Affinage

FOSL2

Fos-related antigen 2 · UniProt P15408

Length
326 aa
Mass
35.2 kDa
Annotated
2026-04-28
100 papers in source corpus 30 papers cited in narrative 30 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FOSL2 (Fra-2) is a leucine-zipper transcription factor of the Fos family that obligatorily heterodimerizes with Jun-family partners (c-Jun, JunB, JunD) to form AP-1 complexes, acting as a context-dependent transcriptional activator or repressor at AP-1/CRE elements across diverse biological processes including fibrosis, immune cell differentiation, alveolar regeneration, and oncogenesis (PMID:2110368, PMID:1945831, PMID:18548006, PMID:34475534). ERK/MAPK phosphorylation of multiple C-terminal serine/threonine residues converts Fra-2 from a transcriptionally inert or repressive factor into a potent transactivator and stabilizes the protein, while MEKK1 promotes its ubiquitin-dependent proteasomal degradation, establishing phosphorylation as the central switch governing Fra-2 output (PMID:8058317, PMID:9188858, PMID:10359014, PMID:15558021). Fra-2 is induced by growth factors, TGF-β/PDGF, HGF/MET, β-catenin, and IL-1β/Notch inhibition, and its promoter contains AP-1 sites enabling positive autoregulation; downstream, Fra-2 directly activates or represses target genes including LIF, Wnt5a, CCL28, SGK1, SOX4, SNAI2, Rgs4, Foxo1/Irf4, and c-Myc, linking it to osteoclast biology, extracellular matrix remodeling, EMT, angiogenesis, Treg/Th17 specification, B cell development, and hepatocellular carcinogenesis (PMID:7862446, PMID:18548006, PMID:33754039, PMID:37380804, PMID:28566276, PMID:32610127, PMID:38657045). FOSL2 mRNA stability is additionally regulated by METTL3-mediated m6A methylation, providing a post-transcriptional control layer (PMID:37179374).

Mechanistic history

Synthesis pass · year-by-year structured walk · 18 steps
  1. 1990 High

    Establishing that Fra-2 heterodimerizes with c-Jun resolved the fundamental question of how this new Fos-family member engages AP-1 biology, placing it as a bona fide AP-1 subunit.

    Evidence Co-immunoprecipitation from retroviral-overexpression system in chicken embryo fibroblasts

    PMID:2110368

    Open questions at the time
    • Transcriptional consequences of Fra-2/Jun dimers unknown
    • Dimerization preferences among Jun partners not characterized
    • Endogenous stoichiometry not addressed
  2. 1991 High

    Demonstrating that Fra-2/c-Jun suppresses AP-1-driven transcription (unlike activating c-Fos/c-Jun), with the difference mapping to the C-terminal half, established that AP-1 activity is dimer-composition-dependent and identified the transactivation domain region.

    Evidence In vitro dimerization, EMSA, chimeric protein analysis, and reporter assay in F9 cells

    PMID:1945831

    Open questions at the time
    • Specific residues mediating repression not identified
    • Role of post-translational modification in switching activity unknown
  3. 1994 High

    Identification of ERK/MAP kinase as the kinase that phosphorylates Fra-2 in a cell-cycle- and serum-dependent manner, enhancing DNA-binding activity, provided the first signaling link converting Fra-2 into a functional transcription factor.

    Evidence In vitro kinase panel, phosphopeptide mapping, gel mobility shift assay

    PMID:8058317

    Open questions at the time
    • Individual phosphorylation sites not mapped
    • Effect on transactivation (vs. DNA binding alone) not tested
  4. 1997 High

    Mapping ERK2 phosphorylation to six C-terminal Ser/Thr residues (aa 266–323) and showing this converts Fra-2 from an inefficient to an active transactivator resolved how signaling switches Fra-2 output, while demonstrating AP-1-site-dependent autoregulation of the fra-2 promoter revealed a positive feedback loop.

    Evidence In-gel kinase assay identifying ERK2, site-directed mutagenesis, fra-2 promoter-reporter with constitutively active MEK1

    PMID:10359014 PMID:9188858

    Open questions at the time
    • Individual contribution of each phosphosite to transactivation not resolved
    • Phosphatase(s) responsible for dephosphorylation unknown
  5. 1998 High

    Showing that Fra-2/JunD binds AP-1 sites in the laminin-α3A promoter to mediate TGF-β-induced transcription placed Fra-2 as a direct effector of TGF-β signaling in extracellular matrix gene regulation, the first identified endogenous target gene context.

