{"gene":"FOSL2","run_date":"2026-06-09T23:54:44","timeline":{"discoveries":[{"year":1990,"finding":"Fra-2 (FOSL2) protein forms a complex with c-Jun in cells, and overexpression of fra-2 causes transformation of chicken embryo fibroblasts, demonstrating shared biochemical functions with c-Fos.","method":"Co-immunoprecipitation in cells; retroviral overexpression transformation assay","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — reciprocal co-IP for complex formation plus functional transformation assay, replicated in subsequent papers","pmids":["2110368"],"is_preprint":false},{"year":1991,"finding":"Fra-2 forms stable heterodimers with c-Jun, JunB, or JunD in vitro; all complexes bind AP-1 sites. Unlike c-Fos/c-Jun (which activates), Fra-2/c-Jun suppresses c-Jun transactivation at AP-1 sites in F9 cells; this suppressive difference maps to the C-terminal half of Fra-2. Fra-2/JunD, however, activates transcription similarly to c-Fos/JunD.","method":"In vitro heterodimer formation assays; DNA-binding assays; transient transfection reporter assays; chimeric protein analysis","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 1–2 / Strong — in vitro reconstitution of heterodimers, DNA-binding assays, reporter assays with chimeric proteins, replicated concept in multiple subsequent studies","pmids":["1945831"],"is_preprint":false},{"year":1991,"finding":"Fra-2 protein is phosphorylated on serine residues upon serum stimulation of chicken embryo fibroblasts, shifting it from hypophosphorylated (40–46 kDa) to a hyperphosphorylated 46 kDa form.","method":"Western blot with alkaline phosphatase treatment; metabolic labeling","journal":"Biochemical and biophysical research communications","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — biochemical fractionation and phosphatase treatment confirm phosphorylation, single lab","pmids":["1899576"],"is_preprint":false},{"year":1993,"finding":"JunD mutants with transforming activity show enhanced transactivation specifically when heterodimerized with Fra-2 (but not c-Fos or Fra-1), indicating Fra-2 functions as a partner-specific transactivation enabler.","method":"Transient transfection reporter assay with AP-1 site in F9 cells; retroviral transformation assay in chicken embryo fibroblasts","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays with multiple Jun mutants and Fos family members, single lab","pmids":["8415709"],"is_preprint":false},{"year":1994,"finding":"Fra-2 is phosphorylated in vivo in a serum-dependent manner during G1 and in asynchronously growing Swiss 3T3 cells; MAP kinase (ERK) phosphorylates Fra-2 in vitro producing a gel-mobility shift similar to in vivo, and this phosphorylation increases Fra-2 DNA-binding activity. PKA, PKC, and cdc2 also phosphorylate Fra-2 in vitro but do not produce the same mobility shift.","method":"In vitro kinase assays (PKA, PKC, cdc2, MAP kinase); alkaline phosphatase treatment; 1D phosphopeptide mapping; EMSA DNA-binding assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase reconstitution with multiple kinases, phosphopeptide mapping comparing in vitro and in vivo, functional DNA-binding consequence measured","pmids":["8058317"],"is_preprint":false},{"year":1995,"finding":"Fra-2 mRNA and protein exhibit a circadian rhythm in the rat pineal gland (absent during the day, robustly increased at night), regulated by an adrenergic→cAMP mechanism; AP-1 binding activity in the pineal parallels Fra-2 protein levels.","method":"Immunoblot; Northern blot; organ culture with adrenergic/cAMP manipulations; EMSA","journal":"The Journal of biological chemistry","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — direct protein/mRNA measurements combined with pharmacological organ culture experiments, single lab","pmids":["7592994"],"is_preprint":false},{"year":1995,"finding":"Fra-2 protein binds AP-1 sites in the fra-2 promoter as a Fra-2/c-Jun complex; serum induction of fra-2 expression is mediated through CRE-like and AP-1 binding sites (not SRE); at late times post-stimulation, Fra-2/c-Jun re-occupies its own promoter, while at early times c-Fos/c-Jun drives fra-2 transcription, establishing a delayed autoregulatory loop.","method":"Promoter deletion/mutation reporter assays; EMSA with CEF nuclear extracts","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — promoter deletion and mutation combined with EMSA, single lab","pmids":["7862446"],"is_preprint":false},{"year":1996,"finding":"In fully differentiated osteoblasts, Fra-2 and JunD are the principal AP-1 complex members detectable, and co-expression of Fra-2/JunD (but not other Fos/Jun pairs) specifically stimulates osteocalcin promoter reporter expression in a site-specific manner; antisense suppression of Fra-2 impairs osteoblast differentiation and bone tissue-like organization.","method":"Western blot; EMSA; transient transfection reporter assays; promoter deletion analysis; antisense oligonucleotide suppression","journal":"Endocrinology","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple orthogonal methods (EMSA, reporter, antisense loss-of-function with phenotype), replicated concept across several bone biology studies","pmids":["8828501"],"is_preprint":false},{"year":1997,"finding":"In v-src-transformed chicken embryo fibroblasts, Fra-2 is extensively phosphorylated at multiple Ser and Thr residues in its C-terminal region (aa 266–323) by ERK2 (identified by in-gel kinase assay as a 42 kDa kinase); this phosphorylation converts Fra-2 from an inefficient into an active transactivator. Fra-2 promoter is autoregulated via AP-1 sites and a CRE-like sequence in response to Fra-2 phosphorylation status.","method":"In-gel kinase assay; site-directed mutagenesis of phosphorylation sites; Fra-2 C-terminal region as substrate; promoter reporter assays","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 1 / Moderate — in vitro kinase substrate identification with mutagenesis and functional reporter assays, single lab but multiple orthogonal methods","pmids":["9188858"],"is_preprint":false},{"year":1997,"finding":"Exogenous Fra-2 expression represses AP-1 transcriptional activity in TPA-treated keratinocytes, whereas c-Fos activates it in calcium-treated cells, demonstrating opposing roles of Fra-2 and c-Fos in regulating AP-1 activity in keratinocytes.","method":"Transient transfection reporter assays; Western blot analysis of AP-1 protein expression","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reporter assays combined with expression analysis, single lab","pmids":["9315102"],"is_preprint":false},{"year":1998,"finding":"Fra-2/JunD heterodimer specifically binds three AP-1 sites in the murine laminin alpha3A (lama3A) promoter and is required for TGF-β-responsive transcription; cooperative contribution of two distal AP-1 sites to TGF-β inducibility was established by mutagenesis.","method":"Site-directed mutagenesis of AP-1 sites; transient transfection reporter assays; EMSA (mobility shift assays)","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis + EMSA + reporter assays in a single study with clear mechanistic resolution","pmids":["9651314"],"is_preprint":false},{"year":1999,"finding":"Phosphorylation of Fra-2 by MAP kinase (MAPK/MEK pathway) converts Fra-2 from a weak transactivator to an active one; MAPK phosphorylation sites were mapped by site-directed mutagenesis to three threonine and three serine residues in the C-terminal region, with threonines being more susceptible; a positive autoregulatory loop exists where phosphorylated Fra-2 drives fra-2 expression through AP-1 sites in the promoter.","method":"Site-directed mutagenesis of phosphorylation sites; constitutively active MEK1 cotransfection; reporter assays; transformation assays","journal":"Cell growth & differentiation","confidence":"High","confidence_rationale":"Tier 1 / Moderate — site-directed mutagenesis of specific residues combined with functional reporter assays and transformation phenotype, single lab but multiple methods","pmids":["10359014"],"is_preprint":false},{"year":2001,"finding":"Fra-2 expression in the rat pineal gland is required for circadian AP-1 binding activity and for expression of two specific target genes: type II iodothyronine deiodinase and nectadrin (CD24), identified by analysis of 1,190 genes in dominant-negative Fra-2 transgenic rats.","method":"Transgenic dominant-negative Fra-2 rat; gene expression profiling of 1,190 genes; targeted validation","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — in vivo loss-of-function via dominant negative transgene with genome-wide expression screen, single lab","pmids":["11340164"],"is_preprint":false},{"year":2001,"finding":"NGF (but not EGF) specifically increases Fra-2 protein levels (particularly phosphorylated forms) and enhances Fra-2/JunD binding to AP-1 and CREB response elements in PC12 cells, correlating with NGF-specific differentiation vs. EGF-mediated mitogenesis; NGF elicits more sustained ERK phosphorylation than EGF.","method":"Gel mobility shift assays; supershift assays; Western blot; time-course ERK phosphorylation analysis","journal":"The Journal of neuroscience","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — supershift identification of Fra-2/JunD complex, systematic comparison of NGF vs EGF, single lab","pmids":["11150315"],"is_preprint":false},{"year":2003,"finding":"Fra-2 does not enhance cell motility when overexpressed in CSML0 adenocarcinoma cells (unlike Fra-1 or c-Fos), but antisense fra-2 knockdown in L929 fibroblastoid cells (which express Fra-1 and Fra-2) reduces motility, indicating Fra-2 contributes to but is not sufficient to drive motility and that this effect requires the cellular context of Fra-1 co-expression.","method":"Transfection of CSML0 cells with Fos family expression vectors; antisense knockdown; motility assays","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — systematic gain- and loss-of-function in two cell lines, single lab","pmids":["12902987"],"is_preprint":false},{"year":2005,"finding":"MEKK1 controls Fra-2 protein stability by inducing Fra-2 ubiquitination and proteasomal degradation; in MEKK1-/- cells, Fra-2 protein accumulates. MEKK1 thus regulates AP-1 complex composition by controlling Fra-2 turnover.","method":"MEKK1 knockout cells; ubiquitination assay; Western blot for Fra-2 protein levels","journal":"Oncogene","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic KO with ubiquitination assay, single lab","pmids":["15558021"],"is_preprint":false},{"year":2007,"finding":"Fra-2 is constitutively and aberrantly expressed in ATL cells; Fra-2/JunD heterodimer activates the CCR4 promoter via an AP-1 site; Fra-2 siRNA (but not JunB siRNA) reduces CCR4 expression and cell growth; Fra-2 drives expression of