuclear factor kappaB activation.","date":"2010","source":"Circulation research","url":"https://pubmed.ncbi.nlm.nih.gov/20224039","citation_count":89,"is_preprint":false},{"pmid":"9615232","id":"PMC_9615232","title":"Expression and cytogenetic localization of the human SM22 gene (TAGLN).","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9615232","citation_count":78,"is_preprint":false},{"pmid":"34538264","id":"PMC_34538264","title":"TAGLN mediated stiffness-regulated ovarian cancer progression via RhoA/ROCK pathway.","date":"2021","source":"Journal of experimental & clinical cancer research : CR","url":"https://pubmed.ncbi.nlm.nih.gov/34538264","citation_count":74,"is_preprint":false},{"pmid":"8359698","id":"PMC_8359698","title":"cDNA cloning and mRNA expression of calponin and SM22 in rat aorta smooth muscle cells.","date":"1993","source":"Gene","url":"https://pubmed.ncbi.nlm.nih.gov/8359698","citation_count":74,"is_preprint":false},{"pmid":"10364069","id":"PMC_10364069","title":"Smooth muscle-specific SM22 protein is expressed in the adventitial cells of balloon-injured rabbit carotid artery.","date":"1999","source":"Arteriosclerosis, thrombosis, and vascular biology","url":"https://pubmed.ncbi.nlm.nih.gov/10364069","citation_count":70,"is_preprint":false},{"pmid":"34338296","id":"PMC_34338296","title":"The canonical smooth muscle cell marker TAGLN is present in endothelial cells and is involved in angiogenesis.","date":"2021","source":"Journal of cell 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/25318625","citation_count":44,"is_preprint":false},{"pmid":"7575400","id":"PMC_7575400","title":"Cloning and analysis of the promoter region of the rat SM22 alpha gene.","date":"1995","source":"The Biochemical journal","url":"https://pubmed.ncbi.nlm.nih.gov/7575400","citation_count":40,"is_preprint":false},{"pmid":"18400761","id":"PMC_18400761","title":"Interactions between the yeast SM22 homologue Scp1 and actin demonstrate the importance of actin bundling in endocytosis.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18400761","citation_count":37,"is_preprint":false},{"pmid":"21183509","id":"PMC_21183509","title":"Arterial injury promotes medial chondrogenesis in Sm22 knockout mice.","date":"2010","source":"Cardiovascular research","url":"https://pubmed.ncbi.nlm.nih.gov/21183509","citation_count":36,"is_preprint":false},{"pmid":"20012321","id":"PMC_20012321","title":"Expression of the actin-associated protein transgelin (SM22) is decreased in prostate cancer.","date":"2009","source":"Cell and tissue research","url":"https://pubmed.ncbi.nlm.nih.gov/20012321","citation_count":35,"is_preprint":false},{"pmid":"23138394","id":"PMC_23138394","title":"TAGLN suppresses proliferation and invasion, and induces apoptosis of colorectal carcinoma cells.","date":"2012","source":"Tumour biology : the journal of the International Society for Oncodevelopmental Biology and Medicine","url":"https://pubmed.ncbi.nlm.nih.gov/23138394","citation_count":31,"is_preprint":false},{"pmid":"21763649","id":"PMC_21763649","title":"TAGLN expression is deregulated in endometriosis and may be involved in cell invasion, migration, and differentiation.","date":"2011","source":"Fertility and sterility","url":"https://pubmed.ncbi.nlm.nih.gov/21763649","citation_count":31,"is_preprint":false},{"pmid":"8117285","id":"PMC_8117285","title":"Purification, characterization, and partial sequence analysis of a new 25-kDa actin-binding protein from bovine aorta: a SM22 homolog.","date":"1994","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8117285","citation_count":29,"is_preprint":false},{"pmid":"12829429","id":"PMC_12829429","title":"Regulation of SM22 alpha expression by arginine vasopressin and PDGF-BB in vascular smooth muscle cells.","date":"2003","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12829429","citation_count":28,"is_preprint":false},{"pmid":"20336793","id":"PMC_20336793","title":"Loss of SM22 is a characteristic signature of colon carcinogenesis and its restoration suppresses colon tumorigenicity in vivo and in vitro.","date":"2010","source":"Cancer","url":"https://pubmed.ncbi.nlm.nih.gov/20336793","citation_count":27,"is_preprint":false},{"pmid":"10412085","id":"PMC_10412085","title":"Differential expression of SM22 isoforms in myofibroblasts and smooth muscle cells from rabbit bladder.","date":"1999","source":"Journal of muscle research and cell motility","url":"https://pubmed.ncbi.nlm.nih.gov/10412085","citation_count":26,"is_preprint":false},{"pmid":"16499980","id":"PMC_16499980","title":"Sm22.6 antigen is an inhibitor to human thrombin.","date":"2006","source":"Molecular and biochemical parasitology","url":"https://pubmed.ncbi.nlm.nih.gov/16499980","citation_count":25,"is_preprint":false},{"pmid":"9693045","id":"PMC_9693045","title":"Paralogous sm22alpha (Tagln) genes map to mouse chromosomes 1 and 9: further evidence for a paralogous relationship.","date":"1998","source":"Genomics","url":"https://pubmed.ncbi.nlm.nih.gov/9693045","citation_count":25,"is_preprint":false},{"pmid":"28525410","id":"PMC_28525410","title":"SM22 a Plasma Biomarker for Human Transmural Intestinal Ischemia.","date":"2018","source":"Annals of surgery","url":"https://pubmed.ncbi.nlm.nih.gov/28525410","citation_count":23,"is_preprint":false},{"pmid":"12521938","id":"PMC_12521938","title":"Human