    Evidence EMSA with antibody supershift, AP-1 site mutagenesis, reporter assay in keratinocytes

    PMID:9651314

    Open questions at the time
    • Whether ERK phosphorylation of Fra-2 is required in this TGF-β context not tested
    • Genome-wide TGF-β/Fra-2 target repertoire unknown
  6. 2005 Medium

    Discovery that MEKK1 promotes Fra-2 ubiquitination and proteasomal degradation established a protein-stability control mechanism complementary to ERK-mediated activation, showing AP-1 dimer composition is regulated at the level of subunit turnover.

    Evidence MEKK1 knockout MEFs, ubiquitination assay, Western blot protein stability

    PMID:15558021

    Open questions at the time
    • E3 ubiquitin ligase responsible not identified
    • Relationship between ERK phosphorylation and MEKK1-driven degradation unclear
    • Not independently confirmed by another lab
  7. 2008 High

    Genetic knockout studies demonstrated that Fra-2 controls osteoclast size and survival in vivo through direct transcriptional activation of LIF (validated by ChIP) and modulates hypoxia signaling via PHD2, establishing Fra-2 as a physiologically essential AP-1 component in bone remodeling.

    Evidence Conditional and germline Fra-2 KO mice, LIF KO epistasis, ChIP at LIF promoter, histomorphometry

    PMID:18548006

    Open questions at the time
    • Full repertoire of Fra-2 target genes in osteoclasts not defined
    • Mechanism of PHD2 regulation not detailed
  8. 2010 High

    Placing Fra-2 downstream of TGF-β/PDGF/ERK signaling in fibroblasts, where it directly promotes collagen production, and downstream of Ask-1 in oxygen-sensitive TGF-β induction in cardiac fibroblasts, consolidated Fra-2 as a central fibrogenic effector integrating multiple upstream pathways.

    Evidence siRNA knockdown, ERK inhibition, EMSA, collagen release assay, Fra-2 transgenic mice; separate study with Ask-1 epistasis and reporter mutagenesis

    PMID:20039427 PMID:20427335

    Open questions at the time
    • Direct chromatin occupancy at collagen gene promoters not shown in the fibroblast study
    • Relative contribution of Jun partner identity in fibrotic contexts unclear
  9. 2011 High

    Identification of Fra-2 binding to a variant AP-1-related (AP-1R) sequence in the Rgs4 promoter, where it displaces the co-activator CBP to repress transcription, revealed a repressive mechanism distinct from simple lack of transactivation and expanded the DNA-binding repertoire beyond canonical AP-1 sites.

    Evidence ChIP, EMSA, AP-1R site mutagenesis, reporter assay in dominant-negative Fra-2 transgenic rat

    PMID:21367864

    Open questions at the time
    • Genome-wide prevalence of AP-1R site usage by Fra-2 unknown
    • Structural basis for CBP displacement not resolved
  10. 2013 High

    Multiple studies demonstrated Fra-2's cooperation with Smad proteins: Fra-2/JunB cooperates with Smads at the LOXL4 promoter downstream of TGF-β1 in an ERK-dependent manner, and FOSL2 directly interacts with Smad3 to promote P300-mediated Smad3 acetylation, establishing Fra-2 as a functional bridge between MAPK and TGF-β/Smad signaling.

    Evidence ChIP, EMSA, promoter mutagenesis, co-IP of FOSL2-Smad3, P300 acetylation assay, ERK inhibitor epistasis

    PMID:23572561 PMID:25375657

    Open questions at the time
    • Structural basis of FOSL2–Smad3 interaction unknown
    • Whether this cooperation applies genome-wide or only at select promoters unclear
  11. 2013 High

    Identification of ERK1/2-dependent phosphorylation at S320/T322 as regulators of Fra-2 protein stability in satellite cells, where Fra-2 marks undifferentiated Pax7+ cells and suppresses myogenic differentiation, extended the phospho-stability mechanism to a stem-cell maintenance context.

    Evidence Mass spectrometry phosphoproteomics, site-directed mutagenesis, siRNA knockdown, immunofluorescence in satellite cells

    PMID:23807221

    Open questions at the time
    • Direct transcriptional targets in satellite cells not identified
    • Whether these sites are the same as the previously mapped C-terminal cluster not clarified
  12. 2017 High

    ChIP-seq in B cells from conditional Fra-2 KO mice identified Foxo1 and Irf4 as direct transcriptional targets, with their re-expression rescuing the B cell differentiation defect, establishing Fra-2 as an essential regulator of early B lymphopoiesis through a defined gene-regulatory circuit.