c-Myb, BCL-6, and MDM2.","method":"siRNA knockdown; transient transfection reporter assays; CCR4 promoter AP-1 site characterization; cell growth assays; microarray","journal":"Oncogene","confidence":"High","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function, reporter assays with AP-1 site mutants, gene expression profiling, single lab but multiple orthogonal methods","pmids":["18071306"],"is_preprint":false},{"year":2008,"finding":"Fra-2 controls osteoclast survival and size by directly regulating LIF transcription (c-Jun co-factor); Fra-2-deficient mice develop giant osteoclasts with impaired LIF/LIF-receptor signaling; Fra-2 and LIF modulate HIF1alpha through transcriptional regulation of PHD2 (prolyl hydroxylase); placenta-specific Fra-2 drives hypoxia-dependent giant osteoclast formation.","method":"Fra-2 germline and conditional knockout mice; LIF knockout mice; LIF promoter identification as direct Fra-2/c-Jun target; PHD2 transcriptional regulation assay; Bcl-2 overexpression in vivo","journal":"Nature","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple knockout models, direct promoter target identification, epistasis via double KO and rescue experiments","pmids":["18548006"],"is_preprint":false},{"year":2010,"finding":"Fra-2 expression is upregulated in SSc fibroblasts by TGF-β and PDGF stimulation in an ERK-dependent manner; Fra-2 binds DNA of target genes in response to these stimuli; Fra-2 siRNA knockdown reduces collagen release from SSc fibroblasts stimulated with TGF-β or PDGF.","method":"siRNA knockdown; real-time PCR; immunohistochemistry; DNA binding assay; ERK inhibitor","journal":"Arthritis and rheumatism","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function with functional collagen readout and pathway inhibition, single lab","pmids":["20039427"],"is_preprint":false},{"year":2010,"finding":"Fra-2 is induced in cardiac fibroblasts by hyperoxia/reoxygenation via an Ask-1-dependent mechanism; Ask-1 controls Fra-2 gene expression and nuclear localization; AP-1 sites in TGF-β1 and TGF-β3 promoters confer oxygen sensitivity; Fra-2 siRNA knockdown blunts O2-induced TGF-β1 and TGF-β3 expression.","method":"Fra-2 siRNA knockdown; Ask-1 siRNA; reporter assays with AP-1 site deletions; nuclear localization assay","journal":"Cardiovascular research","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function for both Fra-2 and Ask-1 combined with reporter assays, single lab","pmids":["20427335"],"is_preprint":false},{"year":2011,"finding":"FRA-2/FOSL2 selectively binds a variant AP-1-related (AP-1R) sequence (distinct from canonical AP-1 sites) in the Rgs4 proximal promoter to repress Rgs4 transcription; binding was confirmed by ChIP and EMSA; FRA-2-dependent repression involves dismissal of the co-activator CBP from the Rgs4 AP-1R sequence.","method":"Dominant-negative Fra-2 transgenic rat expression profiling; ChIP; EMSA; promoter mutagenesis; co-activator CBP co-occupancy analysis","journal":"The Journal of biological chemistry","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP + EMSA + mutagenesis + co-activator mechanism in one study, in vivo validated by transgenic model","pmids":["21367864"],"is_preprint":false},{"year":2013,"finding":"FOSL2 interacts with Smad3 in vitro and in vivo (co-IP); FOSL2 promotes P300 binding to Smad3 and P300-mediated acetylation of Smad3; this complex enhances TGF-β1-induced signaling and is required for TGF-β1-induced cell migration in NSCLC.","method":"Co-immunoprecipitation (in vitro and in vivo); P300 binding assay; Smad3 acetylation assay; migration assays with FOSL2 knockdown","journal":"PloS one","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — reciprocal Co-IP plus downstream acetylation mechanism and functional migration assay, single lab","pmids":["25375657"],"is_preprint":false},{"year":2013,"finding":"TGF-β1 induces LOXL4 expression in aortic endothelial cells via functional cooperation between Smad proteins and a JunB/Fra-2 AP-1 complex; Fra-2 phosphorylation by ERK is required for this cooperation; a distal enhancer containing both an AP-1 site and a Smad binding element is absolutely required.","method":"Promoter deletion and mutagenesis; ChIP; co-transfection; ERK inhibitor treatment; LOXL4 functional assays","journal":"Molecular and cellular biology","confidence":"Medium","confidence_rationale":"Tier 1–2 / Moderate — mutagenesis + ChIP + phosphorylation mechanism, single lab","pmids":["23572561"],"is_preprint":false},{"year":2013,"finding":"Fra-2 directly activates the SOX4 promoter via an AP-1 site together with JUND in ATL cells; SOX4 in turn directly activates the HDAC8 promoter, establishing a Fra-2/JUND → SOX4 → HDAC8 oncogenic cascade required for ATL cell growth.","method":"siRNA knockdown; reporter assay (AP-1 site in SOX4 promoter); microarray; HDAC8 promoter reporter assay","journal":"Blood","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — siRNA loss-of-function + promoter reporter mechanistic cascade, single lab","pmids":["23482931"],"is_preprint":false},{"year":2013,"finding":"Fra-2 expression is restricted to undifferentiated satellite cells and reserve cells in skeletal muscle (not in differentiated myofiber nuclei); Fra-2 silencing enhances myogenic differentiation markers; ERK1/2 signaling (cytokine-mediated) regulates Fra-2 protein stability via phosphorylation at S320 and T322 (identified by mass spectrometry and mutational analysis); S320 phosphorylation occurs transiently in activated satellite cells and is extinguished in differentiating cells.","method":"Fra-2 siRNA knockdown; mass spectrometry; site-directed mutagenesis of S320/T322; immunofluorescence in satellite cells; ERK1/2 signaling manipulation","journal":"Cell death & disease","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — mass spectrometry-identified phosphosites validated by mutagenesis, combined with in vivo localization and loss-of-function, single lab but multiple orthogonal methods","pmids":["23807221"],"is_preprint":false},{"year":2016,"finding":"Fra-2 binds the TIMP-1 promoter (confirmed by ChIP) in monocytes; TLR-8 stimulation combined with histone demethylation (DZNep treatment) enhances Fra-2 and TIMP-1 expression; Fra-2-driven TIMP-1 production by monocytes induces transdifferentiation of dermal fibroblasts into myofibroblasts.","method":"ChIP; luciferase reporter assay; siRNA/inhibitor treatments; co-culture of monocytes and fibroblasts; TIMP-1 blocking antibody","journal":"Arthritis & rheumatology","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmation of TIMP-1 promoter binding plus functional co-culture assay, single lab","pmids":["26814616"],"is_preprint":false},{"year":2017,"finding":"Fra-2 regulates B cell development by directly binding and enhancing transcription of Foxo1 and Irf4 (identified by ChIP-seq); deletion of Fra-2 reduces expression of Foxo1, Irf4, Ikaros, Aiolos, IL7Rα, and Rag1/2; exogenous Foxo1 and Irf4 fully rescue pro-B cell proliferation and small pre-B cell differentiation in Fra-2-deficient cells.","method":"Fra-2 conditional knockout; gene expression profiling; ChIP-seq; IL-7-stimulated pro-B cell cultures; Foxo1/Irf4 rescue experiments","journal":"The Journal of experimental medicine","confidence":"High","confidence_rationale":"Tier 2 / Strong — conditional KO with ChIP-seq for direct targets, rescue experiments with downstream TFs, multiple orthogonal methods","pmids":["28566276"],"is_preprint":false},{"year":2019,"finding":"HGF/MET signaling induces phosphorylation and upregulation of FOSL2 via ERK1/2 kinase in NSCLC cells; FOSL2 binds the SNAI2 promoter and promotes SNAI2 transcription (confirmed by ChIP and dual-luciferase assay), driving EMT, invasion, and migration.","method":"Western blot for phospho-FOSL2; ERK1/2 manipulation; ChIP; dual-luciferase reporter assay; transwell/scratch assays","journal":"OncoTargets and therapy","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP and reporter assay for direct promoter binding, ERK pathway mechanistic link, single lab","pmids":["31807006"],"is_preprint":false},{"year":2020,"finding":"Fosl2 (Fra-2) is induced by TCR signaling in T cells and cell-intrinsically represses Treg development; Fosl2 overexpression reduces FoxP3 expression and other Treg differentiation genes; transfer of Fosl2tg T cells transfers inflammation, suppressible by co-delivery of Tregs; Fosl2 deficiency reduces EAE severity.","method":"Fosl2 transgenic and conditional knockout mice; Rag2-/- cross; T cell transfer experiments; EAE model; gene expression analysis","journal":"Cell reports","confidence":"High","confidence_rationale":"Tier 2 / Strong — multiple genetic models (Tg, KO, Rag2-/- cross), transfer experiments with epistatic rescue by Treg co-delivery, disease model validation","pmids":["32610127"],"is_preprint":false},{"year":2020,"finding":"β-catenin transcriptionally activates FOSL2 in tumor-associated macrophages (TAMs); FOSL2 drives a gene regulatory switch from M1-like to M2-like TAMs promoting immunosuppression; β-catenin ablation in macrophages reprograms M2 to M1 TAMs via FOSL2 suppression.","method":"Pharmacological and macrophage-specific genetic ablation of β-catenin; transcriptome analysis; in vitro TAM model; in vivo lung tumor models","journal":"Science advances","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — genetic ablation in vivo and in vitro with transcriptome analysis, mechanistic pathway placement, single lab","pmids":["32548260"],"is_preprint":false},{"year":2021,"finding":"FOSL2 in breast cancer-associated fibroblasts (CAFs) is regulated by estrogen/cAMP/PKA signaling; FOSL2 directly transcriptionally activates Wnt5a (confirmed by dual luciferase reporter and ChIP); Wnt5a secreted from CAFs activates FZD5/NF-κB/ERK signaling in endothelial cells to promote VEGF-independent angiogenesis.","method":"ChIP; dual luciferase reporter assays; FOSL2/Wnt5a siRNA knockdown; FOSL2 overexpression; tube formation/sprouting/xenograft assays; anti-VEGF blocking","journal":"Theranostics","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — ChIP + reporter assay establish direct FOSL2→Wnt5a transcription, multiple functional angiogenesis readouts, in vivo validation, single lab with multiple orthogonal methods","pmids":["33754039"],"is_preprint":false},{"year":2021,"finding":"IL-1β signaling modulates Jag1/Jag2 expression in ciliated airway cells to inhibit Notch signaling in secretory cells, which activates Fosl2; Fosl2 is required for conversion of secretory cells to alveolar type 2 cells during alveolar regeneration, establishing an IL-1β–Notch–Fosl2 axis in secretory cell fate conversion.","method":"Genetic lineage tracing; Notch inhibition; Fosl2 gain- and loss-of-function; epigenetic signature analysis; human KDR+ secretory cell validation","journal":"Nature cell biology","confidence":"High","confidence_rationale":"Tier 2 / Strong — genetic lineage tracing, epistasis via Notch inhibition plus Fosl2 manipulation, human cell validation, multiple orthogonal approaches","pmids":["34475534"],"is_preprint":false},{"year":2021,"finding":"Fosl-2 (FOSL2) regulates autophagy in cardiac fibroblasts; Fosl-2 overexpression increases LC3BII, Beclin-1, and Atg5 levels; Fosl-2 silencing suppresses collagen, α-SMA, and Beclin-1; silencing LC3B or Beclin-1 reduces Fosl-2 in TGF-β-activated cells (mutual regulation); Fosl-2-deficient or Atg5-deficient stromal cells protect from angiotensin II-induced cardiac fibrosis in vivo.","method":"GapmeR antisense oligonucleotide silencing; Fosl-2tg cardiac fibroblasts; Ccl19Cre Fosl2flox/flox and Ccl19Cre Atg5flox/flox conditional KO mice; osmotic minipump angiotensin II model; immunohistochemistry","journal":"International journal of molecular sciences","confidence":"High","confidence_rationale":"Tier 2 / Moderate — conditional KO in vivo disease model, complementary in vitro silencing with autophagy marker readouts, single lab but multiple orthogonal methods","pmids":["33668422"],"is_preprint":false},{"year":2022,"finding":"FOSL2 co-represses Th17 fate specification together with FOSL1 during human Th17 differentiation (opposite to BATF which promotes Th17); FOSL1, FOSL2, and BATF share genomic binding sites over Th17 lineage regulatory regions; they share protein-interacting partners; SNPs at FOSL2 binding sites alter its DNA binding capacity.","method":"siRNA knockdown of FOSL1/FOSL2/BATF; genome-wide ChIP-seq binding analysis; protein interaction studies; SNP binding assay; human Th17 differentiation cultures","journal":"Nucleic acids research","confidence":"High","confidence_rationale":"Tier 2 / Moderate — genome-wide ChIP-seq with loss-of-function in human primary cells, protein interaction studies, single lab but multiple orthogonal methods","pmids":["35511484"],"is_preprint":false},{"year":2023,"finding":"FOSL2 binds the SGK1 promoter (confirmed by ChIP) and transcriptionally activates SGK1; in TGF-β1-induced renal tubular epithelial cells, FOSL2 silencing reduces SGK1 expression, and SGK1 overexpression rescues the anti-fibrotic effects of FOSL2 knockdown, placing FOSL2 upstream of SGK1 in renal fibrosis via EMT.","method":"ChIP; siRNA knockdown; TGF-β1-induced cell model; UUO mouse model; SGK1 overexpression rescue experiments; Western blot for EMT markers","journal":"Journal of translational internal medicine","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP confirmation of direct SGK1 promoter binding, epistatic rescue by SGK1 overexpression, single lab","pmids":["37662889"],"is_preprint":false},{"year":2023,"finding":"Butyric acid decreases FOSL2 m6A methylation and mRNA expression by suppressing METTL3 (an m6A methyltransferase) in granulosa cells; FOSL2 promotes NLRP3 inflammasome activation and IL-6/TNF-α expression; identified by RNA-seq and MeRIP-seq as a METTL3 target.","method":"RNA-seq; MeRIP-seq; butyric acid treatment; METTL3 siRNA; FOSL2 expression measurement; NLRP3/cytokine assays","journal":"Clinical epigenetics","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — MeRIP-seq identifies m6A modification, functional METTL3 knockdown, cellular assays, single lab","pmids":["37179374"],"is_preprint":false},{"year":2023,"finding":"FOSL2 is a downstream target of the KRAS/MAPK pathway; FOSL2 directly binds the CCL28 promoter and transcriptionally activates CCL28 (confirmed by CUT&Tag and ChIP-qPCR + dual-luciferase reporter); CCL28 recruits regulatory T cells to drive immune suppression in pancreatic ductal adenocarcinoma.","method":"ATAC-seq, H3K27ac ChIP-seq, RNA-seq in GEMMs; CUT&Tag; ChIP-qPCR; dual-luciferase reporter; KRAS/MAPK pathway analysis; xenograft models","journal":"British journal of cancer","confidence":"High","confidence_rationale":"Tier 1–2 / Moderate — CUT&Tag + ChIP-qPCR + reporter assay establish direct FOSL2→CCL28 activation, multiomics epistasis for KRAS→FOSL2, single lab with multiple orthogonal methods","pmids":["37380804"],"is_preprint":false},{"year":2024,"finding":"A single-chain c-Jun~Fra-2 fusion protein (mimicking the c-Jun/Fra-2 AP-1 dimer) drives spontaneous hepatocellular carcinoma when expressed in hepatocytes; c-Myc is a direct transcriptional target of c-Jun/Fra-2 via a conserved distal 3' enhancer; tumors regress when the transgene is switched off (oncogene addiction); BET inhibitor JQ-1 targeting c-Myc reduces tumor growth.","method":"Hepatocyte-restricted c-Jun~Fra-2 transgenic mice; AP-1 enhancer ChIP for c-Myc 3' enhancer; transgene switch-off experiment; JQ-1 BET inhibitor treatment in vivo","journal":"Proceedings of the National Academy of Sciences of the United States of America","confidence":"High","confidence_rationale":"Tier 2 / Strong — in vivo genetic model, direct enhancer ChIP, oncogene addiction rescue, pharmacological validation, single lab but multiple orthogonal methods","pmids":["38657045"],"is_preprint":false},{"year":2024,"finding":"RUNX1 interacts with NPM1 to maintain chromatin accessibility at FOSL2-regulated ECM gene loci; this RUNX1-NPM1 complex facilitates FOSL2-mediated transcriptional activation of ECM-related genes (FN1, COL4A1, LUM) in glioblastoma, independent of RUNX1's own transcriptional function.","method":"ChIP-seq; RNA-seq; Co-IP for RUNX1-NPM1 interaction; ATAC-seq for chromatin accessibility; functional ECM gene expression assays","journal":"Cell death & disease","confidence":"Medium","confidence_rationale":"Tier 2 / Moderate — ChIP-seq and co-IP establish complex and target gene relationships, single lab","pmids":["38286983"],"is_preprint":false}],"current_model":"FOSL2 (Fra-2) is a leucine-zipper transcription factor that obligatorily heterodimerizes with Jun proteins (c-Jun, JunB, JunD) to form AP-1 complexes that bind AP-1 and variant AP-1-related DNA sites; its transcriptional output (activation or repression) is determined by its Jun partner, its phosphorylation state (MAP kinase/ERK phosphorylates multiple C-terminal Ser/Thr residues to convert it from a weak to an active transactivator), and promoter context; it is subject to ubiquitin-mediated degradation controlled by MEKK1, m6A methylation by METTL3, and positive autoregulation through AP-1 sites in its own promoter; established direct transcriptional targets include LIF, Wnt5a, SOX4, CCR4, Rgs4 (repressed via CBP dismissal), SGK1, CCL28, SNAI2, and c-Myc (via a 3' enhancer); and it plays defined roles in osteoclast size control, osteoblast differentiation, B cell development, Treg suppression, cardiac and pulmonary fibrosis (via TGF-β/autophagy axis), airway progenitor fate conversion (IL-1β–Notch–Fosl2 axis), macrophage polarization (downstream of β-catenin), and hepatocellular carcinoma formation (as part of a c-Jun/Fra-2 dimer driving c-Myc)."},"narrative":{"mechanistic_narrative":"FOSL2 (Fra-2) is a leucine-zipper transcription factor that controls cell fate, differentiation, and fibrotic and oncogenic gene programs by forming AP-1 heterodimers with Jun-family partners and binding AP-1 and variant AP-1-related DNA sites [PMID:2110368, PMID:1945831]. Its transcriptional output is partner- and context-dependent: Fra-2/c-Jun can suppress c-Jun-driven AP-1 activity while Fra-2/JunD activates transcription, with the suppressive difference mapping to the Fra-2 C-terminus [PMID:1945831, PMID:8415709]. A central regulatory switch is ERK/MAP-kinase phosphorylation of multiple C-terminal Ser/Thr residues, which converts Fra-2 from a weak into an active transactivator and increases its DNA-binding activity [PMID:8058317, PMID:9188858, PMID:10359014]; phosphorylation also governs Fra-2 protein stability, and MEKK1 directs Fra-2 ubiquitination and proteasomal turnover to set AP-1 complex composition [PMID:15558021, PMID:23807221]. Fra-2 sustains its own expression through a delayed autoregulatory loop acting on AP-1/CRE-like sites in the fra-2 promoter [PMID:7862446, PMID:9188858]. Through these mechanisms FOSL2 directly activates or represses defined targets — LIF in osteoclasts [PMID:18548006], CCR4 and a SOX4→HDAC8 cascade in adult T-cell leukemia [PMID:18071306, PMID:23482931], Foxo1 and Irf4 in B-cell development [PMID:28566276], Wnt5a in cancer-associated fibroblasts [PMID:33754039], SGK1 and SNAI2 in fibrosis and EMT [PMID:37662889, PMID:31807006], CCL28 in pancreatic cancer [PMID:37380804], and Rgs4, which it represses by dismissing the co-activator CBP from a variant AP-1R site [PMID:21367864]. Functionally it controls osteoblast differentiation [PMID:8828501], osteoclast size [PMID:18548006], B-cell development [PMID:28566276], represses regulatory T-cell and Th17 fates [PMID:32610127, PMID:35511484], reprograms tumor-associated macrophages downstream of β-catenin [PMID:32548260], directs airway secretory-cell fate conversion via an IL-1β–Notch axis [PMID:34475534], and drives TGF-β-linked cardiac, pulmonary and renal fibrosis through autophagy and Smad cooperation [PMID:25375657, PMID:33668422, PMID:37662889]. A c-Jun/Fra-2 dimer is sufficient to drive hepatocellular carcinoma through direct activation of a c-Myc 3' enhancer [PMID:38657045].","teleology":[{"year":1990,"claim":"Established that Fra-2 is a functional c-Fos-like factor by showing it physically partners with c-Jun and is oncogenically transforming, defining it as an AP-1 component rather than an orphan immediate-early gene product.","evidence":"Co-immunoprecipitation and retroviral transformation in chicken embryo fibroblasts","pmids":["2110368"],"confidence":"High","gaps":["Did not define which Jun partners predominate physiologically","No direct target genes identified"]},{"year":1991,"claim":"Resolved that Fra-2's transcriptional sign is determined by its Jun partner — Fra-2/c-Jun suppresses while Fra-2/JunD activates AP-1-site transcription — and localized the suppressive activity to the C-terminal half.","evidence":"In vitro heterodimer/DNA-binding assays and chimeric-protein reporter assays in F9 cells","pmids":["1945831","8415709"],"confidence":"High","gaps":["Molecular basis of C-terminal suppression not defined","Partner selection in vivo unaddressed"]},{"year":1999,"claim":"Defined the ERK/MAPK phosphorylation switch: phosphorylation of mapped C-terminal Ser/Thr residues converts Fra-2 from a weak to an active transactivator and increases DNA binding, linking growth-factor signaling to Fra-2 output and autoregulation.","evidence":"In vitro kinase assays, phosphopeptide mapping, site-directed mutagenesis, constitutively active MEK1, EMSA and reporter assays in fibroblasts","pmids":["1899576","8058317","9188858","10359014"],"confidence":"High","gaps":["Did not establish