SM22 alpha BAC encompasses regulatory sequences for expression in vascular and visceral smooth muscles at fetal and adult stages.","date":"2003","source":"American journal of physiology. Heart and circulatory physiology","url":"https://pubmed.ncbi.nlm.nih.gov/12521938","citation_count":21,"is_preprint":false},{"pmid":"25376243","id":"PMC_25376243","title":"The glomerular parietal epithelial cell's responses are influenced by SM22 alpha levels.","date":"2014","source":"BMC nephrology","url":"https://pubmed.ncbi.nlm.nih.gov/25376243","citation_count":17,"is_preprint":false},{"pmid":"33961858","id":"PMC_33961858","title":"m6A demethylase ALKBH5 suppresses proliferation and migration of enteric neural crest cells by regulating TAGLN in Hirschsprung's disease.","date":"2021","source":"Life sciences","url":"https://pubmed.ncbi.nlm.nih.gov/33961858","citation_count":16,"is_preprint":false},{"pmid":"1872880","id":"PMC_1872880","title":"Gene cloning and nucleotide sequence of SM22 alpha from the chicken gizzard smooth muscle.","date":"1991","source":"Biochemistry 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medicine","url":"https://pubmed.ncbi.nlm.nih.gov/35495589","citation_count":11,"is_preprint":false},{"pmid":"29483576","id":"PMC_29483576","title":"Abrogation of TGF-beta signalling in TAGLN expressing cells recapitulates Pentalogy of Cantrell in the mouse.","date":"2018","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/29483576","citation_count":11,"is_preprint":false},{"pmid":"38514830","id":"PMC_38514830","title":"Involvement of TGFBI-TAGLN axis in cancer stem cell property of head and neck squamous cell carcinoma.","date":"2024","source":"Scientific reports","url":"https://pubmed.ncbi.nlm.nih.gov/38514830","citation_count":10,"is_preprint":false},{"pmid":"34910127","id":"PMC_34910127","title":"Colonic healing requires Wnt produced by epithelium as well as Tagln+ and Acta2+ stromal cells.","date":"2022","source":"Development (Cambridge, 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markers","url":"https://pubmed.ncbi.nlm.nih.gov/37781794","citation_count":8,"is_preprint":false},{"pmid":"8954110","id":"PMC_8954110","title":"Presence of Ca(2+)-sensitive and -insensitive SM22 alpha isoproteins in bovine aorta.","date":"1996","source":"Biochemical and biophysical research communications","url":"https://pubmed.ncbi.nlm.nih.gov/8954110","citation_count":8,"is_preprint":false},{"pmid":"37806182","id":"PMC_37806182","title":"LZTS3/TAGLN Suppresses Cancer Progression in Human Colorectal Adenocarcinoma Through Regulating Cell Proliferation, Migration, and Actin Cytoskeleton.","date":"2023","source":"Archives of medical research","url":"https://pubmed.ncbi.nlm.nih.gov/37806182","citation_count":7,"is_preprint":false},{"pmid":"25617350","id":"PMC_25617350","title":"Role of SM22 in the differential regulation of phasic vs. tonic smooth muscle.","date":"2015","source":"American journal of physiology. Gastrointestinal and liver physiology","url":"https://pubmed.ncbi.nlm.nih.gov/25617350","citation_count":7,"is_preprint":false},{"pmid":"17034489","id":"PMC_17034489","title":"Development of a cell-isolation method for human prostatic smooth muscle cells based on cell type-specific activation of the SM22 gene promoter.","date":"2006","source":"BJU international","url":"https://pubmed.ncbi.nlm.nih.gov/17034489","citation_count":7,"is_preprint":false},{"pmid":"40413514","id":"PMC_40413514","title":"Comprehensive analysis of the critical role of the epithelial mesenchymal transition subtype - TAGLN-positive fibroblasts in colorectal cancer progression and immunosuppression.","date":"2025","source":"Cell & bioscience","url":"https://pubmed.ncbi.nlm.nih.gov/40413514","citation_count":5,"is_preprint":false},{"pmid":"39781462","id":"PMC_39781462","title":"TAGLN-RhoA/ROCK2-SLC2A3-mediated Mechano-metabolic Axis Promotes Skin Fibrosis.","date":"2025","source":"International journal of biological sciences","url":"https://pubmed.ncbi.nlm.nih.gov/39781462","citation_count":4,"is_preprint":false},{"pmid":"17009727","id":"PMC_17009727","title":"[The role of SM22 alpha in cytoskeleton organization and vascular remodeling].","date":"2006","source":"Sheng li ke xue jin zhan [Progress in physiology]","url":"https://pubmed.ncbi.nlm.nih.gov/17009727","citation_count":4,"is_preprint":false},{"pmid":"20540360","id":"PMC_20540360","title":"[A study of the single nucleotide polymorphism in seven genes (GHR, IGFBP3, IGFR1, IRS1, FMN1, ANXA2, TaGLN) in ethnic Russians and in patients with prostate cancer].","date":"2010","source":"Molekuliarnaia genetika, mikrobiologiia i virusologiia","url":"https://pubmed.ncbi.nlm.nih.gov/20540360","citation_count":4,"is_preprint":false},{"pmid":"41029755","id":"PMC_41029755","title":"NRF2 promotes the migration of ovarian cancer cell lines by targeting TAGLN mediated epithelial-mesenchymal transition.","date":"2025","source":"Journal of ovarian 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model","date":"2024-11-09","source":"bioRxiv","url":"https://doi.org/10.1101/2024.11.08.622724","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.07.24.603752","title":"Discovery and evaluation of novel biomarkers reveal dasatinib as a potential treatment for a specific subtype of Triple-Negative Breast