Affinage

FHL2

Four and a half LIM domains protein 2 · UniProt Q14192

Length
279 aa
Mass
32.2 kDa
Annotated
2026-04-28
100 papers in source corpus 45 papers cited in narrative 45 extracted findings

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FHL2 is a LIM-domain scaffold protein that functions as a signal-responsive transcriptional coregulator and cytoplasmic adaptor, integrating mechanical, lipid, and growth factor cues across cardiac, vascular, immune, and epithelial contexts. In the nucleus, FHL2 acts as a context-dependent coactivator for AR, β-catenin/TCF, AP-1, SRF/myocardin, LXRs, and WT1 or as a corepressor for PLZF, Nur77, E4F1, and the TGFβ1 promoter, in part by recruiting chromatin modifiers such as CBP/p300 and SIRT1 to modulate acetylation of transcription factor targets (PMID:10654935, PMID:12466281, PMID:15572674, PMID:15692560, PMID:22049082, PMID:28223370). Its nucleocytoplasmic shuttling is controlled by Rho/ROCK signaling, matrix stiffness via FAK phosphorylation, and CRM1-dependent nuclear export, linking extracellular mechanical and biochemical signals to gene expression programs governing wound healing, smooth-muscle differentiation, and cell cycle arrest (PMID:11847121, PMID:27742790, PMID:12644711, PMID:17420295). In the cytoplasm, FHL2 serves as a multivalent adaptor that anchors metabolic enzymes to titin at sarcomeres, inhibits sphingosine kinase-1 activity, stabilizes or promotes degradation of binding partners including EGFR, TRAF6, Arkadia, and IER3, tethers mitochondria to F-actin through O-GlcNAcylated TRAK in a glucose-dependent manner, and mediates Patched-dependent caspase-9 activation during apoptosis (PMID:12432079, PMID:16888242, PMID:29321665, PMID:23775124, PMID:34342639, PMID:19465923).

Mechanistic history

Synthesis pass · year-by-year structured walk · 22 steps
  1. 2000 High

    The first defined nuclear function of FHL2 was established: it selectively coactivates AR-dependent transcription in an agonist- and AF-2-dependent manner, revealing that this LIM-only protein can act directly in the nucleus as a transcription cofactor.

    Evidence In vitro binding, Co-IP, reporter assays, and co-localization in prostate and heart cell lines

    PMID:10654935

    Open questions at the time
    • Mechanism of FHL2 recruitment to AR target gene chromatin not defined
    • Tissue specificity mechanism unclear
  2. 2000 Medium

    FHL2 was identified as an integrin cytoplasmic domain–binding protein localizing to focal adhesions, establishing its dual cytoplasmic adaptor role alongside its nuclear function.

    Evidence Yeast two-hybrid with integrin tails, overexpression in human cells, domain deletion mapping

    PMID:10906324

    Open questions at the time
    • Binding detected by Y2H/overexpression; endogenous integrin–FHL2 complexes not validated
    • Functional consequences of integrin binding not tested
  3. 2002 High

    A burst of discoveries established FHL2 as a multivalent transcriptional coregulator: it coactivates β-catenin/TCF, AP-1, and WT1, corepresses PLZF, and interacts with BRCA1, revealing remarkable context-dependent duality of transcriptional output.

    Evidence Multiple Y2H, Co-IP, in vitro binding, reporter assay, and Xenopus axis duplication studies across several labs

    PMID:12145280 PMID:12151099 PMID:12370240 PMID:12466281 PMID:12644711 PMID:14550570

    Open questions at the time
    • Whether coactivation vs. corepression is determined by cell type, promoter context, or post-translational modification of FHL2 remained unresolved
    • Genome-wide target gene sets unknown
  4. 2002 High

    FHL2 was shown to bridge sarcomeric architecture and metabolism by binding titin at two distinct sites and recruiting metabolic enzymes (creatine kinase, adenylate kinase, PFK) to the sarcomere, defining its structural adaptor role in cardiomyocytes.

    Evidence Y2H, co-localization, Co-IP, and pull-down in cardiomyocytes

    PMID:12432079

    Open questions at the time
    • Functional consequence of metabolic enzyme mis-localization in FHL2-null hearts not tested at this stage
  5. 2002 High

    The Rho/ROCK signaling axis was identified as a trigger for FHL2 nuclear translocation, providing the first mechanistic link between extracellular signals (S1P) and FHL2's nuclear coactivator function.

    Evidence Subcellular fractionation, immunofluorescence, reporter assays, dominant-negative GTPase constructs

    PMID:11847121

    Open questions at the time
    • Direct phosphorylation or modification of FHL2 by Rho effectors not identified
    • Whether nuclear import is active (importin-mediated) or passive not resolved
  6. 2002 High

    FHL2 was found to be required for reconstitution of IKs (slow delayed rectifier K+) current by interacting with the minK channel subunit, revealing a role in ion channel regulation.

    Evidence Electrophysiology in FHL2-lacking HEK cells and antisense knockdown in FHL2-expressing CHO cells, Y2H, GST pulldown

    PMID:12237170

    Open questions at the time
    • In vivo cardiac electrophysiology in FHL2-null mice not reported
    • Stoichiometry and structural basis of FHL2–minK interaction unknown
  7. 2004 High

    FHL2 was established as both a target and a negative-feedback modulator of SRF signaling: it is transcribed downstream of SRF and then competes with MAL/MRTF-A for SRF binding, selectively repressing smooth muscle genes.

    Evidence ChIP on endogenous promoters, Co-IP, reporter assays, competitive binding with MAL

    PMID:15610731

    Open questions at the time
    • Whether FHL2–SRF competition operates genome-wide or only at specific loci unclear
  8. 2004 High

    The coactivation mechanism for β-catenin/TCF was deepened by showing FHL2 recruits CBP/p300 to form a ternary complex that increases β-catenin acetylation, providing an epigenetic amplification step.