which physiological stimuli engage each site","Structural consequence of phosphorylation unknown"]},{"year":1996,"claim":"Connected Fra-2 to tissue differentiation by showing Fra-2/JunD is the dominant osteoblast AP-1 complex and is required for osteocalcin expression and osteoblast/bone organization.","evidence":"EMSA, reporter assays and antisense loss-of-function in osteoblasts","pmids":["8828501"],"confidence":"High","gaps":["Direct osteocalcin promoter occupancy by Fra-2 not shown by ChIP","In vivo genetic confirmation absent at this stage"]},{"year":2008,"claim":"Provided the first germline genetic definition of a Fra-2 in vivo program, identifying LIF as a direct Fra-2/c-Jun target controlling osteoclast survival and size through LIF/HIF1α/PHD2 signaling.","evidence":"Fra-2 and LIF knockout mice, direct promoter mapping, double-KO epistasis and Bcl-2 rescue","pmids":["18548006"],"confidence":"High","gaps":["Partner usage at LIF promoter in other tissues unknown","Phosphorylation-dependence of LIF activation in vivo untested"]},{"year":2013,"claim":"Established Fra-2 as an oncogenic driver in adult T-cell leukemia by defining direct CCR4 and SOX4 activation and a downstream SOX4→HDAC8 cascade required for cell growth.","evidence":"siRNA knockdown, AP-1-site reporter assays, microarray and promoter analysis in ATL cells","pmids":["18071306","23482931"],"confidence":"Medium","gaps":["Genome-wide ATL target set not mapped at this stage","Reciprocal feedback within the cascade undefined"]},{"year":2013,"claim":"Linked Fra-2 to TGF-β/fibrotic signaling by showing it cooperates with Smad3 (promoting P300 recruitment and Smad3 acetylation) and with JunB at composite AP-1/Smad enhancers in an ERK-phosphorylation-dependent manner.","evidence":"Co-IP, acetylation and migration assays in NSCLC; ChIP, mutagenesis and ERK inhibition for LOXL4 enhancer","pmids":["25375657","23572561"],"confidence":"Medium","gaps":["Direct Fra-2–P300 contacts not mapped","Generality of Smad3 cooperation across fibrotic genes untested"]},{"year":2011,"claim":"Demonstrated a repressive transcriptional mechanism: Fra-2 binds a variant AP-1-related (AP-1R) site at Rgs4 and represses transcription by dismissing the co-activator CBP, broadening the set of DNA elements and outputs Fra-2 controls.","evidence":"Dominant-negative Fra-2 transgenic rat profiling, ChIP, EMSA, promoter mutagenesis and CBP co-occupancy analysis","pmids":["21367864"],"confidence":"High","gaps":["Mechanism of CBP dismissal not resolved","Generality of AP-1R-mediated repression unknown"]},{"year":2017,"claim":"Defined Fra-2's direct genome-wide program in lymphocyte development, showing it binds and activates Foxo1 and Irf4 to drive B-cell development, with these targets sufficient to rescue Fra-2 loss.","evidence":"Conditional knockout, ChIP-seq, expression profiling and Foxo1/Irf4 rescue in pro-B cells","pmids":["28566276"],"confidence":"High","gaps":["Jun partner at these loci not specified","Upstream signal controlling Fra-2 in B cells undefined"]},{"year":2020,"claim":"Positioned Fra-2 as a repressor of immunosuppressive T-cell fates and a node in tumor immune regulation, repressing Treg development cell-intrinsically and acting downstream of β-catenin to drive M2-like macrophage polarization.","evidence":"Fosl2 transgenic/conditional KO mice, T-cell transfer and EAE models; macrophage-specific β-catenin ablation with transcriptomics in tumor models","pmids":["32610127","32548260"],"confidence":"High","gaps":["Direct FoxP3-locus targets of Fra-2 not fully mapped","Mechanism of β-catenin→FOSL2 induction undefined"]},{"year":2021,"claim":"Identified Fra-2 as an instructive fate-conversion factor and angiogenic/fibrotic effector, required for IL-1β–Notch-driven secretory-to-AT2 conversion, for autophagy-coupled cardiac fibrosis, and for direct Wnt5a activation in cancer-associated fibroblasts.","evidence":"Lineage tracing and Notch manipulation in airway; conditional KO and Ang-II model with autophagy markers in cardiac fibroblasts; ChIP/reporter and angiogenesis assays in breast CAFs","pmids":["34475534","33668422","33754039"],"confidence":"High","gaps":["Direct Fosl2 targets in alveolar conversion not enumerated","Mechanism of Fra-2/autophagy mutual regulation unresolved"]},{"year":2023,"claim":"Extended the direct fibrotic/immunosuppressive target repertoire and added m6A control, defining FOSL2→SGK1 in renal fibrosis, KRAS/MAPK→FOSL2→CCL28-driven Treg recruitment in pancreatic cancer, and METTL3-dependent m6A regulation of FOSL2 mRNA.","evidence":"ChIP and SGK1 rescue in renal models; CUT&Tag, ChIP-qPCR, reporter and multiomics in PDAC; MeRIP-seq and METTL3 knockdown in granulosa cells","pmids":["37662889","37380804","37179374"],"confidence":"Medium","gaps":["Functional consequence of specific m6A sites on FOSL2 protein not mapped","Jun partner usage at SGK1/CCL28 not defined"]},{"year":2024,"claim":"Provided direct in vivo proof that a c-Jun/Fra-2 dimer is sufficient to cause cancer, driving hepatocellular carcinoma through a direct c-Myc 3' enhancer with oncogene addiction, and showed cofactor chromatin support via a RUNX1-NPM1 complex at FOSL2 ECM target loci.","evidence":"Hepatocyte c-Jun~Fra-2 fusion transgenic mice with enhancer ChIP, transgene switch-off and JQ-1 treatment; ChIP-seq/ATAC-seq and Co-IP in glioblastoma","pmids":["38657045","38286983"],"confidence":"High","gaps":["Whether endogenous c-Jun/Fra-2 ratios reach oncogenic thresholds physiologically unknown","How RUNX1-NPM1 is recruited to FOSL2 loci unresolved"]},{"year":null,"claim":"How phosphorylation, partner choice, m6A modification, and cofactor context are integrated to flip FOSL2 between activator and repressor at individual loci genome-wide remains unresolved.","evidence":"","pmids":[],"confidence":"Medium","gaps":["No unified model linking phospho-state to partner selection at specific targets","Structural basis of canonical vs AP-1R site discrimination unknown","Predictive rules for activation vs repression at a given promoter not established"]}],"mechanism_profile":{"molecular_activity":[{"term_id":"GO:0140110","term_label":"transcription regulator activity","supporting_discovery_ids":[1,16,17,20,26,30,36,37]},{"term_id":"GO:0003677","term_label":"DNA binding","supporting_discovery_ids":[1,4,10,20]}],"localization":[{"term_id":"GO:0005634","term_label":"nucleus","supporting_discovery_ids":[19,24]}],"pathway":[{"term_id":"R-HSA-74160","term_label":"Gene expression (Transcription)","supporting_discovery_ids":[17,26,30,36,37]},{"term_id":"R-HSA-162582","term_label":"Signal Transduction","supporting_discovery_ids":[4,8,11,27,29]},{"term_id":"R-HSA-168256","term_label":"Immune System","supporting_discovery_ids":[26,28,33,36]},{"term_id":"R-HSA-1266738","term_label":"Developmental Biology","supporting_discovery_ids":[7,24,31]},{"term_id":"R-HSA-1643685","term_label":"Disease","supporting_discovery_ids":[16,23,36,37]}],"complexes":["AP-1 (Fra-2/Jun heterodimer)"],"partners":["JUN","JUNB","JUND","SMAD3","EP300","FOSL1","BATF","RUNX1"],"other_free_text":[]}},"prefetch_data":{"uniprot":{"accession":"P15408","full_name":"Fos-related antigen 2","aliases":[],"length_aa":326,"mass_kda":35.2,"function":"Controls osteoclast survival and size (By similarity). As a dimer with JUN, activates LIF transcription (By similarity). Activates CEBPB transcription in PGE2-activated osteoblasts (By similarity)","subcellular_location":"Nucleus","url":"https://www.uniprot.org/uniprotkb/P15408/entry"},"depmap":{"release":"DepMap","has_data":true,"is_common_essential":false,"resolved_as":"","url":"https://depmap.org/portal/gene/FOSL2","classification":"Not Classified","n_dependent_lines":84,"n_total_lines":1208,"dependency_fraction":0.0695364238410596},"opencell":{"profiled":false,"resolved_as":"","ensg_id":"","cell_line_id":"","localizations":[],"interactors":[],"url":"https://opencell.sf.czbiohub.org/search/FOSL2","total_profiled":1310},"omim":[{"mim_id":"620789","title":"APLASIA CUTIS-ENAMEL DYSPLASIA SYNDROME; ACED","url":"https://www.omim.org/entry/620789"},{"mim_id":"601575","title":"FOS-LIKE 2, AP-1 TRANSCRIPTION FACTOR SUBUNIT; FOSL2","url":"https://www.omim.org/entry/601575"},{"mim_id":"176760","title":"PROLACTIN; PRL","url":"https://www.omim.org/entry/176760"},{"mim_id":"136515","title":"FOS-LIKE 1, AP-1 TRANSCRIPTION FACTOR SUBUNIT; FOSL1","url":"https://www.omim.org/entry/136515"}],"hpa":{"profiled":true,"resolved_as":"","reliability":"Enhanced","locations":[{"location":"Nucleoplasm","reliability":"Enhanced"}],"tissue_specificity":"Low tissue specificity","tissue_distribution":"Detected in all","driving_tissues":[],"url":"https://www.proteinatlas.org/search/FOSL2"},"hgnc":{"alias_symbol":["FRA2","FLJ23306"],"prev_symbol":[]},"alphafold":{"accession":"P15408","domains":[],"viewer_url":"https://alphafold.ebi.ac.uk/entry/P15408","model_url":"https://alphafold.ebi.ac.uk/files/AF-P15408-F1-model_v6.cif","pae_url":"https://alphafold.ebi.ac.uk/files/AF-P15408-F1-predicted_aligned_error_v6.png","plddt_mean":61.66},"mouse_models":{"mgi_url":"https://www.informatics.jax.org/marker/summary?nomen=FOSL2","jax_strain_url":"https://www.jax.org/strain/search?query=FOSL2"},"sequence":{"accession":"P15408","fasta_url":"https://rest.uniprot.org/uniprotkb/P15408.fasta","uniprot_url":"https://www.uniprot.org/uniprotkb/P15408/entry","alphafold_viewer_url":"https://alphafold.ebi.ac.uk/entry/P15408"}},"corpus_meta":[{"pmid":"2110368","id":"PMC_2110368","title":"Isolation and characterization of fra-2, an additional member of the fos gene family.","date":"1990","source":"Proceedings of the National Academy of Sciences of the United States of America","url":"https://pubmed.ncbi.nlm.nih.gov/2110368","citation_count":310,"is_preprint":false},{"pmid":"1945831","id":"PMC_1945831","title":"Difference in transcriptional regulatory function between c-Fos and Fra-2.","date":"1991","source":"Nucleic acids research","url":"https://pubmed.ncbi.nlm.nih.gov/1945831","citation_count":209,"is_preprint":false},{"pmid":"18281282","id":"PMC_18281282","title":"Identification of FRA1 and FRA2 as genes involved in regulating the yeast iron regulon in response to decreased mitochondrial iron-sulfur cluster synthesis.","date":"2008","source":"The Journal of biological chemistry","url":"https://pubmed.ncbi.nlm.nih.gov/18281282","citation_count":175,"is_preprint":false},{"pmid":"19715344","id":"PMC_19715344","title":"The yeast iron regulatory proteins Grx3/4 and Fra2 form heterodimeric complexes containing a [2Fe-2S] cluster with cysteinyl and histidyl ligation.","date":"2009","source":"Biochemistry","url":"https://pubmed.ncbi.nlm.nih.gov/19715344","citation_count":168,"is_preprint":false},{"pmid":"8828501","id":"PMC_8828501","title":"Developmental expression and activities of specific fos and jun proteins are functionally related to osteoblast maturation: role of Fra-2 and Jun D during differentiation.","date":"1996","source":"Endocrinology","url":"https://pubmed.ncbi.nlm.nih.gov/8828501","citation_count":165,"is_preprint":false},{"pmid":"32548260","id":"PMC_32548260","title":"Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer.","date":"2020","source":"Science advances","url":"https://pubmed.ncbi.nlm.nih.gov/32548260","citation_count":162,"is_preprint":false},{"pmid":"18548006","id":"PMC_18548006","title":"Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia.","date":"2008","source":"Nature","url":"https://pubmed.ncbi.nlm.nih.gov/18548006","citation_count":153,"is_preprint":false},{"pmid":"28814429","id":"PMC_28814429","title":"Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis.","date":"2017","source":"Annals of the rheumatic diseases","url":"https://pubmed.ncbi.nlm.nih.gov/28814429","citation_count":148,"is_preprint":false},{"pmid":"31234009","id":"PMC_31234009","title":"lncRNA UCA1 Mediates Resistance to Cisplatin by Regulating the miR-143/FOSL2-Signaling Pathway in Ovarian Cancer.","date":"2019","source":"Molecular therapy. 