Cancer","date":"2024-07-24","source":"bioRxiv","url":"https://doi.org/10.1101/2024.07.24.603752","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2024.09.26.614950","title":"<i>In vitro</i>  -generated inflammatory fibroblasts secrete extracellular matrix with biochemical and biophysical properties similar to tissue-remodelling fibroblasts","date":"2024-09-26","source":"bioRxiv","url":"https://doi.org/10.1101/2024.09.26.614950","citation_count":0,"is_preprint":true},{"pmid":null,"id":"bio_10.1101_2025.02.15.638465","title":"Single Cell Proteomics Reveals Novel Cell Phenotypes in Marfan Mouse Aneurysm","date":"2025-02-23","source":"bioRxiv","url":"https://doi.org/10.1101/2025.02.15.638465","citation_count":0,"is_preprint":true}],"cost":{"stage1":{"model":"claude-sonnet-4-6","input_tokens":38902,"output_tokens":5939,"usd":0.102896,"stage1_stop_reason":"end_turn"},"stage2":{"model":"claude-opus-4-8","input_tokens":14720,"output_tokens":4873,"usd":0.097712,"stage2_stop_reason":"end_turn"},"total_usd":0.200608,"stage1_batch_id":"msgbatch_017qqVz33Ga63SCDwzb35XPb","stage2_batch_id":"msgbatch_01Scr2Ei9x4HJMiRGxwrmvLK","note":"batch pricing = 50% of standard"},"stage1_raw":"```json\n{\n  \"discoveries\": [\n    {\n      \"year\": 2000,\n      \"finding\": \"SM22/TAGLN binds actin through multiple regions in its C-terminal domain (residues ~151-201), including a putative actin-binding site (154-KKAQEHKR-161) and residues 170-186. Phosphorylation of Ser-181 by protein kinase C greatly decreases actin binding. A Ser181Asp phosphomimetic mutation also reduced actin binding. Full-length SM22 colocalizes with actin filaments in transfected airway myocytes, while C-terminally truncated SM22-(1-151) does not.\",\n      \"method\": \"Site-directed mutagenesis, in vitro cosedimentation assay, PKC phosphorylation assay, immunofluorescence of transfected cells\",\n      \"journal\": \"Journal of applied physiology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — reconstitution in vitro with systematic mutagenesis, multiple orthogonal methods (cosedimentation, phosphorylation assay, immunofluorescence), single rigorous study\",\n      \"pmids\": [\"11053353\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2000,\n      \"finding\": \"SM22/TAGLN is a substrate of protein kinase C (PKC) in vitro. Upon PKC activation in vivo, SM22 dissociates from the actin cytoskeleton and redistributes diffusely in the cytoplasm, indicating that PKC-mediated phosphorylation controls the intracellular localization of SM22.\",\n      \"method\": \"In vitro PKC kinase assay on tissue lysate fractions, 2D-gel electrophoresis, mass spectrometry, and in vivo PKC activation with subcellular localization assessment\",\n      \"journal\": \"Electrophoresis\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vitro kinase assay plus in vivo localization experiment, single lab, two orthogonal methods\",\n      \"pmids\": [\"10939458\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2006,\n      \"finding\": \"SM22/TAGLN represses MMP-9 expression by attenuating ERK/MAPK activation and reducing AP-1 (c-Fos)-dependent transactivation at the proximal MMP-9 promoter. The N-terminal calponin homology domain of SM22 is required for this repressive activity. SM22 overexpression decreased MMP-9 mRNA/protein and reduced in vitro invasion; siRNA knockdown elevated MMP-9; SM22-null mouse uterus showed strong MMP-9 immunoreactivity.\",\n      \"method\": \"Expression cloning, siRNA knockdown, MMP-9 promoter deletion and mutagenesis, AP-1 reporter assay, nuclear extract c-Fos binding assay, constitutively active MEK construct, SM22-null mouse immunohistochemistry\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (overexpression, siRNA, promoter mutagenesis, AP-1 reporter, in vivo null mouse), single rigorous study with replicated pathway placement\",\n      \"pmids\": [\"16835221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SM22 deficiency in vascular smooth muscle cells increases reactive oxygen species (ROS) production (via both mitochondrial and NADPH oxidase contributions linked to p47phox activation), which activates NF-κB2 (p52 pathway) and upregulates proinflammatory genes (Vcam1, Icam1, Cx3cl1, Ccl2, Ptgs2). This was demonstrated in Sm22 knockout mice after carotid denudation injury, in primary Sm22-/- VSMCs, and in PAC1 cells after Sm22 knockdown; ROS scavengers blocked NF-κB activation and proinflammatory gene induction.\",\n      \"method\": \"Sm22 knockout mouse carotid denudation model, primary VSMC culture, siRNA knockdown, ROS scavenger experiments, NF-κB activation assays, qRT-PCR, Western blot\",\n      \"journal\": \"Circulation research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout plus in vitro knockdown with mechanistic rescue by ROS scavengers, multiple orthogonal methods across multiple experimental systems\",\n      \"pmids\": [\"20224039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"SM22 deficiency alters VSMC actin cytoskeleton (compromised stress fiber formation, increased actin dynamics) and promotes chondrogenic conversion after arterial injury, evidenced by upregulation of SOX9, type II collagen, aggrecan, BMP2, and osteopontin, with concomitant suppression of myocardin and VSMC markers. Enhanced ROS production and NF-κB pathway activation mediate SOX9 upregulation in SM22-deficient VSMCs.