    Evidence Co-IP, reporter assays, in vivo acetyltransferase assay, FHL2 KO fibroblasts

    PMID:15572674

    Open questions at the time
    • Whether acetylation alters β-catenin stability, DNA binding, or co-factor recruitment not dissected
  9. 2005 High

    FHL2 was linked to survival signaling by showing it suppresses FOXO1 transcriptional activity and apoptosis through promoting SIRT1-mediated deacetylation of FOXO1.

    Evidence Co-IP, deacetylation assay, apoptosis assay

    PMID:15692560

    Open questions at the time
    • Whether FHL2 regulates other FOXO family members through the same mechanism not tested
  10. 2006 High

    FHL2 was identified as a direct inhibitor of sphingosine kinase-1 enzymatic activity in cardiomyocytes, with the interaction being dynamically regulated by endothelin-1, linking FHL2 to sphingolipid metabolism and apoptosis regulation.

    Evidence Y2H, Co-IP, kinase activity assay, co-localization, apoptosis assay in cardiomyocytes

    PMID:16888242

    Open questions at the time
    • Structural basis of SK1 inhibition by FHL2 not known
    • Whether SK1 inhibition is direct (allosteric) or indirect not resolved
  11. 2007 High

    FHL2 knockout mice revealed a physiological requirement for FHL2 in wound healing: Fhl2-null fibroblasts fail to contract collagen, migrate, or express α-SMA, establishing an in vivo role for FHL2 in myofibroblast function.

    Evidence Fhl2 KO mice, transgenic rescue, collagen contraction and migration assays

    PMID:17420295

    Open questions at the time
    • Relative contributions of nuclear (transcriptional) vs. cytoplasmic (adhesion) FHL2 functions to the wound phenotype not separated
  12. 2008 High

    FHL2 was shown to dampen integrin-FAK-ERK signaling: FHL2-null cells exhibit hyperactivated FAK (Y925) and ERK, with MAPK inhibition rescuing ECM assembly defects, establishing FHL2 as a negative regulator of this pathway.

    Evidence FHL2 KO cells, recombinant rescue, pFAK/pERK Western blots, MAPK inhibitor epistasis

    PMID:18356303

    Open questions at the time
    • Whether FHL2 directly dephosphorylates or sequesters FAK, or recruits a phosphatase, not determined
  13. 2008 High

    FHL2 was found to stabilize myocardin family proteins by preventing their proteasomal degradation while differentially modulating their transcriptional effects on SRF, refining the FHL2–SRF regulatory circuit.

    Evidence Y2H, GST pulldown, Co-IP, proteasome inhibitor, reporter assays comparing mRNA vs. protein levels

    PMID:18586895

    Open questions at the time
    • Which E3 ligase(s) target myocardin and how FHL2 blocks ubiquitination not identified
  14. 2009 High

    FHL2 was revealed as a critical adaptor in Patched dependence-receptor signaling: in the absence of Shh, Patched recruits FHL2, which assembles a caspase-9-activating complex with TUCAN/NALP1, triggering apoptosis during neural tube development.

    Evidence Co-IP, siRNA, caspase activity assay, in vivo chick neural tube electroporation

    PMID:19465923

    Open questions at the time
    • Whether FHL2 directly activates caspase-9 or serves only as a scaffold not resolved
    • Regulation of FHL2–Patched interaction by Shh binding not mechanistically detailed
  15. 2012 High

    FHL2 was shown to suppress pathological cardiac hypertrophy by binding calcineurin at the sarcomere in an agonist-dependent manner and attenuating calcineurin-NFAT signaling.

    Evidence Co-IP (agonist-dependent), siRNA, NFAT reporter, cell size measurement, FHL2 KO mice with isoproterenol stimulation

    PMID:22851699

    Open questions at the time
    • Whether FHL2 sequesters calcineurin or inhibits its phosphatase activity not distinguished
  16. 2012 High

    A new mechanism for FHL2 in TGF-β signaling was established: FHL2 stabilizes Arkadia E3 ligase by inhibiting K27-linked polyubiquitination, thereby promoting Smad3/4-dependent transcription.

    Evidence Co-IP, ubiquitination assay, half-life analysis, RING domain mutagenesis, reporter assays

    PMID:23212909

    Open questions at the time
    • Identity of the E3 ligase that ubiquitinates Arkadia (targeted by FHL2 inhibition) unknown
  17. 2013 High

    FHL2 was established as an activator of innate immune NF-κB signaling through binding and stabilizing TRAF6, with FHL2-null macrophages showing impaired LPS responses and mice showing impaired liver regeneration.

    Evidence Co-IP, siRNA, reporter, FHL2 KO macrophages, partial hepatectomy mouse model

    PMID:23775124

    Open questions at the time
    • Whether TRAF6 stabilization involves blocking a specific E3 ligase or deubiquitinase not defined
  18. 2016 High

    The mechanotransduction function of FHL2 was molecularly resolved: matrix stiffness controls FHL2 shuttling between focal adhesions and the nucleus via FAK-dependent tyrosine phosphorylation, with nuclear FHL2 upregulating p21 to promote cell cycle arrest on soft substrates.

    Evidence Live-cell imaging, FRAP, FAK inhibitor, FHL2 tyrosine mutant, ChIP for RNA Pol II, p21 qPCR

    PMID:27742790

    Open questions at the time
    • Identity of the specific tyrosine residue(s) phosphorylated by FAK and structural consequences not fully elucidated
    • Whether other mechanosensitive cofactors cooperate with FHL2 at p21 promoter unknown
  19. 2016 High

    FHL2 was identified as a scaffold that bridges MDM2 E3 ligase to IER3, forming a ternary complex that drives K60 ubiquitination and proteasomal degradation of IER3, linking FHL2 to cell cycle control.

    Evidence Co-IP, in vivo ubiquitination assay, K60R mutagenesis, siRNA, cell cycle analysis

    PMID:26973248

    Open questions at the time
    • Whether FHL2 targets other MDM2 substrates beyond IER3 not explored
  20. 2017 High

    FHL2 was shown to function as a direct transcriptional repressor at the TGFβ1 promoter: its loss permits RNA Pol II recruitment and elevated TGFβ1 transcription, with Fhl2-null mice developing exacerbated hepatic fibrosis.