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Unlike c-Fos/c-Jun (which activates), Fra-2/c-Jun suppresses c-Jun transactivation at AP-1 sites in F9 cells; this suppressive difference maps to the C-terminal half of Fra-2. Fra-2/JunD, however, activates transcription similarly to c-Fos/JunD.\",\n      \"method\": \"In vitro heterodimer formation assays; DNA-binding assays; transient transfection reporter assays; chimeric protein analysis\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Strong — in vitro reconstitution of heterodimers, DNA-binding assays, reporter assays with chimeric proteins, replicated concept in multiple subsequent studies\",\n      \"pmids\": [\"1945831\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1991,\n      \"finding\": \"Fra-2 protein is phosphorylated on serine residues upon serum stimulation of chicken embryo fibroblasts, shifting it from hypophosphorylated (40–46 kDa) to a hyperphosphorylated 46 kDa form.\",\n      \"method\": \"Western blot with alkaline phosphatase treatment; metabolic labeling\",\n      \"journal\": \"Biochemical and biophysical research communications\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — biochemical fractionation and phosphatase treatment confirm phosphorylation, single lab\",\n      \"pmids\": [\"1899576\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1993,\n      \"finding\": \"JunD mutants with transforming activity show enhanced transactivation specifically when heterodimerized with Fra-2 (but not c-Fos or Fra-1), indicating Fra-2 functions as a partner-specific transactivation enabler.\",\n      \"method\": \"Transient transfection reporter assay with AP-1 site in F9 cells; retroviral transformation assay in chicken embryo fibroblasts\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays with multiple Jun mutants and Fos family members, single lab\",\n      \"pmids\": [\"8415709\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1994,\n      \"finding\": \"Fra-2 is phosphorylated in vivo in a serum-dependent manner during G1 and in asynchronously growing Swiss 3T3 cells; MAP kinase (ERK) phosphorylates Fra-2 in vitro producing a gel-mobility shift similar to in vivo, and this phosphorylation increases Fra-2 DNA-binding activity. PKA, PKC, and cdc2 also phosphorylate Fra-2 in vitro but do not produce the same mobility shift.\",\n      \"method\": \"In vitro kinase assays (PKA, PKC, cdc2, MAP kinase); alkaline phosphatase treatment; 1D phosphopeptide mapping; EMSA DNA-binding assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase reconstitution with multiple kinases, phosphopeptide mapping comparing in vitro and in vivo, functional DNA-binding consequence measured\",\n      \"pmids\": [\"8058317\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fra-2 mRNA and protein exhibit a circadian rhythm in the rat pineal gland (absent during the day, robustly increased at night), regulated by an adrenergic→cAMP mechanism; AP-1 binding activity in the pineal parallels Fra-2 protein levels.\",\n      \"method\": \"Immunoblot; Northern blot; organ culture with adrenergic/cAMP manipulations; EMSA\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — direct protein/mRNA measurements combined with pharmacological organ culture experiments, single lab\",\n      \"pmids\": [\"7592994\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1995,\n      \"finding\": \"Fra-2 protein binds AP-1 sites in the fra-2 promoter as a Fra-2/c-Jun complex; serum induction of fra-2 expression is mediated through CRE-like and AP-1 binding sites (not SRE); at late times post-stimulation, Fra-2/c-Jun re-occupies its own promoter, while at early times c-Fos/c-Jun drives fra-2 transcription, establishing a delayed autoregulatory loop.\",\n      \"method\": \"Promoter deletion/mutation reporter assays; EMSA with CEF nuclear extracts\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — promoter deletion and mutation combined with EMSA, single lab\",\n      \"pmids\": [\"7862446\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1996,\n      \"finding\": \"In fully differentiated osteoblasts, Fra-2 and JunD are the principal AP-1 complex members detectable, and co-expression of Fra-2/JunD (but not other Fos/Jun pairs) specifically stimulates osteocalcin promoter reporter expression in a site-specific manner; antisense suppression of Fra-2 impairs osteoblast differentiation and bone tissue-like organization.\",\n      \"method\": \"Western blot; EMSA; transient transfection reporter assays; promoter deletion analysis; antisense oligonucleotide suppression\",\n      \"journal\": \"Endocrinology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple orthogonal methods (EMSA, reporter, antisense loss-of-function with phenotype), replicated concept across several bone biology studies\",\n      \"pmids\": [\"8828501\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"In v-src-transformed chicken embryo fibroblasts, Fra-2 is extensively phosphorylated at multiple Ser and Thr residues in its C-terminal region (aa 266–323) by ERK2 (identified by in-gel kinase assay as a 42 kDa kinase); this phosphorylation converts Fra-2 from an inefficient into an active transactivator. Fra-2 promoter is autoregulated via AP-1 sites and a CRE-like sequence in response to Fra-2 phosphorylation status.\",\n      \"method\": \"In-gel kinase assay; site-directed mutagenesis of phosphorylation sites; Fra-2 C-terminal region as substrate; promoter reporter assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — in vitro kinase substrate identification with mutagenesis and functional reporter assays, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"9188858\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1997,\n      \"finding\": \"Exogenous Fra-2 expression represses AP-1 transcriptional activity in TPA-treated keratinocytes, whereas c-Fos activates it in calcium-treated cells, demonstrating opposing roles of Fra-2 and c-Fos in regulating AP-1 activity in keratinocytes.\",\n      \"method\": \"Transient transfection reporter assays; Western blot analysis of AP-1 protein expression\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reporter assays combined with expression analysis, single lab\",\n      \"pmids\": [\"9315102\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1998,\n      \"finding\": \"Fra-2/JunD heterodimer specifically binds three AP-1 sites in the murine laminin alpha3A (lama3A) promoter and is required for TGF-β-responsive transcription; cooperative contribution of two distal AP-1 sites to TGF-β inducibility was established by mutagenesis.\",\n      \"method\": \"Site-directed mutagenesis of AP-1 sites; transient transfection reporter assays; EMSA (mobility shift assays)\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis + EMSA + reporter assays in a single study with clear mechanistic resolution\",\n      \"pmids\": [\"9651314\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 1999,\n      \"finding\": \"Phosphorylation of Fra-2 by MAP kinase (MAPK/MEK pathway) converts Fra-2 from a weak transactivator to an active one; MAPK phosphorylation sites were mapped by site-directed mutagenesis to three threonine and three serine residues in the C-terminal region, with threonines being more susceptible; a positive autoregulatory loop exists where phosphorylated Fra-2 drives fra-2 expression through AP-1 sites in the promoter.\",\n      \"method\": \"Site-directed mutagenesis of phosphorylation sites; constitutively active MEK1 cotransfection; reporter assays; transformation assays\",\n      \"journal\": \"Cell growth & differentiation\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1 / Moderate — site-directed mutagenesis of specific residues combined with functional reporter assays and transformation phenotype, single lab but multiple methods\",\n      \"pmids\": [\"10359014\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"Fra-2 expression in the rat pineal gland is required for circadian AP-1 binding activity and for expression of two specific target genes: type II iodothyronine deiodinase and nectadrin (CD24), identified by analysis of 1,190 genes in dominant-negative Fra-2 transgenic rats.\",\n      \"method\": \"Transgenic dominant-negative Fra-2 rat; gene expression profiling of 1,190 genes; targeted validation\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — in vivo loss-of-function via dominant negative transgene with genome-wide expression screen, single lab\",\n      \"pmids\": [\"11340164\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2001,\n      \"finding\": \"NGF (but not EGF) specifically increases Fra-2 protein levels (particularly phosphorylated forms) and enhances Fra-2/JunD binding to AP-1 and CREB response elements in PC12 cells, correlating with NGF-specific differentiation vs. EGF-mediated mitogenesis; NGF elicits more sustained ERK phosphorylation than EGF.\",\n      \"method\": \"Gel mobility shift assays; supershift assays; Western blot; time-course ERK phosphorylation analysis\",\n      \"journal\": \"The Journal of neuroscience\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — supershift identification of Fra-2/JunD complex, systematic comparison of NGF vs EGF, single lab\",\n      \"pmids\": [\"11150315\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2003,\n      \"finding\": \"Fra-2 does not enhance cell motility when overexpressed in CSML0 adenocarcinoma cells (unlike Fra-1 or c-Fos), but antisense fra-2 knockdown in L929 fibroblastoid cells (which express Fra-1 and Fra-2) reduces motility, indicating Fra-2 contributes to but is not sufficient to drive motility and that this effect requires the cellular context of Fra-1 co-expression.