\",\n      \"method\": \"Sm22 knockout mouse carotid denudation model, primary Sm22-/- VSMC culture, VSMC line Sm22 knockdown, actin dynamics assays, gene expression analysis, immunofluorescence\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo knockout model plus in vitro knockdown, multiple chondrogenic markers measured, ROS-NF-κB pathway mechanistically linked, single lab but multiple orthogonal approaches\",\n      \"pmids\": [\"21183509\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"The yeast SM22 homologue Scp1 contains two actin-binding domains that allow it to both bind and bundle actin without dimerization. Scp1 localizes to cortical actin patches during endocytosis. Key residues in the actin interface are required for patch localization. Loss of Scp1 impairs patch movement away from the plasma membrane; double deletion of scp1 and fimbrin/sac6 dramatically increases patch lifetime, establishing a redundant role for actin-bundling proteins in endocytosis.\",\n      \"method\": \"Live cell imaging of GFP-tagged mutants, in vitro actin-bundling assays, genetic epistasis (scp1Δ, sac6Δ, double mutant), site-directed mutagenesis of actin-binding domains\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Strong — in vitro reconstitution of actin bundling plus mutagenesis plus live imaging plus genetic epistasis, yeast ortholog with conserved function\",\n      \"pmids\": [\"18400761\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"Fission yeast Stg1, a SM22/transgelin-like protein, crosslinks F-actin in vitro and localizes to actin patches. Overexpression of Stg1 suppresses contractile ring formation and causes abnormal F-actin aggregates, implicating it in cytokinesis control through actin cytoskeleton regulation.\",\n      \"method\": \"Biochemical F-actin crosslinking assay, microscopic localization, overexpression phenotype analysis in S. pombe\",\n      \"journal\": \"FEBS letters\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — in vitro crosslinking assay and localization confirmed, but only overexpression phenotype studied in single lab with no mutagenesis; fission yeast ortholog\",\n      \"pmids\": [\"16256112\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"A bovine aorta SM22 homolog (25-kDa protein, corresponding to WS3-10) directly binds F-actin at a molar ratio of 1:6 actin monomers with a binding constant of 7.0 × 10^5 M^-1, and associates with the membrane fraction in a Ca2+-sensitive manner (membrane association promoted by Ca2+, dissociated by EGTA).\",\n      \"method\": \"Protein purification, F-actin cosedimentation/binding assay, membrane fractionation with Ca2+/EGTA treatment, partial sequence analysis\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Weak — direct in vitro binding assay with quantified binding constant and Ca2+ modulation, single lab, single study\",\n      \"pmids\": [\"8117285\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2015,\n      \"finding\": \"SM22 phosphorylation by Rho kinase (ROCK), but not by PKC, negatively regulates SM22-actin binding in smooth muscle cells. Higher phospho-SM22 levels and decreased SM22-actin binding were found in internal anal sphincter (IAS) vs. rectal smooth muscle (RSM) cells. SM22 overexpression caused concentration-dependent relaxation of IAS SMCs greater than RSM SMCs; SM22 siRNA caused contraction in both. This links Rho kinase-mediated SM22 phosphorylation to basal smooth muscle tone regulation.\",\n      \"method\": \"pFLAG-SM22 transfection, SM22 siRNA, SMC length measurement, phospho-SM22 western blot, ROCK inhibitor Y-27632 and PKC inhibitor Gö-6850 treatment, SM22-actin binding assay\",\n      \"journal\": \"American journal of physiology. Gastrointestinal and liver physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — multiple methods (overexpression, siRNA, kinase inhibitors, binding assay) in single lab, defines ROCK as the relevant kinase for SM22 phosphorylation and functional consequence\",\n      \"pmids\": [\"25617350\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TAGLN upregulation in cancer-associated fibroblasts (CAFs) from gastric carcinoma promotes cancer cell migration and invasion in vitro and in vivo. TAGLN knockdown via siRNA in CAFs significantly reduced MMP-2 expression and decreased tumor metastatic capacity, placing TAGLN upstream of MMP-2 in a stromal pro-metastatic pathway.\",\n      \"method\": \"siRNA knockdown in CAFs, qRT-PCR, Western blot for MMP-2, transwell migration/invasion assay, in vivo metastasis model\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA knockdown with defined cellular phenotype and identification of MMP-2 as downstream effector, single lab but multiple orthogonal assays\",\n      \"pmids\": [\"23510049\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2012,\n      \"finding\": \"Depletion of SM22/TAGLN in REF52 fibroblasts disrupts actin organization, increases cell motility, and enables spontaneous podosome formation with increased Matrigel invasion capacity. Conversely, re-expression of SM22 in SM22-negative PC3 prostate cancer cells reduces Matrigel invasion. SM22-depleted cells also show reduced reactive oxygen species levels under serum starvation stress.