Affinage

FHL2

Four and a half LIM domains protein 2 · UniProt Q14192

Length
279 aa
Mass
32.2 kDa
Annotated
2026-06-09
100 papers in source corpus 56 papers cited in narrative 56 extracted findings
Cross-family judge vs UniProt: Affinage preferred faithfulness: 7/7 claims corpus-supported (100%)

Mechanistic narrative

Synthesis pass · prose summary of the discoveries below

FHL2 (DRAL) is a four-and-a-half LIM-domain scaffold/adaptor that converts mechanical and signaling inputs into transcriptional and cytoskeletal outputs by shuttling between cell-adhesion structures and the nucleus (PMID:10906324, PMID:27742790). At the cell periphery it binds integrin α and β cytoplasmic tails and localizes to focal adhesions through its second LIM domain, redistributing to cardiac Z-discs during myofibrillogenesis, and it scaffolds metabolic enzymes to titin at the sarcomere (PMID:10906324, PMID:11124707, PMID:12432079). Its nucleocytoplasmic distribution is controlled by CRM1-dependent export and by Rho GTPase/Rho-kinase signaling triggered by sphingosine-1-phosphate, and is mechanosensitive: on soft matrices or after force loss, FAK-mediated tyrosine phosphorylation drives FHL2 to RNA polymerase II sites where it raises p21 to restrain proliferation, defining a stiffness-dependent FHL2–p21 dormancy axis (PMID:12644711, PMID:11847121, PMID:27742790, PMID:39504377). In the nucleus FHL2 acts as a context-dependent transcriptional cofactor, coactivating androgen receptor, β-catenin/TCF (in concert with CBP/p300), AP-1, SRF/myocardin, WT1, NR5A receptors and LXR, while repressing PLZF, Nur77 and E4F1, thereby tuning programs from myogenic and osteoblast differentiation to cholesterol efflux (PMID:10654935, PMID:12466281, PMID:15572674, PMID:12644711, PMID:15610731, PMID:22049082, PMID:25332231, PMID:12370240, PMID:18653765). FHL2 also operates as a protein-stability and signaling hub, stabilizing TRAF6 to promote NF-κB signaling, restraining calcineurin–NFAT and ERK to limit cardiac hypertrophy, inhibiting sphingosine kinase-1, and scaffolding E3-ligase-mediated ubiquitination of substrates such as IER3 and Arkadia (PMID:23775124, PMID:22851699, PMID:14729955, PMID:16888242, PMID:26973248, PMID:23212909). Beyond transcription it anchors mitochondria to F-actin via O-GlcNAcylated TRAK in response to glucose flux (PMID:34342639). FHL2-null mice are viable but show exaggerated β-adrenergic cardiac hypertrophy, impaired wound healing, and altered osteoclast/osteoblast and muscle regeneration, reflecting these convergent roles (PMID:11390345, PMID:17420295, PMID:16184196, PMID:20013826).

Mechanistic history

Synthesis pass · year-by-year structured walk · 14 steps
  1. 2000 High

    Establishing FHL2 as a selective transcriptional coactivator addressed whether this LIM-only protein had nuclear regulatory function, showing it specifically boosts androgen receptor activity in a tissue-restricted manner.

    Evidence In vitro/in vivo binding, reporter assays and colocalization with AR in heart and prostate cells

    PMID:10654935

    Open questions at the time
    • Did not define how AR-specificity is achieved versus other nuclear receptors
    • Nuclear import trigger unresolved
  2. 2000 High

    Identifying integrin cytoplasmic-tail binding placed FHL2 at cell-adhesion complexes, suggesting it links the actin/adhesion machinery to its nuclear roles.

    Evidence Yeast two-hybrid, co-IP and deletion mapping of integrin α/β tail binding plus adhesion-complex localization

    PMID:10906324

    Open questions at the time
    • Functional consequence of integrin binding for signaling not measured
    • Connection between adhesion pool and nuclear pool untested here
  3. 2000 High

    Linking DRAL/FHL2 to p53 induction and apoptosis framed it as a stress-responsive gene rather than only a structural scaffold.

    Evidence p53 transfection and ionizing radiation induction with promoter analysis, ectopic-expression apoptosis assay, immunofluorescence across cytoplasm/nucleus/Z-discs

    PMID:11062252

    Open questions at the time
    • Pro-apoptotic effector mechanism not defined here
    • Whether p53 induction is direct vs indirect unsettled
  4. 2002 High

    Demonstrating S1P/Rho/Rho-kinase-driven nuclear translocation answered how extracellular signals control FHL2 localization and coupled it to AR-dependent transcription.