    Evidence B cell-specific conditional KO, ChIP-seq, IL-7-stimulated pro-B culture, Foxo1/Irf4 rescue

    PMID:28566276

    Open questions at the time
    • Mechanism by which Fra-2 activates vs. represses different targets in B cells not resolved
    • Jun partner(s) involved not specified
  13. 2020 High

    Genetic gain- and loss-of-function studies established that Fosl2 cell-intrinsically represses Treg development and that β-catenin directly induces FOSL2 in macrophages to drive M2-like polarization, broadening Fra-2's immune regulatory roles to T cell tolerance and tumor-associated macrophage programming.

    Evidence Fosl2 transgenic and conditional KO T cells with adoptive transfer/EAE model; macrophage-specific β-catenin KO with TAM transcriptomics

    PMID:32548260 PMID:32610127

    Open questions at the time
    • Direct Fra-2 target genes mediating Treg suppression not identified by ChIP
    • Whether β-catenin binds the FOSL2 promoter directly not shown
  14. 2021 High

    Lineage tracing and conditional KO demonstrated that Fosl2 mediates IL-1β/Notch-inhibition-driven secretory-to-alveolar type 2 cell conversion during lung regeneration, revealing a regenerative role for Fra-2 beyond fibrosis and cancer.

    Evidence Genetic lineage tracing, conditional Fosl2 loss-of-function, Notch/IL-1β epistasis, single-cell transcriptomics

    PMID:34475534

    Open questions at the time
    • Direct transcriptional targets of Fosl2 in alveolar regeneration not identified
    • Whether this role is conserved in human lung repair unknown
  15. 2021 High

    Establishing Fosl2 as an upstream activator of autophagy (LC3BII, Beclin-1, Atg5) in cardiac fibroblasts, with genetic epistasis between Fosl2 and Atg5 deletion both protecting from cardiac fibrosis, linked Fra-2's fibrogenic activity to autophagy regulation.

    Evidence Fosl2 transgenic fibroblasts, GapmeR silencing, conditional Fosl2 and Atg5 KO mice, angiotensin II model

    PMID:33668422

    Open questions at the time
    • Whether Fosl2 directly binds autophagy gene promoters not tested
    • Mechanism connecting Fra-2 transcriptional activity to autophagy induction unclear
  16. 2022 High

    Genome-wide ChIP-seq during human Th17 differentiation revealed that FOSL2 co-occupies Th17 lineage regulatory regions with FOSL1 and BATF and co-represses Th17 fate, with shared protein interaction partners suggesting functional redundancy through common AP-1-containing complexes.

    Evidence siRNA knockdown during Th17 polarization, ChIP-seq, protein interaction proteomics

    PMID:35511484

    Open questions at the time
    • Specific Th17 genes directly repressed by FOSL2 vs. FOSL1 not distinguished
    • Whether FOSL2 and BATF form direct heterodimers not established
  17. 2023 High

    Multiple studies identified new direct Fra-2 target genes in disease contexts: CCL28 in KRAS-driven pancreatic cancer (recruiting Tregs for immunosuppression), SGK1 in TGF-β-driven renal fibrosis, and demonstrated that METTL3-catalyzed m6A methylation of FOSL2 mRNA regulates its stability, adding a post-transcriptional epitranscriptomic control layer.

    Evidence CUT&Tag/ChIP-qPCR/reporter at CCL28 promoter with KRAS GEMM; ChIP/reporter/SGK1 rescue in UUO model; MeRIP-seq identifying m6A on FOSL2 mRNA with METTL3 manipulation

    PMID:37179374 PMID:37380804 PMID:37662889

    Open questions at the time
    • Whether m6A regulation of FOSL2 operates in non-granulosa cell contexts unknown
    • E3 ligase for FOSL2 ubiquitination still unidentified
    • Reader protein recognizing m6A on FOSL2 mRNA not characterized
  18. 2024 High

    A single-chain c-Jun~Fra-2 dimer was shown to be sufficient to drive hepatocellular carcinoma through direct transcriptional activation of c-Myc via a distal 3′ enhancer, with tumors showing oncogene addiction; this established that the c-Jun/Fra-2 AP-1 dimer is an autonomous oncogenic transcription factor.