\",\n      \"method\": \"SM22 siRNA knockdown in REF52 fibroblasts, SM22 re-expression in PC3 cells, actin organization assays, podosome scoring, Matrigel invasion assay, ROS measurement under stress\",\n      \"journal\": \"BMC cell biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal loss-of-function and gain-of-function experiments with defined actin and invasion phenotypes, single lab, multiple cell lines\",\n      \"pmids\": [\"22257561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TRAF6 (an E3 ubiquitin ligase) catalyzes mono-ubiquitination of TAGLN at K89 or K108 residues (with E2 UBE2A/E2A), targeting it for proteasomal degradation. This TRAF6-mediated ubiquitination and degradation of TAGLN leads to activation of NF-κB and Myc signaling pathways. Ablation of TAGLN in prostate cancer cells promoted cell proliferation and suppressed migration.\",\n      \"method\": \"In vitro ubiquitination assay screening >20 E2-E3 pairs, site-directed mutagenesis of ubiquitination sites (K89/K108), proteasome inhibitor treatment, TRAF6 overexpression/knockdown, NF-κB and Myc pathway activation assays\",\n      \"journal\": \"Molecular cancer research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro ubiquitination reconstitution with mutagenesis identifying specific sites, plus functional pathway consequence assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33771884\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TAGLN is expressed in vascular endothelial cells (ECs), where its expression is activated during EC elongation downstream of VEGF-A signaling and PI3K-Akt/mTORC1 pathway inhibition. Genetic disruption of TAGLN (and paralogs TAGLN2, TAGLN3) augmented angiogenic behaviors of HUVECs, identifying TAGLN as a negative regulator of EC elongation and angiogenesis.\",\n      \"method\": \"Mouse ESC Tagln promoter-driven fluorescence reporter, VEGF-A treatment, PI3K-Akt/mTORC1 inhibition, HUVEC angiogenesis model, TAGLN/TAGLN2/TAGLN3 CRISPR knockout, immunofluorescence in mouse embryo ECs\",\n      \"journal\": \"Journal of cell science\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic disruption with defined angiogenic phenotype plus promoter reporter and in vivo EC expression confirmation, single lab with multiple orthogonal approaches\",\n      \"pmids\": [\"34338296\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"TAGLN acts as a mechanosensitive protein in ovarian cancer cells that responds to extracellular matrix stiffness, forms a regulation loop with Src kinase activation, and mediates stiffness-regulated tumor progression through the RhoA/ROCK pathway.\",\n      \"method\": \"Atomic force microscopy (AFM) for stiffness measurement, collagen-coated polyacrylamide hydrogel system for stiffness modulation, transwell assay, immunofluorescence, western blot for RhoA/ROCK pathway, in vivo tumor model\",\n      \"journal\": \"Journal of experimental & clinical cancer research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Weak — defined mechanosensitive pathway placement with multiple assays but single lab and Src-TAGLN loop characterization is incompletely described in abstract\",\n      \"pmids\": [\"34538264\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"ALKBH5, an m6A RNA demethylase, binds to m6A sites in TAGLN mRNA and reduces its m6A methylation level, thereby inhibiting TAGLN mRNA degradation and increasing TAGLN protein expression. Elevated TAGLN then inhibits enteric neural crest cell proliferation and migration, contributing to Hirschsprung's disease pathogenesis.\",\n      \"method\": \"MeRIP-qPCR for m6A site identification, dual-luciferase reporter, ALKBH5 overexpression/knockdown, cell proliferation and migration assays, zebrafish ALKBH5 overexpression model\",\n      \"journal\": \"Life sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-qPCR identifies m6A sites, dual-luciferase validates regulation, functional phenotype confirmed in vitro and in vivo zebrafish model, single lab\",\n      \"pmids\": [\"33961858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"TAGLN physically interacts with HMGA2 (by co-immunoprecipitation), and this complex mediates TGF-β-induced colorectal cancer cell migration and invasion. TGF-β promotes TAGLN protein expression and nuclear translocation. TAGLN knockdown reverses TGF-β-induced EMT (rescues E-cadherin loss, reduces vimentin, fibronectin, MMP9, MMP2); HMGA2 overexpression restores these effects when TAGLN is inhibited, both in vitro and in vivo.\",\n      \"method\": \"Co-immunoprecipitation, siRNA knockdown, HMGA2 overexpression, EMT marker western blot (E-cadherin, vimentin, fibronectin), MMP2/MMP9 assay, in vivo tumor model\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — Co-IP identifies TAGLN-HMGA2 interaction, functional epistasis with HMGA2 rescue experiments, multiple EMT markers assessed, single lab\",\n      \"pmids\": [\"33116628\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"The C-terminal domain of SM22α interacts with F-actin. SM22α colocalizes with F-actin during VSMC re-differentiation (serum withdrawal/restimulation). GST pulldown and co-immunoprecipitation confirmed that SM22α interacts with F-actin via its C-terminal domains to participate in cytoskeleton reorganization.