    Evidence ChIP on TGFβ1 promoter, RNA Pol II ChIP, FHL2 KO cells and mice, in vivo fibrosis model

    PMID:28223370

    Open questions at the time
    • Mechanism by which FHL2 excludes Pol II (direct steric block vs. co-repressor recruitment) not determined
  21. 2018 High

    FHL2 was found to stabilize EGFR and EGFRvIII protein, promoting their phosphorylation and downstream AKT signaling in glioblastoma, implicating FHL2 in receptor tyrosine kinase regulation.

    Evidence Co-IP, siRNA, FHL2 KO astrocytes with rescue, Western blot distinguishing mRNA vs. protein, xenograft

    PMID:29321665

    Open questions at the time
    • Whether FHL2 blocks a specific E3 ligase (e.g., c-Cbl) or inhibits receptor endocytosis not dissected
  22. 2021 High

    A glucose-sensing cytoplasmic function was uncovered: FHL2 anchors mitochondria to F-actin by binding O-GlcNAcylated TRAK, arresting mitochondrial motility in high-glucose conditions, establishing FHL2 as a metabolic sensor linking nutrient status to organelle dynamics.

    Evidence Co-IP, live-cell mitochondrial tracking, cytochalasin D rescue, forced mitochondrial FHL2 targeting, siRNA, O-GlcNAcylation assay

    PMID:34342639

    Open questions at the time
    • Whether FHL2 reads O-GlcNAc marks directly or via an intermediary reader not determined
    • Consequences for mitochondrial function (respiration, fission/fusion) not assessed

Open questions

Synthesis pass · forward-looking unresolved questions
  • Despite extensive characterization of individual FHL2 interactions, how the cell coordinates the mutually exclusive nuclear and cytoplasmic pools of FHL2 across simultaneous signals, and whether post-translational modifications beyond FAK phosphorylation encode interaction specificity, remain open questions.
  • No systematic proteomics of FHL2 post-translational modifications across conditions
  • No structural model of any FHL2–partner complex at atomic resolution
  • Genome-wide transcriptional targets defined by ChIP-seq are lacking

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 11 GO:0060090 molecular adaptor activity 5 GO:0098772 molecular function regulator activity 5
Localization
GO:0005634 nucleus 6 GO:0005829 cytosol 5 GO:0005856 cytoskeleton 3
Pathway
R-HSA-74160 Gene expression (Transcription) 10 R-HSA-162582 Signal Transduction 6 R-HSA-1500931 Cell-Cell communication 3 R-HSA-392499 Metabolism of proteins 2 R-HSA-5357801 Programmed Cell Death 2 R-HSA-168256 Immune System 1
Partners
ARCBPCTNNB1PTCH1SPHK1SRFTRAF6TRAK1