\",\n      \"method\": \"Transfection of CSML0 cells with Fos family expression vectors; antisense knockdown; motility assays\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — systematic gain- and loss-of-function in two cell lines, single lab\",\n      \"pmids\": [\"12902987\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2005,\n      \"finding\": \"MEKK1 controls Fra-2 protein stability by inducing Fra-2 ubiquitination and proteasomal degradation; in MEKK1-/- cells, Fra-2 protein accumulates. MEKK1 thus regulates AP-1 complex composition by controlling Fra-2 turnover.\",\n      \"method\": \"MEKK1 knockout cells; ubiquitination assay; Western blot for Fra-2 protein levels\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic KO with ubiquitination assay, single lab\",\n      \"pmids\": [\"15558021\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2007,\n      \"finding\": \"Fra-2 is constitutively and aberrantly expressed in ATL cells; Fra-2/JunD heterodimer activates the CCR4 promoter via an AP-1 site; Fra-2 siRNA (but not JunB siRNA) reduces CCR4 expression and cell growth; Fra-2 drives expression of c-Myb, BCL-6, and MDM2.\",\n      \"method\": \"siRNA knockdown; transient transfection reporter assays; CCR4 promoter AP-1 site characterization; cell growth assays; microarray\",\n      \"journal\": \"Oncogene\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function, reporter assays with AP-1 site mutants, gene expression profiling, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"18071306\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2008,\n      \"finding\": \"Fra-2 controls osteoclast survival and size by directly regulating LIF transcription (c-Jun co-factor); Fra-2-deficient mice develop giant osteoclasts with impaired LIF/LIF-receptor signaling; Fra-2 and LIF modulate HIF1alpha through transcriptional regulation of PHD2 (prolyl hydroxylase); placenta-specific Fra-2 drives hypoxia-dependent giant osteoclast formation.\",\n      \"method\": \"Fra-2 germline and conditional knockout mice; LIF knockout mice; LIF promoter identification as direct Fra-2/c-Jun target; PHD2 transcriptional regulation assay; Bcl-2 overexpression in vivo\",\n      \"journal\": \"Nature\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple knockout models, direct promoter target identification, epistasis via double KO and rescue experiments\",\n      \"pmids\": [\"18548006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fra-2 expression is upregulated in SSc fibroblasts by TGF-β and PDGF stimulation in an ERK-dependent manner; Fra-2 binds DNA of target genes in response to these stimuli; Fra-2 siRNA knockdown reduces collagen release from SSc fibroblasts stimulated with TGF-β or PDGF.\",\n      \"method\": \"siRNA knockdown; real-time PCR; immunohistochemistry; DNA binding assay; ERK inhibitor\",\n      \"journal\": \"Arthritis and rheumatism\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function with functional collagen readout and pathway inhibition, single lab\",\n      \"pmids\": [\"20039427\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2010,\n      \"finding\": \"Fra-2 is induced in cardiac fibroblasts by hyperoxia/reoxygenation via an Ask-1-dependent mechanism; Ask-1 controls Fra-2 gene expression and nuclear localization; AP-1 sites in TGF-β1 and TGF-β3 promoters confer oxygen sensitivity; Fra-2 siRNA knockdown blunts O2-induced TGF-β1 and TGF-β3 expression.\",\n      \"method\": \"Fra-2 siRNA knockdown; Ask-1 siRNA; reporter assays with AP-1 site deletions; nuclear localization assay\",\n      \"journal\": \"Cardiovascular research\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function for both Fra-2 and Ask-1 combined with reporter assays, single lab\",\n      \"pmids\": [\"20427335\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2011,\n      \"finding\": \"FRA-2/FOSL2 selectively binds a variant AP-1-related (AP-1R) sequence (distinct from canonical AP-1 sites) in the Rgs4 proximal promoter to repress Rgs4 transcription; binding was confirmed by ChIP and EMSA; FRA-2-dependent repression involves dismissal of the co-activator CBP from the Rgs4 AP-1R sequence.\",\n      \"method\": \"Dominant-negative Fra-2 transgenic rat expression profiling; ChIP; EMSA; promoter mutagenesis; co-activator CBP co-occupancy analysis\",\n      \"journal\": \"The Journal of biological chemistry\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP + EMSA + mutagenesis + co-activator mechanism in one study, in vivo validated by transgenic model\",\n      \"pmids\": [\"21367864\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"FOSL2 interacts with Smad3 in vitro and in vivo (co-IP); FOSL2 promotes P300 binding to Smad3 and P300-mediated acetylation of Smad3; this complex enhances TGF-β1-induced signaling and is required for TGF-β1-induced cell migration in NSCLC.\",\n      \"method\": \"Co-immunoprecipitation (in vitro and in vivo); P300 binding assay; Smad3 acetylation assay; migration assays with FOSL2 knockdown\",\n      \"journal\": \"PloS one\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — reciprocal Co-IP plus downstream acetylation mechanism and functional migration assay, single lab\",\n      \"pmids\": [\"25375657\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"TGF-β1 induces LOXL4 expression in aortic endothelial cells via functional cooperation between Smad proteins and a JunB/Fra-2 AP-1 complex; Fra-2 phosphorylation by ERK is required for this cooperation; a distal enhancer containing both an AP-1 site and a Smad binding element is absolutely required.\",\n      \"method\": \"Promoter deletion and mutagenesis; ChIP; co-transfection; ERK inhibitor treatment; LOXL4 functional assays\",\n      \"journal\": \"Molecular and cellular biology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mutagenesis + ChIP + phosphorylation mechanism, single lab\",\n      \"pmids\": [\"23572561\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fra-2 directly activates the SOX4 promoter via an AP-1 site together with JUND in ATL cells; SOX4 in turn directly activates the HDAC8 promoter, establishing a Fra-2/JUND → SOX4 → HDAC8 oncogenic cascade required for ATL cell growth.\",\n      \"method\": \"siRNA knockdown; reporter assay (AP-1 site in SOX4 promoter); microarray; HDAC8 promoter reporter assay\",\n      \"journal\": \"Blood\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — siRNA loss-of-function + promoter reporter mechanistic cascade, single lab\",\n      \"pmids\": [\"23482931\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2013,\n      \"finding\": \"Fra-2 expression is restricted to undifferentiated satellite cells and reserve cells in skeletal muscle (not in differentiated myofiber nuclei); Fra-2 silencing enhances myogenic differentiation markers; ERK1/2 signaling (cytokine-mediated) regulates Fra-2 protein stability via phosphorylation at S320 and T322 (identified by mass spectrometry and mutational analysis); S320 phosphorylation occurs transiently in activated satellite cells and is extinguished in differentiating cells.\",\n      \"method\": \"Fra-2 siRNA knockdown; mass spectrometry; site-directed mutagenesis of S320/T322; immunofluorescence in satellite cells; ERK1/2 signaling manipulation\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — mass spectrometry-identified phosphosites validated by mutagenesis, combined with in vivo localization and loss-of-function, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"23807221\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2016,\n      \"finding\": \"Fra-2 binds the TIMP-1 promoter (confirmed by ChIP) in monocytes; TLR-8 stimulation combined with histone demethylation (DZNep treatment) enhances Fra-2 and TIMP-1 expression; Fra-2-driven TIMP-1 production by monocytes induces transdifferentiation of dermal fibroblasts into myofibroblasts.\",\n      \"method\": \"ChIP; luciferase reporter assay; siRNA/inhibitor treatments; co-culture of monocytes and fibroblasts; TIMP-1 blocking antibody\",\n      \"journal\": \"Arthritis & rheumatology\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmation of TIMP-1 promoter binding plus functional co-culture assay, single lab\",\n      \"pmids\": [\"26814616\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2017,\n      \"finding\": \"Fra-2 regulates B cell development by directly binding and enhancing transcription of Foxo1 and Irf4 (identified by ChIP-seq); deletion of Fra-2 reduces expression of Foxo1, Irf4, Ikaros, Aiolos, IL7Rα, and Rag1/2; exogenous Foxo1 and Irf4 fully rescue pro-B cell proliferation and small pre-B cell differentiation in Fra-2-deficient cells.\",\n      \"method\": \"Fra-2 conditional knockout; gene expression profiling; ChIP-seq; IL-7-stimulated pro-B cell cultures; Foxo1/Irf4 rescue experiments\",\n      \"journal\": \"The Journal of experimental medicine\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — conditional KO with ChIP-seq for direct targets, rescue experiments with downstream TFs, multiple orthogonal methods\",\n      \"pmids\": [\"28566276\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2019,\n      \"finding\": \"HGF/MET signaling induces phosphorylation and upregulation of FOSL2 via ERK1/2 kinase in NSCLC cells; FOSL2 binds the SNAI2 promoter and promotes SNAI2 transcription (confirmed by ChIP and dual-luciferase assay), driving EMT, invasion, and migration.\",\n      \"method\": \"Western blot for phospho-FOSL2; ERK1/2 manipulation; ChIP; dual-luciferase reporter assay; transwell/scratch assays\",\n      \"journal\": \"OncoTargets and therapy\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP and reporter assay for direct promoter binding, ERK pathway mechanistic link, single lab\",\n      \"pmids\": [\"31807006\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"Fosl2 (Fra-2) is induced by TCR signaling in T cells and cell-intrinsically represses Treg development; Fosl2 overexpression reduces FoxP3 expression and other Treg differentiation genes; transfer of Fosl2tg T cells transfers inflammation, suppressible by co-delivery of Tregs; Fosl2 deficiency reduces EAE severity.\",\n      \"method\": \"Fosl2 transgenic and conditional knockout mice; Rag2-/- cross; T cell transfer experiments; EAE model; gene expression analysis\",\n      \"journal\": \"Cell reports\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — multiple genetic models (Tg, KO, Rag2-/- cross), transfer experiments with epistatic rescue by Treg co-delivery, disease model validation\",\n      \"pmids\": [\"32610127\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2020,\n      \"finding\": \"β-catenin transcriptionally activates FOSL2 in tumor-associated macrophages (TAMs); FOSL2 drives a gene regulatory switch from M1-like to M2-like TAMs promoting immunosuppression; β-catenin ablation in macrophages reprograms M2 to M1 TAMs via FOSL2 suppression.