\",\n      \"method\": \"GST pulldown assay, co-immunoprecipitation, immunofluorescence, F-actin/G-actin fractionation by western blot, prokaryotic expression of GST-SM22α\",\n      \"journal\": \"Chinese journal of applied physiology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal pulldown and co-IP plus localization, consistent with mutagenesis data from PMID 11053353, single lab\",\n      \"pmids\": [\"21162287\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"TAGLN promotes skin fibrosis through a mechano-metabolic axis: TAGLN activates the RhoA/ROCK2 pathway, which in turn upregulates the glucose transporter SLC2A3, thereby promoting glycolysis and enhancing fibroblast motility, contraction, and collagen secretion. Downregulation of TAGLN inhibited fibroblast invasion, migration, contraction, and collagen secretion in vitro, and reduced fibrosis in a bleomycin mouse model.\",\n      \"method\": \"Transwell assay, wound healing assay, collagen gel contraction assay, immunofluorescence, RNA-seq, RhoA/ROCK2 pathway inhibition, TAGLN knockdown, bleomycin mouse model\",\n      \"journal\": \"International journal of biological sciences\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — RNA-seq identifies SLC2A3 as downstream target, RhoA/ROCK2 pathway mechanistically placed between TAGLN and SLC2A3, functional assays with in vivo validation, single lab\",\n      \"pmids\": [\"39781462\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2025,\n      \"finding\": \"NRF2 directly transcriptionally activates TAGLN expression by binding a functional antioxidant response element (ARE) in the TAGLN promoter, as confirmed by dual luciferase and ChIP assays. TAGLN overexpression promotes ovarian cancer cell migration and EMT (increased N-cadherin, decreased E-cadherin); TAGLN siRNA knockdown in NRF2-overexpressing cells reverses these effects, placing TAGLN downstream of NRF2 in a pro-migratory EMT pathway.\",\n      \"method\": \"Dual luciferase reporter assay, chromatin immunoprecipitation (ChIP), TAGLN overexpression, siRNA knockdown, wound-healing assay, Transwell assay, EMT marker western blot\",\n      \"journal\": \"Journal of ovarian research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and dual luciferase confirm direct ARE-mediated transcriptional regulation by NRF2, functional rescue experiments confirm epistasis, single lab\",\n      \"pmids\": [\"41029755\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1987,\n      \"finding\": \"SM22α from chicken gizzard smooth muscle is a 197-residue single polypeptide chain (Mr ~21,978) that exists as a monomer at physiological ionic strengths and is a moderately asymmetric globular protein. Its complete amino acid sequence was determined; no significant homology to previously known proteins was found at the time of publication.\",\n      \"method\": \"Automated and manual Edman degradation sequencing, sedimentation equilibrium, CD spectroscopy, Stokes radius determination\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — direct biochemical characterization of purified protein by multiple physical methods; primary structural determination\",\n      \"pmids\": [\"3571244\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"TAGLN (SM22/transgelin) is an actin-binding and actin-bundling protein that binds F-actin through multiple regions in its C-terminal domain; PKC-mediated phosphorylation at Ser-181 (and Rho kinase-mediated phosphorylation) reduces actin binding and redistributes the protein from the cytoskeleton to the cytoplasm. TAGLN suppresses MMP-9 expression by attenuating ERK/MAPK signaling and AP-1-dependent transcription; it is degraded via TRAF6-catalyzed mono-ubiquitination at K89/K108 followed by proteasomal degradation, leading to NF-κB/Myc activation; SM22 deficiency promotes inflammatory signaling in VSMCs through ROS-mediated NF-κB2 activation; TAGLN mediates mechanosensitive signaling through RhoA/ROCK2, regulates glycolysis via SLC2A3 in fibroblasts, and is a direct transcriptional target of NRF2 through an ARE in its promoter, collectively placing it as a multifunctional cytoskeletal regulator that integrates mechanical, metabolic, and inflammatory signals.\"\n}\n```","stage2_raw":"{\n  \"mechanistic_narrative\": \"TAGLN (SM22/transgelin) is an actin-binding and actin-bundling cytoskeletal protein that integrates mechanical, metabolic, and inflammatory signals to control cell shape, motility, and invasion [#0, #10, #17]. It binds F-actin through multiple regions in its C-terminal domain (residues ~151-201, including a 154-KKAQEHKR-161 site and residues 170-186) and colocalizes with actin filaments, whereas C-terminally truncated protein fails to associate [#0, #16]; phosphorylation at Ser-181 by protein kinase C, and phosphorylation by Rho kinase (ROCK), reduces actin binding and redistributes the protein from the cytoskeleton to the cytoplasm, thereby tuning smooth muscle tone [#0, #1, #8]. Loss of TAGLN destabilizes the actin cytoskeleton, compromises stress fibers, increases motility, and permits podosome formation and matrix invasion, while re-expression suppresses invasion [#10, #4]. Through its N-terminal calponin homology domain, TAGLN represses MMP-9 expression by attenuating ERK/MAPK and AP-1 (c-Fos)-dependent transcription [#2], and SM22 deficiency in vascular smooth muscle elevates ROS that drive NF-\\u03baB2 activation, proinflammatory gene induction, and chondrogenic conversion after arterial