Evidence

Reading pass · 45 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 FHL2 acts as a tissue-specific transcriptional coactivator of the androgen receptor (AR) in an agonist- and AF-2-dependent manner, binding directly to AR in vitro and in vivo, and selectively increasing AR transcriptional activity but not that of other nuclear receptors. In vitro binding assay, Co-IP, transient transfection reporter assays, immunofluorescence co-localization The EMBO journal High 10654935
2000 FHL2/DRAL binds to cytoplasmic domains of multiple alpha (α3A, α3B, α7A) and beta integrin subunits, with specific LIM domain combinations mediating different interactions, and localizes to cell adhesion complexes, suggesting a role as an adaptor/docking protein in integrin signaling. Yeast two-hybrid, overexpression in human cells, deletion analysis The Journal of biological chemistry Medium 10906324
2002 FHL2/DRAL mediates targeting of metabolic enzymes (creatine kinase, adenylate kinase, phosphofructokinase) to the sarcomere by binding two distinct sites on titin (N2B region in the I-band and is2 region in the M-band) in cardiomyocytes. Yeast two-hybrid, co-localization, co-immunoprecipitation, protein pull-down assays Journal of cell science High 12432079
2002 Stimulation of the Rho signaling pathway (via sphingosine-1-phosphate or Rho GTPase overexpression) induces translocation of FHL2 from the cytoplasm to the nucleus in a Rho-kinase-dependent manner, leading to activation of FHL2- and AR-dependent gene expression. Subcellular fractionation, immunofluorescence, reporter assays, dominant-negative GTPase constructs The EMBO journal High 11847121
2002 FHL2 interacts with beta-catenin (requiring the NH2-terminal part including the first armadillo repeat) and represses beta-catenin/TCF/LEF-dependent transcription in a muscle cell-specific manner, promoting myogenic differentiation. Yeast two-hybrid, direct in vitro binding, co-immunoprecipitation, reporter assays, Xenopus axis duplication assay The Journal of cell biology High 12370240
2002 FHL2 interacts with beta-catenin via armadillo repeats 1-9 and acts as a transcriptional coactivator, cooperating with beta-catenin to activate TCF/LEF-dependent transcription from cyclin D1 and interleukin-8 promoters. Yeast two-hybrid, co-immunoprecipitation, reporter assays The Journal of biological chemistry High 12466281
2002 FHL2 interacts specifically with PLZF in vitro and in vivo and augments PLZF-mediated transcriptional repression, functioning as a corepressor. Yeast two-hybrid, in vitro binding, co-immunoprecipitation, reporter assays The Journal of biological chemistry Medium 12145280
2002 FHL2 interacts with hCDC47 via its second and third LIM domains in conjunction with the first half-LIM domain, as demonstrated by yeast two-hybrid and in vitro interaction studies. Yeast two-hybrid, in vitro binding, domain deletion analysis Journal of cellular biochemistry Low 10649446
2002 FHL2 colocalizes with and interacts with ADAM-17 via ADAM-17 residues 721-739, anchoring ADAM-17 to the actin-based cytoskeleton and regulating ADAM-17 surface localization and substrate-shedding activity. Yeast two-hybrid, co-localization, immunoprecipitation, functional shedding assay in macrophages Journal of cellular physiology Medium 16619241
2002 FHL2 interacts with TUCAN/CARDINAL, and while TUCAN/CARDINAL suppresses NF-κB activity, DRAL/FHL2 expression enhances NF-κB activation, placing them in a common pathway modulating NF-κB signaling. Co-immunoprecipitation, reporter assays FEBS letters Low 12067710
2002 The second LIM domain (LIM2) of FHL2 is the principal determinant of focal adhesion localization, and FHL2 translocates from focal adhesions to Z-discs during myofibrillogenesis. Site-directed mutagenesis, live-cell imaging (GFP/CFP constructs), co-localization with vinculin Cell motility and the cytoskeleton Medium 11124707
2002 FHL2/DRAL coactivates WT1-dependent transcription of MIS and DAX1 promoters by physically interacting with WT1 in vitro and in vivo. Co-immunoprecipitation, reporter assays, in vitro binding Biochimica et biophysica acta Medium 12151099
2003 FHL2 is a serum-inducible coactivator of AP-1: it associates with both Jun and Fos in vitro and in vivo, requires the Ser-63/Ser-73 JNK phosphoacceptor sites (but not their phosphorylation) in c-Jun for binding, and potently stimulates Fos- and Jun-dependent transcription. Nuclear export of FHL2 is CRM1-dependent. Co-immunoprecipitation, in vitro binding, reporter assays, CRM1 inhibitor (leptomycin B) treatment Proceedings of the National Academy of Sciences of the United States of America High 12644711
2004 FHL2 is a direct SRF target gene; its protein competes with the coactivator MAL/MRTF-A for SRF binding at smooth muscle gene promoters, selectively antagonizing RhoA/MAL-dependent activation of smooth muscle (SM) genes but not immediate-early genes. ChIP, reporter assays, Co-IP, expression profiling, genetic epistasis (dominant-negative MAL) Molecular cell High 15610731
2004 FHL2 and CBP/p300 synergistically activate beta-catenin/TCF-mediated transcription; FHL2 directly binds CBP/p300 predominantly through the CH3 domain, forming a ternary complex with beta-catenin, and increases acetylation of beta-catenin by p300 in vivo. Co-immunoprecipitation, reporter assays, FHL2 knockout fibroblasts, acetyltransferase assay Molecular and cellular biology High 15572674
2004 FHL2 interacts with Hand1 via the bHLH domain and differentially regulates Hand1 activity: it represses Hand1/E12 heterodimer-induced transcription but has no effect on Hand1/Hand1 homodimer activity, without altering dimerization or DNA binding of Hand1/E12. Co-immunoprecipitation, reporter assays, EMSA, yeast two-hybrid Molecular and cellular biology Medium 15509787
2004 FHL2 interacts with FAK (pp125FAK), forming a protein complex in human ovarian carcinoma cells. Co-immunoprecipitation Anticancer research Low 15161045