\",\n      \"method\": \"Pharmacological and macrophage-specific genetic ablation of β-catenin; transcriptome analysis; in vitro TAM model; in vivo lung tumor models\",\n      \"journal\": \"Science advances\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genetic ablation in vivo and in vitro with transcriptome analysis, mechanistic pathway placement, single lab\",\n      \"pmids\": [\"32548260\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"FOSL2 in breast cancer-associated fibroblasts (CAFs) is regulated by estrogen/cAMP/PKA signaling; FOSL2 directly transcriptionally activates Wnt5a (confirmed by dual luciferase reporter and ChIP); Wnt5a secreted from CAFs activates FZD5/NF-κB/ERK signaling in endothelial cells to promote VEGF-independent angiogenesis.\",\n      \"method\": \"ChIP; dual luciferase reporter assays; FOSL2/Wnt5a siRNA knockdown; FOSL2 overexpression; tube formation/sprouting/xenograft assays; anti-VEGF blocking\",\n      \"journal\": \"Theranostics\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — ChIP + reporter assay establish direct FOSL2→Wnt5a transcription, multiple functional angiogenesis readouts, in vivo validation, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"33754039\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"IL-1β signaling modulates Jag1/Jag2 expression in ciliated airway cells to inhibit Notch signaling in secretory cells, which activates Fosl2; Fosl2 is required for conversion of secretory cells to alveolar type 2 cells during alveolar regeneration, establishing an IL-1β–Notch–Fosl2 axis in secretory cell fate conversion.\",\n      \"method\": \"Genetic lineage tracing; Notch inhibition; Fosl2 gain- and loss-of-function; epigenetic signature analysis; human KDR+ secretory cell validation\",\n      \"journal\": \"Nature cell biology\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — genetic lineage tracing, epistasis via Notch inhibition plus Fosl2 manipulation, human cell validation, multiple orthogonal approaches\",\n      \"pmids\": [\"34475534\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2021,\n      \"finding\": \"Fosl-2 (FOSL2) regulates autophagy in cardiac fibroblasts; Fosl-2 overexpression increases LC3BII, Beclin-1, and Atg5 levels; Fosl-2 silencing suppresses collagen, α-SMA, and Beclin-1; silencing LC3B or Beclin-1 reduces Fosl-2 in TGF-β-activated cells (mutual regulation); Fosl-2-deficient or Atg5-deficient stromal cells protect from angiotensin II-induced cardiac fibrosis in vivo.\",\n      \"method\": \"GapmeR antisense oligonucleotide silencing; Fosl-2tg cardiac fibroblasts; Ccl19Cre Fosl2flox/flox and Ccl19Cre Atg5flox/flox conditional KO mice; osmotic minipump angiotensin II model; immunohistochemistry\",\n      \"journal\": \"International journal of molecular sciences\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — conditional KO in vivo disease model, complementary in vitro silencing with autophagy marker readouts, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"33668422\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2022,\n      \"finding\": \"FOSL2 co-represses Th17 fate specification together with FOSL1 during human Th17 differentiation (opposite to BATF which promotes Th17); FOSL1, FOSL2, and BATF share genomic binding sites over Th17 lineage regulatory regions; they share protein-interacting partners; SNPs at FOSL2 binding sites alter its DNA binding capacity.\",\n      \"method\": \"siRNA knockdown of FOSL1/FOSL2/BATF; genome-wide ChIP-seq binding analysis; protein interaction studies; SNP binding assay; human Th17 differentiation cultures\",\n      \"journal\": \"Nucleic acids research\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — genome-wide ChIP-seq with loss-of-function in human primary cells, protein interaction studies, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"35511484\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOSL2 binds the SGK1 promoter (confirmed by ChIP) and transcriptionally activates SGK1; in TGF-β1-induced renal tubular epithelial cells, FOSL2 silencing reduces SGK1 expression, and SGK1 overexpression rescues the anti-fibrotic effects of FOSL2 knockdown, placing FOSL2 upstream of SGK1 in renal fibrosis via EMT.\",\n      \"method\": \"ChIP; siRNA knockdown; TGF-β1-induced cell model; UUO mouse model; SGK1 overexpression rescue experiments; Western blot for EMT markers\",\n      \"journal\": \"Journal of translational internal medicine\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP confirmation of direct SGK1 promoter binding, epistatic rescue by SGK1 overexpression, single lab\",\n      \"pmids\": [\"37662889\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"Butyric acid decreases FOSL2 m6A methylation and mRNA expression by suppressing METTL3 (an m6A methyltransferase) in granulosa cells; FOSL2 promotes NLRP3 inflammasome activation and IL-6/TNF-α expression; identified by RNA-seq and MeRIP-seq as a METTL3 target.\",\n      \"method\": \"RNA-seq; MeRIP-seq; butyric acid treatment; METTL3 siRNA; FOSL2 expression measurement; NLRP3/cytokine assays\",\n      \"journal\": \"Clinical epigenetics\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — MeRIP-seq identifies m6A modification, functional METTL3 knockdown, cellular assays, single lab\",\n      \"pmids\": [\"37179374\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2023,\n      \"finding\": \"FOSL2 is a downstream target of the KRAS/MAPK pathway; FOSL2 directly binds the CCL28 promoter and transcriptionally activates CCL28 (confirmed by CUT&Tag and ChIP-qPCR + dual-luciferase reporter); CCL28 recruits regulatory T cells to drive immune suppression in pancreatic ductal adenocarcinoma.\",\n      \"method\": \"ATAC-seq, H3K27ac ChIP-seq, RNA-seq in GEMMs; CUT&Tag; ChIP-qPCR; dual-luciferase reporter; KRAS/MAPK pathway analysis; xenograft models\",\n      \"journal\": \"British journal of cancer\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 1–2 / Moderate — CUT&Tag + ChIP-qPCR + reporter assay establish direct FOSL2→CCL28 activation, multiomics epistasis for KRAS→FOSL2, single lab with multiple orthogonal methods\",\n      \"pmids\": [\"37380804\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"A single-chain c-Jun~Fra-2 fusion protein (mimicking the c-Jun/Fra-2 AP-1 dimer) drives spontaneous hepatocellular carcinoma when expressed in hepatocytes; c-Myc is a direct transcriptional target of c-Jun/Fra-2 via a conserved distal 3' enhancer; tumors regress when the transgene is switched off (oncogene addiction); BET inhibitor JQ-1 targeting c-Myc reduces tumor growth.\",\n      \"method\": \"Hepatocyte-restricted c-Jun~Fra-2 transgenic mice; AP-1 enhancer ChIP for c-Myc 3' enhancer; transgene switch-off experiment; JQ-1 BET inhibitor treatment in vivo\",\n      \"journal\": \"Proceedings of the National Academy of Sciences of the United States of America\",\n      \"confidence\": \"High\",\n      \"confidence_rationale\": \"Tier 2 / Strong — in vivo genetic model, direct enhancer ChIP, oncogene addiction rescue, pharmacological validation, single lab but multiple orthogonal methods\",\n      \"pmids\": [\"38657045\"],\n      \"is_preprint\": false\n    },\n    {\n      \"year\": 2024,\n      \"finding\": \"RUNX1 interacts with NPM1 to maintain chromatin accessibility at FOSL2-regulated ECM gene loci; this RUNX1-NPM1 complex facilitates FOSL2-mediated transcriptional activation of ECM-related genes (FN1, COL4A1, LUM) in glioblastoma, independent of RUNX1's own transcriptional function.\",\n      \"method\": \"ChIP-seq; RNA-seq; Co-IP for RUNX1-NPM1 interaction; ATAC-seq for chromatin accessibility; functional ECM gene expression assays\",\n      \"journal\": \"Cell death & disease\",\n      \"confidence\": \"Medium\",\n      \"confidence_rationale\": \"Tier 2 / Moderate — ChIP-seq and co-IP establish complex and target gene relationships, single lab\",\n      \"pmids\": [\"38286983\"],\n      \"is_preprint\": false\n    }\n  ],\n  \"current_model\": \"FOSL2 (Fra-2) is a leucine-zipper transcription factor that obligatorily heterodimerizes with Jun proteins (c-Jun, JunB, JunD) to form AP-1 complexes that bind AP-1 and variant AP-1-related DNA sites; its transcriptional output (activation or repression) is determined by its Jun partner, its phosphorylation state (MAP kinase/ERK phosphorylates multiple C-terminal Ser/Thr residues to convert it from a weak to an active transactivator), and promoter context; it is subject to ubiquitin-mediated degradation controlled by MEKK1, m6A methylation by METTL3, and positive autoregulation through AP-1 sites in its own promoter; established direct transcriptional targets include LIF, Wnt5a, SOX4, CCR4, Rgs4 (repressed via CBP dismissal), SGK1, CCL28, SNAI2, and c-Myc (via a 3' enhancer); and it plays defined roles in osteoclast size control, osteoblast differentiation, B cell development, Treg suppression, cardiac and pulmonary fibrosis (via TGF-β/autophagy axis), airway progenitor fate conversion (IL-1β–Notch–Fosl2 axis), macrophage polarization (downstream of β-catenin), and hepatocellular carcinoma formation (as part of a c-Jun/Fra-2 dimer driving c-Myc).\"\n}\n```","stage2_raw":"```json\n{\n  \"mechanistic_narrative\": \"FOSL2 (Fra-2) is a leucine-zipper transcription factor that controls cell fate, differentiation, and fibrotic and oncogenic gene programs by forming AP-1 heterodimers with Jun-family partners and binding AP-1 and variant AP-1-related DNA sites [#0, #1]. Its transcriptional output is partner- and context-dependent: Fra-2/c-Jun can suppress c-Jun-driven AP-1 activity while Fra-2/JunD activates transcription, with the suppressive difference mapping to the Fra-2 C-terminus [#1, #3]. A central regulatory switch is ERK/MAP-kinase phosphorylation of multiple C-terminal Ser/Thr residues, which converts Fra-2 from a weak into an active transactivator and increases its DNA-binding activity [#4, #8, #11]; phosphorylation also governs Fra-2 protein stability, and MEKK1 directs Fra-2 ubiquitination and proteasomal turnover to set AP-1 complex composition [#15, #24]. Fra-2 sustains its own expression through a delayed autoregulatory loop acting on AP-1/CRE-like sites in the fra-2 promoter [#6, #8]. Through these mechanisms FOSL2 directly activates or represses defined targets — LIF in osteoclasts [#17], CCR4 and a SOX4→HDAC8 cascade in adult T-cell leukemia [#16, #23], Foxo1 and Irf4 in B-cell development [#26], Wnt5a in cancer-associated fibroblasts [#30], SGK1 and SNAI2 in fibrosis and EMT [#34, #27], CCL28 in pancreatic cancer [#36], and Rgs4, which it represses by dismissing the co-activator CBP from a variant AP-1R site [#20]. Functionally it controls osteoblast differentiation [#7], osteoclast size [#17], B-cell development [#26], represses regulatory T-cell and Th17 fates [#28, #33], reprograms tumor-associated macrophages downstream of \\u03b2-catenin [#29], directs airway secretory-cell fate conversion via an IL-1\\u03b2\\u2013Notch axis [#31], and drives TGF-\\u03b2-linked cardiac, pulmonary and renal fibrosis through autophagy and Smad cooperation [#21, #32, #34]. A c-Jun/Fra-2 dimer is sufficient to drive hepatocellular carcinoma through direct activation of a c-Myc 3' enhancer [#37].