    Evidence Hepatocyte-specific single-chain transgenic mice, ChIP at c-Myc enhancer, JQ-1 inhibition, doxycycline transgene switch-off

    PMID:38657045

    Open questions at the time
    • Whether endogenous c-Jun/Fra-2 dimers are sufficient for hepatocarcinogenesis unknown
    • Genome-wide target landscape of the c-Jun/Fra-2 dimer in liver not mapped

Open questions

Synthesis pass · forward-looking unresolved questions
  • Key unresolved questions include the identity of the E3 ubiquitin ligase mediating MEKK1-induced Fra-2 degradation, the structural basis for dimer-partner-dependent switching between activation and repression, and how Fra-2's activating versus repressive roles are specified at different genomic loci.
  • E3 ligase for Fra-2 ubiquitination unidentified
  • No crystal structure of Fra-2/Jun heterodimer on DNA
  • Genome-wide rules distinguishing activating from repressive Fra-2 binding events remain uncharacterized

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 12 GO:0003677 DNA binding 8
Localization
GO:0005634 nucleus 4
Pathway
R-HSA-74160 Gene expression (Transcription) 12 R-HSA-162582 Signal Transduction 8 R-HSA-1643685 Disease 5 R-HSA-168256 Immune System 4 R-HSA-1266738 Developmental Biology 1 R-HSA-9612973 Autophagy 1
Partners
BATFEP300FOSL1JUNJUNBJUNDSMAD3
Complex memberships
AP-1 (Fra-2/JunB)AP-1 (Fra-2/JunD)AP-1 (Fra-2/c-Jun)