2005 FHL2 suppresses FOXO1 transcriptional activity and FOXO1-induced apoptosis by promoting SIRT1-mediated deacetylation of FOXO1: FHL2 binds FOXO1 in the nucleus, enhances FOXO1-SIRT1 interaction, and increases deacetylation of FOXO1 by SIRT1. Co-immunoprecipitation, reporter assays, deacetylation assay, apoptosis assay The EMBO journal High 15692560
2006 FHL2 interacts with sphingosine kinase-1 (SK1) via at least 4 LIM domains of FHL2 and the C-terminal portion of SK1; FHL2 overexpression attenuates SK1 enzymatic activity and its anti-apoptotic effects in cardiomyocytes, and endothelin-1 inhibits FHL2-SK1 association to increase SK1 activity. Yeast two-hybrid, co-immunoprecipitation, co-localization, kinase activity assay, apoptosis assay Circulation research High 16888242
2006 FHL2 interacts with the full-length E4F1 (p120 form) but not the truncated p50 form in vitro and in vivo; this nuclear interaction inhibits E4F1's capacity to block cell proliferation and its repressive effect on transcription, and reduces nuclear E4F1-p53 complexes. Co-immunoprecipitation, in vitro binding, reporter assays, UV-induced nuclear localization experiment Oncogene Medium 16652157
2007 Fhl2 deficiency impairs cutaneous wound healing; Fhl2-null fibroblasts show severely impaired collagen contraction and cell migration, reduced alpha-smooth muscle actin expression, and reduced p130Cas expression. S1P/RhoA-induced nuclear translocation of Fhl2 regulates these processes. Fhl2 knockout mice, transgenic rescue, collagen contraction assay, cell migration assay, immunofluorescence The Journal of cell biology High 17420295
2008 FHL2 mediates dexamethasone-induced osteoblast differentiation by interacting with beta-catenin and potentiating its nuclear translocation and TCF/LEF transcription, resulting in increased Runx2 and alkaline phosphatase expression. DKK1 inhibits this pathway. shRNA knockdown, overexpression, co-immunoprecipitation, reporter assays, in vitro mineralization FASEB journal High 18653765
2008 FHL2 interacts with SRF and all three myocardin family members; it enhances myocardin and MRTF-A protein stability by preventing proteasome-mediated degradation, while attenuating the effects of RhoA and MRTF-B on promoter activity. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, reporter assays, proteasome inhibitor treatment, mRNA vs protein level analysis American journal of physiology. Heart and circulatory physiology High 18586895
2008 FHL2 deficiency leads to impaired ECM assembly on the cell surface and impaired focal adhesion bundling; molecularly, FHL2-null cells display higher FAK phosphorylation at Y925 and more pronounced ERK activation upon adhesion, and inhibiting MAPK restores ECM organization. FHL2 knockout cells, recombinant FHL2 rescue, Western blot (pFAK, pERK), MAPK inhibitor, ECM assembly assay FASEB journal High 18356303
2009 In the absence of Shh, Patched (Ptc) interacts with DRAL/FHL2 as an adaptor to recruit a caspase-activating complex including TUCAN or NALP1 and caspase-9, triggering caspase-9 activation and apoptosis; DRAL is required for this pro-apoptotic activity in vitro and during neural tube development in vivo. Co-immunoprecipitation, siRNA knockdown, caspase activity assay, chick neural tube in vivo experiments Nature cell biology High 19465923
2009 FHL2 directly interacts with and suppresses sphingosine kinase-1 (SK1) activity in endothelial cells, inhibiting VEGF-induced SK1 activity, PI3K activity, and phosphorylation of Akt and eNOS; VEGF stimulation decreases the FHL2-SK1 interaction. FHL2 mRNA injection into Xenopus embryos inhibits vascular network development. Co-immunoprecipitation, kinase activity assay, siRNA knockdown, Western blot (pAkt, peNOS), Xenopus in vivo assay Arteriosclerosis, thrombosis, and vascular biology High 19325137
2010 Fhl2 interacts with Foxk1 and promotes Foxk1-mediated transcriptional repression of Foxo4 in a dose-dependent manner; Fhl2 knockdown causes cell cycle arrest and Fhl2-null mice have perturbed skeletal muscle regeneration. Yeast two-hybrid, transcriptional reporter assays, shRNA knockdown, mouse KO model with histological analysis Stem cells (Dayton, Ohio) Medium 20013826
2011 FHL2 physically interacts with Snail1 (requiring intact FHL2 structure) and promotes nuclear accumulation of Snail1, thereby decreasing transcription from E-cadherin promoters containing E-box sites in colon cancer cells. Co-immunoprecipitation, immunofluorescence, reporter assays (dual luciferase with E-box mutation controls) European journal of cancer Medium 20801642
2011 FHL2 is a novel co-repressor of Nur77 (NR4A1): each of its four LIM domains can bind Nur77; FHL2 represses Nur77 transcriptional activity in a dose-dependent manner and inhibits Nur77 association with the enolase3 promoter as shown by ChIP. Yeast two-hybrid, co-immunoprecipitation, reporter assays, shRNA knockdown, ChIP The Journal of biological chemistry High 22049082
2012 FHL2 binds calcineurin in an agonist-dependent manner at the sarcomere in cardiomyocytes; FHL2 suppresses calcineurin-NFAT signaling—FHL2 KO amplifies NFAT target gene (RCAN1.4, BNP) induction by isoproterenol and constitutively active calcineurin, while FHL2 overexpression reduces hypertrophic growth induced by active calcineurin. Co-immunoprecipitation (agonist-dependent), siRNA knockdown, NFAT reporter assays, cell cross-sectional area measurement, fetal gene expression, FHL2 KO mice Molecular and cellular biology High 22851699
2012 FHL2 binds and cooperates with Arkadia E3 ubiquitin ligase to activate TGF-β/Smad3/Smad4 signaling; FHL2 increases Arkadia protein half-life by inhibiting ubiquitin chain assembly on Arkadia (specifically K27-linked polyubiquitination), while Arkadia undergoes autocatalytic ubiquitination. Co-immunoprecipitation, siRNA knockdown, reporter assays, ubiquitination assay, half-life analysis, RING domain mutagenesis The Journal of biological chemistry High 23212909