injury [#3, #4]. TAGLN protein levels are set by multiple regulatory inputs: TRAF6-catalyzed mono-ubiquitination at K89/K108 targets it for proteasomal degradation and de-represses NF-\\u03baB and Myc signaling [#11]; ALKBH5-mediated m6A demethylation stabilizes TAGLN mRNA [#14]; and NRF2 directly transactivates TAGLN through an ARE in its promoter [#18]. In disease contexts TAGLN functions as a mechanosensor responding to matrix stiffness via RhoA/ROCK, drives a mechano-metabolic fibrotic axis that upregulates the glucose transporter SLC2A3 to fuel glycolysis, and acts in stromal and tumor cells to promote migration, EMT, and metastasis [#13, #17, #9, #15]. Conserved orthologs in budding and fission yeast bundle and crosslink actin and localize to actin patches and the contractile ring, underscoring an ancient role in actin organization [#5, #6].\",\n  \"teleology\": [\n    {\n      \"year\": 1987,\n      \"claim\": \"Establishing the primary structure and physical state of SM22\\u03b1 was the foundation for all later mechanistic work; the question was simply what this abundant smooth-muscle protein is.\",\n      \"evidence\": \"Edman sequencing, sedimentation equilibrium, and CD spectroscopy of chicken gizzard SM22\\u03b1\",\n      \"pmids\": [\"3571244\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No binding partner or function assigned at this stage\", \"No homology to known proteins identified at the time\"]\n    },\n    {\n      \"year\": 1994,\n      \"claim\": \"Whether SM22 has a cytoskeletal function was answered by showing it directly binds F-actin with measurable stoichiometry and affinity and associates with membranes in a Ca2+-sensitive manner.\",\n      \"evidence\": \"Protein purification and F-actin cosedimentation with quantified binding constant, plus membrane fractionation under Ca2+/EGTA\",\n      \"pmids\": [\"8117285\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Actin-binding region not mapped\", \"Functional consequence of binding not defined\", \"Physiological role of Ca2+-sensitive membrane association unclear\"]\n    },\n    {\n      \"year\": 2000,\n      \"claim\": \"These studies localized the actin-binding determinants to the C-terminal domain and identified PKC phosphorylation of Ser-181 as a switch that releases SM22 from the cytoskeleton, defining how its localization is regulated.\",\n      \"evidence\": \"Site-directed mutagenesis with in vitro cosedimentation, PKC kinase assay, and immunofluorescence of transfected myocytes; in vivo PKC activation with subcellular localization\",\n      \"pmids\": [\"11053353\", \"10939458\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Physiological signal triggering PKC phosphorylation in vivo not defined\", \"Whether other kinases regulate binding not addressed\"]\n    },\n    {\n      \"year\": 2005,\n      \"claim\": \"Ortholog work tested whether actin regulation is a conserved property; the fission yeast Stg1 crosslinks F-actin and influences cytokinesis, generalizing the actin-organizing role beyond vertebrate smooth muscle.\",\n      \"evidence\": \"In vitro F-actin crosslinking, localization, and overexpression phenotype in S. pombe\",\n      \"pmids\": [\"16256112\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Only overexpression studied, no loss-of-function mutagenesis\", \"Direct relevance to mammalian TAGLN function inferred from homology\"]\n    },\n    {\n      \"year\": 2006,\n      \"claim\": \"Beyond a structural actin role, this work established TAGLN as a transcriptional/signaling regulator, showing its calponin homology domain represses MMP-9 by dampening ERK/MAPK and AP-1 activity.\",\n      \"evidence\": \"Overexpression, siRNA, MMP-9 promoter mutagenesis, AP-1 reporter, constitutively active MEK, and SM22-null mouse immunohistochemistry\",\n      \"pmids\": [\"16835221\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism linking cytoplasmic actin-binding protein to ERK/AP-1 suppression not resolved\", \"Direct versus indirect effect on the pathway unclear\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"The budding yeast ortholog Scp1 clarified the biochemical mode of action, showing two actin-binding domains permit bundling without dimerization and a redundant role with fimbrin in endocytic patch dynamics.\",\n      \"evidence\": \"Live imaging of GFP mutants, in vitro bundling assays, site-directed mutagenesis, and scp1\\u0394/sac6\\u0394 genetic epistasis\",\n      \"pmids\": [\"18400761\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mammalian TAGLN bundling stoichiometry not directly compared\", \"Endocytic role in mammalian cells not established\"]\n    },\n    {\n      \"year\": 2010,\n      \"claim\": \"Knockout studies linked SM22 loss to inflammatory and phenotypic conversion of VSMCs, defining a ROS\\u2013NF-\\u03baB2 axis and chondrogenic transdifferentiation after vascular injury.\",\n      \"evidence\": \"Sm22 knockout mouse carotid denudation, primary VSMC culture, knockdown, ROS scavengers, and gene/marker expression analysis\",\n      \"pmids\": [\"20224039\", \"21183509\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How cytoskeletal disruption mechanistically elevates ROS not fully resolved\", \"Direct target of SM22 in the NADPH oxidase/NF-\\u03baB pathway not identified\"]\n    },\n    {\n      \"year\": 2012,\n      \"claim\": \"Reciprocal gain- and loss-of-function in fibroblasts and prostate cancer cells established TAGLN as a suppressor of motility, podosome formation, and matrix invasion through actin organization.