Evidence

Reading pass · 30 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
1990 Fra-2 (FOSL2) protein forms a complex with c-Jun in cells, demonstrating heterodimerization with Jun family members as a fundamental biochemical property shared with c-Fos. Co-immunoprecipitation from cell lysates; retroviral overexpression transformation assay in chicken embryo fibroblasts Proceedings of the National Academy of Sciences of the United States of America High 2110368
1991 Fra-2 forms stable heterodimers in vitro with c-Jun, JunB, and JunD that bind AP-1 sites, but unlike c-Fos, Fra-2/c-Jun suppresses rather than activates transcription at AP-1 sites in F9 cells; this difference maps to the C-terminal half of the proteins via chimeric protein analysis. In vitro dimerization assay, DNA-binding EMSA, transient transfection reporter assay in F9 cells, chimeric protein deletion analysis Nucleic acids research High 1945831
1994 Fra-2 is phosphorylated during the cell cycle in a serum-dependent manner; MAP kinase (ERK) phosphorylates Fra-2 in vitro causing a mobility shift identical to that seen in vivo, and this phosphorylation increases Fra-2 DNA-binding activity. Alkaline phosphatase treatment, in vitro kinase assays (PKA, PKC, cdc2, MAP kinase), one-dimensional phosphopeptide mapping, gel mobility shift assay Oncogene High 8058317
1995 Fra-2 promoter activity is induced by serum through AP-1 binding sites (and a CRE-like sequence); early after serum stimulation, c-Fos/c-Jun heterodimers bind the fra-2 promoter and strongly activate it, while Fra-2/c-Jun complex (present at basal and later times) has lower transactivation activity, establishing a feed-forward mechanism for fra-2 induction. Promoter deletion analysis with CAT reporter, EMSA with AP-1 site probes, transient expression in F9 cells Oncogene High 7862446
1997 In v-src-transformed chicken embryo fibroblasts, Fra-2 is extensively phosphorylated by ERK2 (identified by in-gel kinase assay) at Ser/Thr residues in the C-terminal region (aa 266–323), converting Fra-2 from an inefficient to an active transactivator; fra-2 promoter is autoregulated through AP-1 sites, creating a positive feedback loop. In-gel kinase assay, site-directed mutagenesis of phosphorylation sites, fra-2 promoter-reporter analysis, co-transfection with constitutively active MEK1 Oncogene High 9188858
1999 Phosphorylation of Fra-2 by MAPK at three threonine and three serine residues in its C-terminal region greatly enhances Fra-2/c-Jun heterodimer transcriptional activity, and this phosphorylated Fra-2 induces fra-2 gene expression through AP-1 sites in the fra-2 promoter, constituting a positive autoregulatory loop. Site-directed mutagenesis of six C-terminal phosphorylation sites, co-transfection with constitutively active MEK-DD mutant, reporter assay in F9 cells Cell growth & differentiation High 10359014
1998 Fra-2/JunD heterodimer binds AP-1 sites in the laminin alpha3A (lama3A) promoter and cooperatively mediates TGF-β-induced transcriptional activation of lama3A in keratinocytes; mutation of individual AP-1 sites reduces TGF-β responsiveness. Promoter deletion analysis, site-directed mutagenesis, EMSA with Fra-2/JunD antibody supershift, transient transfection reporter assay The Journal of biological chemistry High 9651314
2001 In the rat pineal gland, Fra-2 knockdown (via dominant-negative Fra-2 transgene) suppresses nocturnal fra-2 mRNA/protein and identifies type II iodothyronine deiodinase and nectadrin (CD24) as genes whose expression is strongly linked to Fra-2 activity. Transgenic knockdown rat model (dominant-negative Fra-2 under AANAT promoter), microarray expression profiling of 1190 genes, Northern/Western validation Molecular and cellular biology High 11340164
2005 MEKK1 regulates Fra-2 protein stability by inducing Fra-2 ubiquitination and proteasomal degradation, thereby controlling AP-1 dimer composition. MEKK1 knockout MEFs, Fra-2 ubiquitination assay, Western blot protein stability analysis Oncogene Medium 15558021
2008 Fra-2 controls osteoclast survival and size in vivo by directly transcriptionally activating LIF (leukaemia inhibitory factor) as a direct target gene of Fra-2/c-Jun; Fra-2 also modulates hypoxia signalling through transcriptional regulation of the HIF prolyl hydroxylase PHD2, affecting HIF1α levels. Fra-2 conditional and germline knockout mice, LIF knockout mice, Bcl-2 overexpression in vivo, chromatin immunoprecipitation for Fra-2/c-Jun at LIF promoter, histomorphometry Nature High 18548006
2010 Fra-2 acts downstream of TGF-β and PDGF signalling to promote extracellular matrix (collagen) production in systemic sclerosis fibroblasts; TGF-β/PDGF induce Fra-2 expression and DNA binding in an ERK-dependent manner, and Fra-2 knockdown reduces collagen release. siRNA knockdown of Fra-2, TGF-β/PDGF stimulation, ERK inhibition, EMSA DNA-binding assay, collagen release measurement, transgenic Fra-2 overexpressing mice Arthritis and rheumatism High 20039427