2013 FHL2 activates NF-κB signaling by binding and stabilizing TRAF6 protein; FHL2 knockdown impairs LPS-induced NF-κB activity and cytokine (TNF, IL-6) production in macrophages, and FHL2-null mice show impaired liver regeneration after hepatectomy. Co-immunoprecipitation, siRNA knockdown, reporter assays, FHL2 KO macrophages, partial hepatectomy mouse model Molecular and cellular biology High 23775124
2013 Nuclear localization of FHL2 and AR coactivation is driven by calpain cleavage of filamin; calpain-cleaved filamin fragment and FHL2 form a transcription complex with AR in the nucleus specifically in castrate-resistant prostate cancer (CRPC). This mechanism enables coactivation of ligand-independent AR splice variants (including AR-V7). Co-immunoprecipitation, nuclear fractionation, calpain inhibitor treatment, patient tissue analysis Cancer research Medium 23801747
2016 FHL2 shuttles between focal adhesions and the nucleus depending on matrix mechanics: on soft surfaces or after force loss, FHL2 moves into the nucleus to RNA Pol II sites and increases p21 expression. This shuttling requires a specific tyrosine in FHL2 and phosphorylation by FAK. Live-cell imaging, FRAP, FAK inhibitor, tyrosine mutant FHL2, ChIP (RNA Pol II), p21 qPCR Proceedings of the National Academy of Sciences of the United States of America High 27742790
2016 FHL2 serves as a scaffold facilitating MDM2-mediated ubiquitination and proteasomal degradation of IER3 by simultaneously binding both MDM2 and IER3, forming a ternary complex; polyubiquitination at lysine 60 of IER3 is essential for degradation. Co-immunoprecipitation, ubiquitination assay, site-directed mutagenesis (K60R IER3), siRNA knockdown, cell cycle assay Oncogene High 26973248
2017 FHL2 is a transcriptional corepressor of TGF-β1 gene expression: FHL2 associates with the TGF-β1 promoter, and its loss facilitates RNA polymerase II recruitment and increased TGF-β1 transcription; Fhl2-null mice develop more severe hepatic fibrosis with elevated TGF-β1. ChIP, reporter assays, FHL2 KO cells and mice, RNA Pol II ChIP, in vivo fibrosis model Molecular and cellular biology High 28223370
2021 FHL2 anchors mitochondria to F-actin by associating with O-GlcNAcylated TRAK (Milton), a mitochondrial motor-adaptor component, in response to increased glucose. FHL2 is both necessary and sufficient for F-actin accumulation around mitochondria and for arresting mitochondrial movement; disruption of F-actin restores movement. Co-immunoprecipitation, live-cell imaging of mitochondrial movement, F-actin disruption (cytochalasin D), forced mitochondrial targeting of FHL2, siRNA knockdown, O-GlcNAcylation assay The Journal of cell biology High 34342639
2002 FHL2 interacts with BRCA1 through BRCA1's second BRCT domain and FHL2's last three LIM domains, and BRCA1 enhances FHL2-mediated transcriptional activity; tumor-derived transactivation-deficient BRCA1 mutants show reduced ability to enhance FHL2 transactivation. Yeast two-hybrid, in vitro binding, co-immunoprecipitation, reporter assays, mutagenesis FEBS letters Medium 14550570
2000 DRAL/FHL2 interacts with presenilin 2 (PS2) specifically at a hydrophilic loop region (aa 269-298) in the PS2 N-terminal fragment; this interaction is abolished by multiple point mutations; PS2 overexpression increases FHL2 membrane fraction abundance and PS2-FHL2 co-immunoprecipitation. Yeast two-hybrid, affinity column assay, co-immunoprecipitation, point mutagenesis Human molecular genetics Medium 11001931
2002 FHL2 is required for generating IKs current in HEK cells (which lack endogenous FHL2): co-expression of KvLQT1 and minK with FHL2 generates IKs, while in CHO-K1 cells (which express endogenous FHL2), anti-FHL2 antisense suppresses IKs. FHL2 interacts with minK cytoplasmic C-terminus. Yeast two-hybrid, GST pulldown, electrophysiology, antisense knockdown, immunocytochemistry Cardiovascular research High 12237170
2009 FHL2 interacts with all members of the Id protein family (Id1-4) via the N-terminal loop-helix structure of Id proteins; FHL2 antagonizes Id protein inhibitory effects on E47-mediated transcription by competitively preventing Id2-E47 heterodimer formation and releasing E47 to bind DNA. Co-immunoprecipitation, reporter assays, deletion mutagenesis, competitive binding assay Nucleic acids research High 19417068
2018 FHL2 physically interacts with EGFR and EGFRvIII, increasing their protein stability (not mRNA) and promoting their phosphorylation; FHL2 knockdown reduces EGFR/EGFRvIII levels and AKT phosphorylation, and FHL2-null astrocytes show reduced EGFR levels restored by FHL2 re-expression. Co-immunoprecipitation, siRNA knockdown, FHL2 KO astrocytes, rescue experiment, Western blot, in vivo xenograft Oncogene High 29321665
2018 PARP12 interacts with FHL2 and prevents its ubiquitination-mediated proteasomal degradation, thereby maintaining FHL2 protein levels; PARP12 deficiency decreases FHL2 protein by promoting its ubiquitination, independently of PARP12's enzymatic ADP-ribosyltransferase activity. Protein affinity purification, co-immunoprecipitation, ubiquitination assay, PARP12 enzymatic mutant Cell death & disease Medium 30154409
2020 FHL2 inhibits ovulation-related gene expression (phospho-ERK1/2, C/EBPβ, COX2, HAS2) in granulosa cells partly by interacting with AR to act as its co-regulator inhibiting C/EBPβ expression, and by binding ERK1/2 to inhibit its phosphorylation. In vivo FHL2 overexpression in rat ovaries impairs superovulatory response. Co-immunoprecipitation, siRNA, lentiviral overexpression in rat ovaries, hormone stimulation assay EBioMedicine Medium 32028069
2014 FHL2 interacts with LXRα and LXRβ and acts as their transcriptional coactivator in smooth muscle cells: FHL2 enhances LXR transcriptional activity, promotes LXRβ association with the ABCG1 promoter (by ChIP), and FHL2 KO SMCs show reduced LXR target gene expression and attenuated cholesterol efflux. Co-immunoprecipitation, reporter assays, ChIP, FHL2 KO SMCs, cholesterol efflux assay Molecular and cellular biology High 25332231