\",\n  \"teleology\": [\n    {\n      \"year\": 1990,\n      \"claim\": \"Established that Fra-2 is a functional c-Fos-like factor by showing it physically partners with c-Jun and is oncogenically transforming, defining it as an AP-1 component rather than an orphan immediate-early gene product.\",\n      \"evidence\": \"Co-immunoprecipitation and retroviral transformation in chicken embryo fibroblasts\",\n      \"pmids\": [\"2110368\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not define which Jun partners predominate physiologically\", \"No direct target genes identified\"]\n    },\n    {\n      \"year\": 1991,\n      \"claim\": \"Resolved that Fra-2's transcriptional sign is determined by its Jun partner — Fra-2/c-Jun suppresses while Fra-2/JunD activates AP-1-site transcription — and localized the suppressive activity to the C-terminal half.\",\n      \"evidence\": \"In vitro heterodimer/DNA-binding assays and chimeric-protein reporter assays in F9 cells\",\n      \"pmids\": [\"1945831\", \"8415709\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Molecular basis of C-terminal suppression not defined\", \"Partner selection in vivo unaddressed\"]\n    },\n    {\n      \"year\": 1999,\n      \"claim\": \"Defined the ERK/MAPK phosphorylation switch: phosphorylation of mapped C-terminal Ser/Thr residues converts Fra-2 from a weak to an active transactivator and increases DNA binding, linking growth-factor signaling to Fra-2 output and autoregulation.\",\n      \"evidence\": \"In vitro kinase assays, phosphopeptide mapping, site-directed mutagenesis, constitutively active MEK1, EMSA and reporter assays in fibroblasts\",\n      \"pmids\": [\"1899576\", \"8058317\", \"9188858\", \"10359014\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Did not establish which physiological stimuli engage each site\", \"Structural consequence of phosphorylation unknown\"]\n    },\n    {\n      \"year\": 1996,\n      \"claim\": \"Connected Fra-2 to tissue differentiation by showing Fra-2/JunD is the dominant osteoblast AP-1 complex and is required for osteocalcin expression and osteoblast/bone organization.\",\n      \"evidence\": \"EMSA, reporter assays and antisense loss-of-function in osteoblasts\",\n      \"pmids\": [\"8828501\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct osteocalcin promoter occupancy by Fra-2 not shown by ChIP\", \"In vivo genetic confirmation absent at this stage\"]\n    },\n    {\n      \"year\": 2008,\n      \"claim\": \"Provided the first germline genetic definition of a Fra-2 in vivo program, identifying LIF as a direct Fra-2/c-Jun target controlling osteoclast survival and size through LIF/HIF1\\u03b1/PHD2 signaling.\",\n      \"evidence\": \"Fra-2 and LIF knockout mice, direct promoter mapping, double-KO epistasis and Bcl-2 rescue\",\n      \"pmids\": [\"18548006\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Partner usage at LIF promoter in other tissues unknown\", \"Phosphorylation-dependence of LIF activation in vivo untested\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Established Fra-2 as an oncogenic driver in adult T-cell leukemia by defining direct CCR4 and SOX4 activation and a downstream SOX4\\u2192HDAC8 cascade required for cell growth.\",\n      \"evidence\": \"siRNA knockdown, AP-1-site reporter assays, microarray and promoter analysis in ATL cells\",\n      \"pmids\": [\"18071306\", \"23482931\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Genome-wide ATL target set not mapped at this stage\", \"Reciprocal feedback within the cascade undefined\"]\n    },\n    {\n      \"year\": 2013,\n      \"claim\": \"Linked Fra-2 to TGF-\\u03b2/fibrotic signaling by showing it cooperates with Smad3 (promoting P300 recruitment and Smad3 acetylation) and with JunB at composite AP-1/Smad enhancers in an ERK-phosphorylation-dependent manner.\",\n      \"evidence\": \"Co-IP, acetylation and migration assays in NSCLC; ChIP, mutagenesis and ERK inhibition for LOXL4 enhancer\",\n      \"pmids\": [\"25375657\", \"23572561\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Direct Fra-2\\u2013P300 contacts not mapped\", \"Generality of Smad3 cooperation across fibrotic genes untested\"]\n    },\n    {\n      \"year\": 2011,\n      \"claim\": \"Demonstrated a repressive transcriptional mechanism: Fra-2 binds a variant AP-1-related (AP-1R) site at Rgs4 and represses transcription by dismissing the co-activator CBP, broadening the set of DNA elements and outputs Fra-2 controls.\",\n      \"evidence\": \"Dominant-negative Fra-2 transgenic rat profiling, ChIP, EMSA, promoter mutagenesis and CBP co-occupancy analysis\",\n      \"pmids\": [\"21367864\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Mechanism of CBP dismissal not resolved\", \"Generality of AP-1R-mediated repression unknown\"]\n    },\n    {\n      \"year\": 2017,\n      \"claim\": \"Defined Fra-2's direct genome-wide program in lymphocyte development, showing it binds and activates Foxo1 and Irf4 to drive B-cell development, with these targets sufficient to rescue Fra-2 loss.\",\n      \"evidence\": \"Conditional knockout, ChIP-seq, expression profiling and Foxo1/Irf4 rescue in pro-B cells\",\n      \"pmids\": [\"28566276\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Jun partner at these loci not specified\", \"Upstream signal controlling Fra-2 in B cells undefined\"]\n    },\n    {\n      \"year\": 2020,\n      \"claim\": \"Positioned Fra-2 as a repressor of immunosuppressive T-cell fates and a node in tumor immune regulation, repressing Treg development cell-intrinsically and acting downstream of \\u03b2-catenin to drive M2-like macrophage polarization.\",\n      \"evidence\": \"Fosl2 transgenic/conditional KO mice, T-cell transfer and EAE models; macrophage-specific \\u03b2-catenin ablation with transcriptomics in tumor models\",\n      \"pmids\": [\"32610127\", \"32548260\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct FoxP3-locus targets of Fra-2 not fully mapped\", \"Mechanism of \\u03b2-catenin\\u2192FOSL2 induction undefined\"]\n    },\n    {\n      \"year\": 2021,\n      \"claim\": \"Identified Fra-2 as an instructive fate-conversion factor and angiogenic/fibrotic effector, required for IL-1\\u03b2\\u2013Notch-driven secretory-to-AT2 conversion, for autophagy-coupled cardiac fibrosis, and for direct Wnt5a activation in cancer-associated fibroblasts.\",\n      \"evidence\": \"Lineage tracing and Notch manipulation in airway; conditional KO and Ang-II model with autophagy markers in cardiac fibroblasts; ChIP/reporter and angiogenesis assays in breast CAFs\",\n      \"pmids\": [\"34475534\", \"33668422\", \"33754039\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Direct Fosl2 targets in alveolar conversion not enumerated\", \"Mechanism of Fra-2/autophagy mutual regulation unresolved\"]\n    },\n    {\n      \"year\": 2023,\n      \"claim\": \"Extended the direct fibrotic/immunosuppressive target repertoire and added m6A control, defining FOSL2\\u2192SGK1 in renal fibrosis, KRAS/MAPK\\u2192FOSL2\\u2192CCL28-driven Treg recruitment in pancreatic cancer, and METTL3-dependent m6A regulation of FOSL2 mRNA.\",\n      \"evidence\": \"ChIP and SGK1 rescue in renal models; CUT&Tag, ChIP-qPCR, reporter and multiomics in PDAC; MeRIP-seq and METTL3 knockdown in granulosa cells\",\n      \"pmids\": [\"37662889\", \"37380804\", \"37179374\"],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"Functional consequence of specific m6A sites on FOSL2 protein not mapped\", \"Jun partner usage at SGK1/CCL28 not defined\"]\n    },\n    {\n      \"year\": 2024,\n      \"claim\": \"Provided direct in vivo proof that a c-Jun/Fra-2 dimer is sufficient to cause cancer, driving hepatocellular carcinoma through a direct c-Myc 3' enhancer with oncogene addiction, and showed cofactor chromatin support via a RUNX1-NPM1 complex at FOSL2 ECM target loci.\",\n      \"evidence\": \"Hepatocyte c-Jun~Fra-2 fusion transgenic mice with enhancer ChIP, transgene switch-off and JQ-1 treatment; ChIP-seq/ATAC-seq and Co-IP in glioblastoma\",\n      \"pmids\": [\"38657045\", \"38286983\"],\n      \"confidence\": \"High\",\n      \"gaps\": [\"Whether endogenous c-Jun/Fra-2 ratios reach oncogenic thresholds physiologically unknown\", \"How RUNX1-NPM1 is recruited to FOSL2 loci unresolved\"]\n    },\n    {\n      \"year\": null,\n      \"claim\": \"How phosphorylation, partner choice, m6A modification, and cofactor context are integrated to flip FOSL2 between activator and repressor at individual loci genome-wide remains unresolved.\",\n      \"evidence\": \"\",\n      \"pmids\": [],\n      \"confidence\": \"Medium\",\n      \"gaps\": [\"No unified model linking phospho-state to partner selection at specific targets\", \"Structural basis of canonical vs AP-1R site discrimination unknown\", \"Predictive rules for activation vs repression at a given promoter not established\"]\n    }\n  ],\n  \"mechanism_profile\": {\n    \"molecular_activity\": [\n      {\"term_id\": \"GO:0140110\", \"supporting_discovery_ids\": [1, 16, 17, 20, 26, 30, 36, 37]},\n      {\"term_id\": \"GO:0003677\", \"supporting_discovery_ids\": [1, 4, 10, 20]}\n    ],\n    \"localization\": [\n      {\"term_id\": \"GO:0005634\", \"supporting_discovery_ids\": [19, 24]}\n    ],\n    \"pathway\": [\n      {\"term_id\": \"R-HSA-74160\", \"supporting_discovery_ids\": [17, 26, 30, 36, 37]},\n      {\"term_id\": \"R-HSA-162582\", \"supporting_discovery_ids\": [4, 8, 11, 27, 29]},\n      {\"term_id\": \"R-HSA-168256\", \"supporting_discovery_ids\": [26, 28, 33, 36]},\n      {\"term_id\": \"R-HSA-1266738\", \"supporting_discovery_ids\": [7, 24, 31]},\n      {\"term_id\": \"R-HSA-1643685\", \"supporting_discovery_ids\": [16, 23, 36, 37]}\n    ],\n    \"complexes\": [\"AP-1 (Fra-2/Jun heterodimer)\"],\n    \"partners\": [\"JUN\", \"JUNB\", \"JUND\", \"SMAD3\", \"EP300\", \"FOSL1\", \"BATF\", \"RUNX1\"],\n    \"other_free_text\": []\n  }\n}\n```","audit_flag":null,"evaluation":{"pairwise":"win","faith_supported":7,"faith_total":7,"faith_pct":100.0}}