2010 Fra-2 mediates oxygen-sensitive (hyperoxia-induced) transcriptional induction of TGF-β in cardiac fibroblasts; AP-1 binding sites in the TGF-β promoter confer O2-sensitivity, Fra-2 knockdown blunts O2-induced TGF-β1 and TGF-β3 expression, and Ask-1 kinase is required upstream of hyperoxia-induced Fra-2 nuclear localization. siRNA knockdown, Ask-1 knockdown, AP-1 site deletion/mutation in TGF-β reporter, subcellular fractionation/nuclear localization, in vivo laser capture microdissection Cardiovascular research High 20427335
2011 FRA-2 selectively binds a variant AP-1-related (AP-1R) sequence in the Rgs4 gene promoter (distinct from consensus AP-1 sites), and represses Rgs4 transcription by displacing the co-activator CBP from the AP-1R sequence; mutation of the AP-1R site abolishes repression. Dominant-negative transgenic rat, bioinformatic target analysis, ChIP (ex vivo), EMSA, AP-1R site mutagenesis, reporter assay The Journal of biological chemistry High 21367864
2013 Fra-2 (FOSL2) positively regulates LOXL4 transcription downstream of TGF-β1 by forming a JunB/Fra-2 AP-1 complex that cooperates with Smad proteins at a distal AP-1 site in the LOXL4 promoter; this induction requires ERK-dependent phosphorylation of Fra-2. Promoter deletion mapping, site-directed mutagenesis, EMSA, ChIP, co-transfection with Smad/AP-1 constructs, ERK inhibition Molecular and cellular biology High 23572561
2013 FRA-2/JUND heterodimer directly activates the SOX4 promoter via an AP-1 site; SOX4 in turn directly activates the HDAC8 promoter, establishing a FRA-2/JUND→SOX4→HDAC8 oncogenic cascade in ATL. siRNA knockdown of FRA-2, JUND, SOX4; reporter assay with SOX4 and HDAC8 promoter constructs; microarray; ChIP implied by AP-1 site mutagenesis Blood Medium 23482931
2013 Fra-2 is expressed specifically in Pax7-positive satellite cells and undifferentiated reserve cells but not in differentiated myofiber nuclei; Fra-2 silencing enhances myogenic differentiation markers; ERK1/2 signalling stabilizes Fra-2 protein, with S320 and T322 identified by mass spectrometry and mutagenesis as regulators of Fra-2 protein stability in muscle cells. siRNA knockdown, immunofluorescence localization, mass spectrometry phosphoproteomics, site-directed mutagenesis (S320A, T322A), cytokine ERK1/2 stimulation, satellite cell immunostaining Cell death & disease High 23807221
2014 FOSL2 interacts directly with Smad3 (demonstrated in vitro and in vivo by co-IP), promotes P300 binding to Smad3 and Smad3 acetylation by P300, thereby potentiating TGF-β1-induced signalling and migration in NSCLC cells. Co-immunoprecipitation (in vitro and in vivo), P300 binding assay, acetylation assay, siRNA knockdown of FOSL2, TGF-β1 migration assay PloS one High 25375657
2016 Fra-2 binds to the TIMP-1 promoter (by ChIP) in monocytes stimulated with TLR-8 agonist and drives TIMP-1 production; histone demethylation (DZNep) enhances this Fra-2-mediated TIMP-1 expression, which in turn promotes fibroblast transdifferentiation to myofibroblasts. ChIP (Fra-2 at TIMP-1 promoter), luciferase reporter assay, siRNA AP-1 inhibition, DZNep/apicidin histone modifier treatment, fibroblast co-culture Arthritis & rheumatology Medium 26814616
2017 Fra-2 is required for normal B cell development; Fra-2 deficiency reduces proliferation and differentiation of pro-B and pre-B cells, and ChIP-seq demonstrates Fra-2 directly binds regulatory regions of Foxo1, Irf4, Ikaros, and Aiolos genes; re-expression of Foxo1 and Irf4 rescues the Fra-2-deficient B cell differentiation defect. Conditional Fra-2 knockout mice (B cell-specific), ChIP-seq, IL-7-stimulated pro-B cell cultures, gene expression profiling, rescue by Foxo1/Irf4 re-expression The Journal of experimental medicine High 28566276
2019 HGF/MET signalling induces phosphorylation and upregulation of FOSL2 via ERK1/2 kinase; FOSL2 then directly binds the SNAI2 promoter and activates its transcription, promoting EMT, invasion and migration in NSCLC cells. Western blot (FOSL2 phosphorylation/upregulation), ERK1/2 inhibition, ChIP (FOSL2 at SNAI2 promoter), dual-luciferase reporter assay, transwell migration/invasion assay OncoTargets and therapy Medium 31807006
2020 β-catenin directly transcriptionally activates FOSL2 in macrophages, and FOSL2 drives a gene-regulatory switch from M1-like to M2-like tumor-associated macrophage polarization; pharmacological and genetic β-catenin ablation represses FOSL2 and reprograms TAMs. Macrophage-specific β-catenin knockout, pharmacological β-catenin inhibition, transcriptome analysis of human TAMs, in vitro TAM model, in vivo tumor models Science advances Medium 32548260