Source papers

Stage 0 corpus · 100 papers · ranked by NIH iCite citations
Year Title Journal Citations PMID
2005 Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation. The EMBO journal 299 15692560
2000 FHL2, a novel tissue-specific coactivator of the androgen receptor. The EMBO journal 287 10654935
2002 Subcellular targeting of metabolic enzymes to titin in heart muscle may be mediated by DRAL/FHL-2. Journal of cell science 216 12432079
2006 The multifunctional roles of the four-and-a-half-LIM only protein FHL2. Cellular and molecular life sciences : CMLS 209 16389449
2002 The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus. The EMBO journal 163 11847121
2008 FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/beta-catenin signaling-dependent Runx2 expression. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 149 18653765
2004 The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF. Molecular cell 136 15610731
2001 Cardiac-specific LIM protein FHL2 modifies the hypertrophic response to beta-adrenergic stimulation. Circulation 135 11390345
2002 The LIM-only protein FHL2 interacts with beta-catenin and promotes differentiation of mouse myoblasts. The Journal of cell biology 129 12370240
1998 Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart. Gene 125 9573400
2002 Identification of the LIM protein FHL2 as a coactivator of beta-catenin. The Journal of biological chemistry 122 12466281
2003 The LIM-only protein FHL2 is a serum-inducible transcriptional coactivator of AP-1. Proceedings of the National Academy of Sciences of the United States of America 120 12644711
2000 The LIM-only protein DRAL/FHL2 binds to the cytoplasmic domain of several alpha and beta integrin chains and is recruited to adhesion complexes. The Journal of biological chemistry 120 10906324
1997 Subtractive cloning and characterization of DRAL, a novel LIM-domain protein down-regulated in rhabdomyosarcoma. DNA and cell biology 112 9150430
2009 The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nature cell biology 111 19465923
2004 Interaction and functional cooperation between the LIM protein FHL2, CBP/p300, and beta-catenin. Molecular and cellular biology 102 15572674
2000 DRAL is a p53-responsive gene whose four and a half LIM domain protein product induces apoptosis. The Journal of cell biology 96 11062252
2000 FHL2 (SLIM3) is not essential for cardiac development and function. Molecular and cellular biology 89 11003643
2004 Focal adhesion kinase interacts with the transcriptional coactivator FHL2 and both are overexpressed in epithelial ovarian cancer. Anticancer research 83 15161045
2006 Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis. Gastroenterology 77 17383428
2007 Deficiency in the LIM-only protein Fhl2 impairs skin wound healing. The Journal of cell biology 73 17420295
2002 The LIM-only protein DRAL/FHL2 interacts with and is a corepressor for the promyelocytic leukemia zinc finger protein. The Journal of biological chemistry 70 12145280
2015 Protein-protein interactions of the LIM-only protein FHL2 and functional implication of the interactions relevant in cardiovascular disease. Biochimica et biophysica acta 60 26548523
2014 FHL2 expression and variants in hypertrophic cardiomyopathy. Basic research in cardiology 60 25358972
2007 The biological relevance of FHL2 in tumour cells and its role as a putative cancer target. Anticancer research 60 17352216
2012 FHL2 binds calcineurin and represses pathological cardiac growth. Molecular and cellular biology 59 22851699
2016 Matrix mechanics controls FHL2 movement to the nucleus to activate p21 expression. Proceedings of the National Academy of Sciences of the United States of America 58 27742790
2016 FOXK1 interaction with FHL2 promotes proliferation, invasion and metastasis in colorectal cancer. Oncogenesis 57 27892920
2002 TUCAN/CARDINAL and DRAL participate in a common pathway for modulation of NF-kappaB activation. FEBS letters 57 12067710
2002 The LIM-only coactivator FHL2 modulates WT1 transcriptional activity during gonadal differentiation. Biochimica et biophysica acta 56 12151099
2007 FHL2 regulates cell cycle-dependent and doxorubicin-induced p21Cip1/Waf1 expression in breast cancer cells. Cell cycle (Georgetown, Tex.) 55 17682292
2021 FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply. The Journal of cell biology 51 34342639
2020 Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary. Nature communications 51 31896750
2013 Regulation of the transcriptional coactivator FHL2 licenses activation of the androgen receptor in castrate-resistant prostate cancer. Cancer research 51 23801747
2000 Alzheimer's disease-associated presenilin 2 interacts with DRAL, an LIM-domain protein. Human molecular genetics 49 11001931
2003 BRCA1 interacts with FHL2 and enhances FHL2 transactivation function. FEBS letters 47 14550570
2004 Differential regulation of Hand1 homodimer and Hand1-E12 heterodimer activity by the cofactor FHL2. Molecular and cellular biology 46 15509787
2019 miR-340-FHL2 axis inhibits cell growth and metastasis in ovarian cancer. Cell death & disease 45 31068580
2020 Up-regulated FHL2 inhibits ovulation through interacting with androgen receptor and ERK1/2 in polycystic ovary syndrome. EBioMedicine 43 32028069
2006 FHL2/SLIM3 decreases cardiomyocyte survival by inhibitory interaction with sphingosine kinase-1. Circulation research 43 16888242
2000 Protein-protein interaction of FHL2, a LIM domain protein preferentially expressed in human heart, with hCDC47. Journal of cellular biochemistry 43 10649446
2005 Four and half lim protein 2 (FHL2) stimulates osteoblast differentiation. Journal of bone and mineral research : the official journal of the American Society for Bone and Mineral Research 42 16355270
2015 KLF8 promotes tumorigenesis, invasion and metastasis of colorectal cancer cells by transcriptional activation of FHL2. Oncotarget 41 26320172
2011 Four and a half LIM protein 2 (FHL2) negatively regulates the transcription of E-cadherin through interaction with Snail1. European journal of cancer (Oxford, England : 1990) 41 20801642
2004 FHL2, UBC9, and PIAS1 are novel estrogen receptor alpha-interacting proteins. Endocrine research 41 15666801
2001 Translocation of a human focal adhesion LIM-only protein, FHL2, during myofibrillogenesis and identification of LIM2 as the principal determinants of FHL2 focal adhesion localization. Cell motility and the cytoskeleton 41 11124707
2017 Autophagy Induced FHL2 Upregulation Promotes IL-6 Production by Activating the NF-κB Pathway in Mouse Aortic Endothelial Cells after Exposure to PM2.5. International journal of molecular sciences 40 28714941
2013 LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis. Molecular and cellular biology 40 23775124
2011 FHL2 protein is a novel co-repressor of nuclear receptor Nur77. The Journal of biological chemistry 40 22049082
2008 The LIM-only protein FHL2 regulates cyclin D1 expression and cell proliferation. The Journal of biological chemistry 40 18378678
2018 PARP12 (ARTD12) suppresses hepatocellular carcinoma metastasis through interacting with FHL2 and regulating its stability. Cell death & disease 38 30154409