\",\n      \"evidence\": \"siRNA in REF52 fibroblasts and re-expression in PC3 cells with actin, podosome, invasion, and ROS assays\",\n      \"pmids\": [\"22257561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Molecular link between actin organization and podosome suppression not defined\", \"ROS reduction under starvation mechanistically unexplained\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"TAGLN was found to act non-cell-autonomously, with stromal CAF expression promoting metastasis upstream of MMP-2, expanding its role to the tumor microenvironment.\",\n      \"evidence\": \"siRNA knockdown in gastric carcinoma CAFs, MMP-2 readouts, migration/invasion assays, and in vivo metastasis model\",\n      \"pmids\": [\"23510049\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Whether TAGLN regulates MMP-2 transcriptionally or via cytoskeleton unclear\", \"Context dependence versus its MMP-9 suppressive role unresolved\"]\n    },\n    {\n      \"year\": 2015,\n      \"claim\": \"This work identified ROCK, rather than PKC, as the kinase regulating SM22-actin binding in specific smooth muscle and tied SM22 phosphorylation to basal tone.\",\n      \"evidence\": \"pFLAG-SM22 transfection, siRNA, ROCK (Y-27632) and PKC (G\\u00f66850) inhibitors, phospho-SM22 westerns, SMC length, and binding assays\",\n      \"pmids\": [\"25617350\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Reconciliation with earlier PKC/Ser-181 model not addressed\", \"Phosphosite targeted by ROCK not mapped\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Identification of a TAGLN-HMGA2 complex showed TAGLN can act in TGF-\\u03b2-driven EMT, with nuclear translocation linking it to a pro-invasive transcriptional program.\",\n      \"evidence\": \"Co-immunoprecipitation, siRNA, HMGA2 overexpression rescue, EMT marker westerns, and in vivo tumor model\",\n      \"pmids\": [\"33116628\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Single Co-IP without reciprocal structural validation of the interaction\", \"Functional role of nuclear TAGLN not mechanistically defined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"A cluster of studies defined the regulatory inputs and outputs that set TAGLN levels and signaling: TRAF6 ubiquitination/degradation, m6A control by ALKBH5, mechanosensing via RhoA/ROCK, and negative regulation of angiogenesis.\",\n      \"evidence\": \"In vitro ubiquitination with E2-E3 screening and K89/K108 mutagenesis; MeRIP-qPCR and luciferase; AFM/stiffness hydrogels with RhoA/ROCK readouts; ESC reporter and TAGLN/TAGLN2/TAGLN3 CRISPR knockout in HUVECs\",\n      \"pmids\": [\"33771884\", \"33961858\", \"34538264\", \"34338296\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"How ubiquitination-coupled degradation integrates with kinase regulation unknown\", \"Mechanism by which TAGLN feeds back on Src and RhoA/ROCK incompletely described\", \"Redundancy with TAGLN2/TAGLN3 in non-angiogenic contexts unexplored\"]\n    },\n    {\n      \"year\": 2025,\n      \"claim\": \"The most recent work placed TAGLN at the center of a mechano-metabolic fibrotic axis and as a direct NRF2 target, connecting matrix stiffness, RhoA/ROCK2, SLC2A3-driven glycolysis, and antioxidant transcriptional control.\",\n      \"evidence\": \"RNA-seq, RhoA/ROCK2 inhibition, knockdown, bleomycin fibrosis model; dual luciferase and ChIP for NRF2 ARE binding with EMT rescue assays\",\n      \"pmids\": [\"39781462\", \"41029755\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"How TAGLN activates RhoA/ROCK2 mechanistically not defined\", \"Whether NRF2-driven TAGLN connects to its antioxidant/ROS roles in VSMCs unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"A unifying mechanism for how a single C-terminal actin-binding protein switches between cytoskeletal, transcriptional, and signaling outputs remains undefined.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No structural model explaining context-dependent nuclear versus cytoskeletal function\", \"Direct molecular link from actin binding to ERK/AP-1, NF-\\u03baB, and RhoA/ROCK signaling not established\", \"Integration of competing PKC and ROCK phosphorylation regulation unresolved\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0008092\", \"supporting_discovery_ids\": [0, 5, 6, 7, 16]},\n      {\"term_id\": \"GO:0098772\", \"supporting_discovery_ids\": [2, 3, 11]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005856\", \"supporting_discovery_ids\": [0, 5, 16]},\n      {\"term_id\": \"GO:0005829\", \"supporting_discovery_ids\": [1]},\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [15]},\n      {\"term_id\": \"GO:0005886\", \"supporting_discovery_ids\": [7]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [3, 11, 13, 17]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [9, 14, 17, 18]},\n      {\"term_id\": \"R-HSA-8953897\", \"supporting_discovery_ids\": [3, 13, 17]}\n    ],\n    \"complexes\": [],\n    \"partners\": [\"ACTB\", \"TRAF6\", \"UBE2A\", \"HMGA2\"],\n    \"other_free_text\": []\n  }\n}","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}