2020 Fosl2 (Fra-2) represses Treg development in a T cell-intrinsic manner; Fosl2-overexpressing T cells transfer inflammation that is suppressed by co-delivered Tregs, and T cell-specific Fosl2 deficiency reduces autoimmunity in the EAE model; Fosl2 affects FoxP3 and other Treg development gene expression. Fosl2 transgenic mice, Fosl2×Rag2-/- mice, T cell adoptive transfer, conditional Fosl2 KO in T cells, EAE model, gene expression analysis Cell reports High 32610127
2021 FOSL2 in breast cancer-associated fibroblasts directly transcriptionally activates Wnt5a (confirmed by dual luciferase reporter and ChIP); secreted Wnt5a activates FZD5/NF-κB/ERK signalling in endothelial cells to promote VEGF-independent angiogenesis; FOSL2 expression in CAFs is regulated upstream by estrogen/cAMP/PKA signalling. Dual luciferase reporter assay, ChIP (FOSL2 at Wnt5a promoter), FOSL2 silencing/overexpression, tube formation assay, 3D sprouting assay, orthotopic xenograft Theranostics High 33754039
2021 Fosl2 is identified as the transcription factor mediating secretory cell fate conversion to alveolar type 2 cells during alveolar regeneration, downstream of an IL-1β–Notch inhibition axis; IL-1β signalling modulates Jag1/Jag2 in ciliated cells to inhibit Notch in secretory cells, which drives Fosl2-dependent reprogramming. Genetic lineage tracing, conditional Fosl2 loss-of-function, IL-1β signalling manipulation, Notch inhibition, single-cell transcriptomics, epigenetic profiling Nature cell biology High 34475534
2021 Fosl-2 regulates autophagy in cardiac fibroblasts; cardiac fibroblasts from Fosl-2 transgenic mice have elevated LC3BII, Beclin-1, and Atg5; silencing Fosl-2 suppresses autophagy markers and collagen production; mice with stromal cell-specific Fosl-2 or Atg5 deletion are protected from cardiac fibrosis, placing Fosl-2 upstream of autophagy in the TGF-β fibrogenic pathway. Fosl-2 transgenic cardiac fibroblasts, antisense GapmeR Fosl-2 silencing, Ccl19-Cre conditional Fosl-2 and Atg5 KO mice, angiotensin II cardiac hypertrophy model, LC3B/Beclin-1/Atg5 Western blot International journal of molecular sciences High 33668422
2022 FOSL2 co-represses Th17 fate-specification during human Th17 differentiation; genome-wide ChIP-seq shows FOSL2 shares genomic occupancy over Th17 lineage gene regulatory regions with FOSL1 and BATF; FOSL2 shares protein-interacting partners with FOSL1 and BATF, suggesting functional interplay through shared complexes. siRNA knockdown of FOSL1/FOSL2/BATF during Th17 differentiation, ChIP-seq genome-wide binding, protein interaction proteomics, SNP-binding analysis Nucleic acids research High 35511484
2023 FOSL2 binds the SGK1 promoter directly (by ChIP) and transcriptionally activates SGK1 expression; FOSL2 knockdown reduces TGF-β1-induced SGK1 expression and blocks EMT in proximal tubular epithelial cells, and SGK1 overexpression reverses the effects of FOSL2 silencing, placing FOSL2 upstream of SGK1 in renal fibrosis. siRNA FOSL2 knockdown, ChIP (FOSL2 at SGK1 promoter), reporter assay, SGK1 overexpression rescue, UUO mouse model, TGF-β1 cell model Journal of translational internal medicine Medium 37662889
2023 FOSL2 acts downstream of the KRAS/MAPK pathway and directly transcriptionally activates CCL28 (confirmed by ChIP-qPCR and dual-luciferase reporter assay), thereby recruiting regulatory T cells and promoting immunosuppression in pancreatic ductal adenocarcinoma. ATAC-seq/H3K27ac ChIP-seq/RNA-seq multiomics in KRAS/TP53 GEMMs, CUT&Tag for FOSL2 targets, ChIP-qPCR at CCL28 promoter, dual-luciferase reporter, FOSL2 KD functional assays, xenograft British journal of cancer High 37380804
2023 Butyric acid suppresses METTL3 expression, reducing N6-methyladenosine (m6A) methylation of FOSL2 mRNA, thereby decreasing FOSL2 mRNA stability and expression, which in turn reduces NLRP3 inflammasome activation and inflammatory cytokine production in granulosa cells. RNA-seq, MeRIP-seq (m6A profiling), METTL3 manipulation, butyric acid treatment, FOSL2 siRNA knockdown, PCOS mouse model Clinical epigenetics Medium 37179374
2024 A single-chain c-Jun~Fra-2 fusion protein (mimicking the c-Jun/Fra-2 AP-1 dimer) drives spontaneous hepatocellular carcinoma in mice; the c-Jun/Fra-2 dimer directly activates c-Myc transcription through a conserved distal 3' enhancer; inhibition of c-Myc with the BET inhibitor JQ-1 reduces tumor growth, and tumors regress upon transgene switch-off demonstrating oncogene addiction. Hepatocyte-specific c-Jun~Fra-2 single-chain transgenic mice, ChIP at c-Myc enhancer, JQ-1 pharmacological inhibition, transgene doxycycline switch-off, transcriptomic analysis Proceedings of the National Academy of Sciences of the United States of America High 38657045