2016 The four and a half LIM domains 2 (FHL2) regulates ovarian granulosa cell tumor progression via controlling AKT1 transcription. Cell death & disease 37 27415427
2015 LIM-only protein FHL2 critically determines survival and radioresistance of pancreatic cancer cells. Cancer letters 37 25917075
2013 FHL2 silencing reduces Wnt signaling and osteosarcoma tumorigenesis in vitro and in vivo. PloS one 37 23383046
2006 The LIM-only protein FHL2 is a negative regulator of E4F1. Oncogene 37 16652157
2008 IL-1beta regulates FHL2 and other cytoskeleton-related genes in human chondrocytes. Molecular medicine (Cambridge, Mass.) 36 18224250
2006 Expression of the transcriptional coregulator FHL2 in human breast cancer: a clinicopathologic study. Journal of the Society for Gynecologic Investigation 36 16378916
2015 The FHL2 regulation in the transcriptional circuitry of human cancers. Gene 35 26211626
2008 Deficiency in the LIM-only protein FHL2 impairs assembly of extracellular matrix proteins. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 34 18356303
2006 FHL2 interacts with both ADAM-17 and the cytoskeleton and regulates ADAM-17 localization and activity. Journal of cellular physiology 34 16619241
2010 Fhl2 interacts with Foxk1 and corepresses Foxo4 activity in myogenic progenitors. Stem cells (Dayton, Ohio) 33 20013826
2008 Regulation of myocardin factor protein stability by the LIM-only protein FHL2. American journal of physiology. Heart and circulatory physiology 32 18586895
2011 FHL2 exhibits anti-proliferative and anti-apoptotic activities in liver cancer cells. Cancer letters 31 21377781
2009 FHL-2 suppresses VEGF-induced phosphatidylinositol 3-kinase/Akt activation via interaction with sphingosine kinase-1. Arteriosclerosis, thrombosis, and vascular biology 31 19325137
2016 Scaffold protein FHL2 facilitates MDM2-mediated degradation of IER3 to regulate proliferation of cervical cancer cells. Oncogene 30 26973248
2002 Cardiac-enriched LIM domain protein fhl2 is required to generate I(Ks) in a heterologous system. Cardiovascular research 30 12237170
2018 FHL2 interacts with EGFR to promote glioblastoma growth. Oncogene 29 29321665
2017 FHL2 promotes tubular epithelial-to-mesenchymal transition through modulating β-catenin signalling. Journal of cellular and molecular medicine 28 29193729
2020 LncRNA DLX6-AS1 aggravates the development of ovarian cancer via modulating FHL2 by sponging miR-195-5p. Cancer cell international 27 32774164
2019 The role of FHL2 in wound healing and inflammation. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 27 30939249
2013 Deletion of FHL2 gene impaired ischemia-induced blood flow recovery by modulating circulating proangiogenic cells. Arteriosclerosis, thrombosis, and vascular biology 27 23413425
2012 The four and a half LIM-only protein 2 (FHL2) activates transforming growth factor β (TGF-β) signaling by regulating ubiquitination of the E3 ligase Arkadia. The Journal of biological chemistry 27 23212909
2015 FHL2: a scaffold protein of carcinogenesis, tumour-stroma interactions and treatment response. Histology and histopathology 26 26676939
2013 Structural and functional analysis of perforin mutations in association with clinical data of familial hemophagocytic lymphohistiocytosis type 2 (FHL2) patients. Protein science : a publication of the Protein Society 26 23592409
2009 Enhanced expression of FHL2 leads to abnormal myelopoiesis in vivo. Leukemia 26 19369964
2020 Deletion of FHL2 in fibroblasts attenuates fibroblasts activation and kidney fibrosis via restraining TGF-β1-induced Wnt/β-catenin signaling. Journal of molecular medicine (Berlin, Germany) 25 31927599
2013 The LIM-only protein FHL2 attenuates lung inflammation during bleomycin-induced fibrosis. PloS one 24 24260575
2010 Sp1 upregulates the four and half lim 2 (FHL2) expression in gastrointestinal cancers through transcription regulation. Molecular carcinogenesis 24 20607723
2016 Plumbagin exhibits an anti-proliferative effect in human osteosarcoma cells by downregulating FHL2 and interfering with Wnt/β-catenin signalling. Oncology letters 22 27446400
2014 LIM-only protein FHL2 is a positive regulator of liver X receptors in smooth muscle cells involved in lipid homeostasis. Molecular and cellular biology 22 25332231
2014 The LIM-only protein FHL2 reduces vascular lesion formation involving inhibition of proliferation and migration of smooth muscle cells. PloS one 21 24736599
2014 FHL2 regulates hematopoietic stem cell functions under stress conditions. Leukemia 21 25179730
2023 FHL2 deficiency impairs follicular development and fertility by attenuating EGF/EGFR/YAP signaling in ovarian granulosa cells. Cell death & disease 20 37015904
2008 Deletion of the FHL2 gene attenuating neovascularization after corneal injury. Investigative ophthalmology & visual science 20 18708619
2002 Expression of FHL2 and cytokine messenger RNAs in human myocardium after cardiopulmonary bypass. International journal of cardiology 20 12419565
2009 FHL2 interacts with and acts as a functional repressor of Id2 in human neuroblastoma cells. Nucleic acids research 19 19417068
2024 Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis. Science advances 18 39504377
2012 FHL2 inhibits the Id3-promoted proliferation and invasive growth of human MCF-7 breast cancer cells. Chinese medical journal 18 22882857
2010 FHL2 suppresses growth and differentiation of the colon cancer cell line HT-29. Oncology reports 18 20428824
2010 Synergistic repression of estrogen receptor transcriptional activity by FHL2 and Smad4 in breast cancer cells. IUBMB life 18 20734429
2022 QiShenYiQi Pill Ameliorates Cardiac Fibrosis After Pressure Overload-Induced Cardiac Hypertrophy by Regulating FHL2 and the Macrophage RP S19/TGF-β1 Signaling Pathway. Frontiers in pharmacology 17 35910357
2017 LIM-Only Protein FHL2 Is a Negative Regulator of Transforming Growth Factor β1 Expression. Molecular and cellular biology 17 28223370
2009 The cell migration protein Grb7 associates with transcriptional regulator FHL2 in a Grb7 phosphorylation-dependent manner. Journal of molecular recognition : JMR 17 18853468
2008 Impaired intestinal wound healing in Fhl2-deficient mice is due to disturbed collagen metabolism. Experimental cell research 17 18950620
2024 FHL2 expression by cancer-associated fibroblasts promotes metastasis and angiogenesis in lung adenocarcinoma. International journal of cancer 16 39244734
2022 Glucose-mediated insulin secretion is improved in FHL2-deficient mice and elevated FHL2 expression in humans is associated with type 2 diabetes. Diabetologia 16 35802167
2020 Four and a Half LIM Domains 2 (FHL2) Contribute to the Epithelial Ovarian Cancer Carcinogenesis. International journal of molecular sciences 16 33092075
2019 LIM-only protein FHL2 attenuates inflammation in vascular smooth muscle cells through inhibition of the NFκB pathway. Vascular pharmacology 16 31866461
2013 A novel colon cancer gene therapy using rAAV‑mediated expression of human shRNA-FHL2. International journal of oncology 16 24008552
2010 Deletion of the FHL2 gene attenuates the formation of atherosclerotic lesions after a cholesterol-enriched diet. Life sciences 16 20096293