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
1990 Isolation and characterization of fra-2, an additional member of the fos gene family. Proceedings of the National Academy of Sciences of the United States of America 310 2110368
1991 Difference in transcriptional regulatory function between c-Fos and Fra-2. Nucleic acids research 209 1945831
2008 Identification of FRA1 and FRA2 as genes involved in regulating the yeast iron regulon in response to decreased mitochondrial iron-sulfur cluster synthesis. The Journal of biological chemistry 175 18281282
2009 The yeast iron regulatory proteins Grx3/4 and Fra2 form heterodimeric complexes containing a [2Fe-2S] cluster with cysteinyl and histidyl ligation. Biochemistry 168 19715344
1996 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. Endocrinology 165 8828501
2020 Reprogramming of tumor-associated macrophages by targeting β-catenin/FOSL2/ARID5A signaling: A potential treatment of lung cancer. Science advances 157 32548260
2008 Osteoclast size is controlled by Fra-2 through LIF/LIF-receptor signalling and hypoxia. Nature 153 18548006
2017 Nintedanib inhibits macrophage activation and ameliorates vascular and fibrotic manifestations in the Fra2 mouse model of systemic sclerosis. Annals of the rheumatic diseases 145 28814429
2019 lncRNA UCA1 Mediates Resistance to Cisplatin by Regulating the miR-143/FOSL2-Signaling Pathway in Ovarian Cancer. Molecular therapy. Nucleic acids 141 31234009
1994 Regulation of Fra-1 and Fra-2 phosphorylation differs during the cell cycle of fibroblasts and phosphorylation in vitro by MAP kinase affects DNA binding activity. Oncogene 139 8058317
2003 The cold-regulated transcriptional activator Cbf3 is linked to the frost-tolerance locus Fr-A2 on wheat chromosome 5A. Molecular genetics and genomics : MGG 122 12715154
1995 Differential expression of the fos and jun family members c-fos, fosB, Fra-1, Fra-2, c-jun, junB and junD during human epidermal keratinocyte differentiation. Oncogene 121 8545126
2004 The role of the AP-1 transcription factors c-Fos, FosB, Fra-1 and Fra-2 in the invasion process of mammary carcinomas. Breast cancer research and treatment 110 15319566
2000 Regulation of AP1 (Jun/Fos) factor expression and activation in ovarian granulosa cells. Relation of JunD and Fra2 to terminal differentiation. The Journal of biological chemistry 104 10934195
2021 FOSL2 promotes VEGF-independent angiogenesis by transcriptionnally activating Wnt5a in breast cancer-associated fibroblasts. Theranostics 101 33754039
2018 miR-143-3p inhibits the proliferation, migration and invasion in osteosarcoma by targeting FOSL2. Scientific reports 95 29330462
1996 Transcription factor AP-1, and the role of Fra-2. Immunology and cell biology 94 8723999
2010 The transcription factor Fra-2 regulates the production of extracellular matrix in systemic sclerosis. Arthritis and rheumatism 93 20039427
2012 Fra-2 transgenic mice as a novel model of pulmonary hypertension associated with systemic sclerosis. Annals of the rheumatic diseases 88 22523431
2000 High levels of phosphorylated c-Jun, Fra-1, Fra-2 and ATF-2 proteins correlate with malignant phenotypes in the multistage mouse skin carcinogenesis model. Oncogene 86 10962557
1995 Circadian expression of transcription factor Fra-2 in the rat pineal gland. The Journal of biological chemistry 85 7592994
2020 The AP1 Transcription Factor Fosl2 Promotes Systemic Autoimmunity and Inflammation by Repressing Treg Development. Cell reports 84 32610127
2019 lncRNA UCA1 Promotes Gefitinib Resistance as a ceRNA to Target FOSL2 by Sponging miR-143 in Non-small Cell Lung Cancer. Molecular therapy. Nucleic acids 84 31951852
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2014 Copy number and haplotype variation at the VRN-A1 and central FR-A2 loci are associated with frost tolerance in hexaploid wheat. TAG. Theoretical and applied genetics. Theoretische und angewandte Genetik 70 24626953
2007 Aberrant expression of Fra-2 promotes CCR4 expression and cell proliferation in adult T-cell leukemia. Oncogene 63 18071306
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2023 LncRNA ITGB2-AS1 promotes cisplatin resistance of non-small cell lung cancer by inhibiting ferroptosis via activating the FOSL2/NAMPT axis. Cancer biology & therapy 59 37370246
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2001 Nerve growth factor, but not epidermal growth factor, increases Fra-2 expression and alters Fra-2/JunD binding to AP-1 and CREB binding elements in pheochromocytoma (PC12) cells. The Journal of neuroscience : the official journal of the Society for Neuroscience 37 11150315
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2009 Aberrant selection and function of invariant NKT cells in the absence of AP-1 transcription factor Fra-2. Journal of immunology (Baltimore, Md. : 1950) 24 19620306
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2020 Circ_0091581 Promotes the Progression of Hepatocellular Carcinoma Through Targeting miR-591/FOSL2 Axis. Digestive diseases and sciences 17 33040214