    Evidence Fractionation, immunofluorescence, dominant-negative GTPases and Rho-kinase inhibition with reporter assays

    PMID:11847121

    Open questions at the time
    • Direct phosphorylation/modification mediating translocation not identified at this stage
    • Cargo specificity of the Rho pathway unclear
  5. 2002 High

    Resolving the β-catenin interaction established FHL2 as a Wnt-pathway cofactor whose coactivator-versus-repressor output is promoter- and cell-context dependent.

    Evidence Y2H, in vitro binding, co-IP, armadillo/LIM domain mapping and TCF/LEF reporters across muscle, kidney and colon cells

    PMID:12370240 PMID:12466281

    Open questions at the time
    • Molecular basis switching coactivation vs repression not defined
    • Endogenous target-gene scope incomplete
  6. 2003 High

    Showing AP-1 coactivation and CRM1-dependent nuclear export connected FHL2 to mitogenic transcription and explained its predominantly cytoplasmic steady-state distribution.

    Evidence Pull-down, co-IP, reporter assays and leptomycin B-sensitive export with immunofluorescence

    PMID:12644711

    Open questions at the time
    • NES sequence not mapped
    • Interplay between export and Rho-driven import unresolved
  7. 2004 High

    Linking FHL2 to ERK2 nuclear exclusion and SRF/MAL competition revealed it as a negative regulator of hypertrophic and smooth-muscle transcriptional programs.

    Evidence Y2H, co-IP, ChIP of SRF on the Fhl2 promoter and FHL2 on SM gene promoters, ERK nuclear-exclusion and reporter assays

    PMID:14729955 PMID:15610731

    Open questions at the time
    • Structural basis of MAL/MRTF competition not defined
    • In vivo contribution to hypertrophy quantified only partially
  8. 2004 High

    Defining the FHL2–CBP/p300–β-catenin ternary complex provided a biochemical mechanism for coactivation, with FHL2 enhancing p300-mediated β-catenin acetylation.

    Evidence Co-IP, deletion mapping, knockout-fibroblast reconstitution and in vivo acetylation assay

    PMID:15572674

    Open questions at the time
    • Whether acetylation is required for all FHL2 coactivation events untested
    • Promoter selectivity mechanism unclear
  9. 2006 High

    Identifying sphingosine kinase-1 inhibition extended FHL2 into lipid-signaling control of apoptosis and angiogenesis.

    Evidence Y2H, co-IP, SK1 activity and apoptosis assays in cardiomyocytes, plus VEGF-responsive SK1/Akt/eNOS regulation and Xenopus vascular assay

    PMID:16888242 PMID:19325137

    Open questions at the time
    • Structural basis of SK1 inhibition not solved
    • Quantitative contribution to in vivo angiogenesis incomplete
  10. 2011 High

    Reconciling opposing TRAF6/NF-κB reports clarified that FHL2 binds TRAF6 and can both attenuate RANK-driven osteoclast signaling and stabilize TRAF6 to promote NF-κB output, depending on cellular context.

    Evidence Co-IP, NF-κB reporters, FHL2-null osteoclasts/macrophages, in vivo RANKL and hepatectomy models

    PMID:16184196 PMID:23775124

    Open questions at the time
    • Determinants of inhibitory vs stabilizing outcome not defined
    • Direct effect on TRAF6 ubiquitination/half-life mechanism partial
  11. 2012 High

    Demonstrating direct calcineurin binding and NFAT suppression, plus genetic epistasis downstream of ROCK2, anchored FHL2 as an endogenous brake on pathological cardiac hypertrophy.

    Evidence Co-IP at the sarcomere, FHL2-/- mice, NFAT reporters with cyclosporine, and ROCK2/FHL2 double-haploinsufficiency epistasis

    PMID:22851699 PMID:23271052

    Open questions at the time
    • Mechanism of agonist-dependent calcineurin inhibition not structurally defined
    • Relative weighting of ERK/SRF/NFAT arms unresolved
  12. 2012 High

    Defining FHL2 as a scaffold for E3-ligase reactions (Arkadia stabilization, later MDM2-mediated IER3 ubiquitination) established a non-transcriptional mode controlling partner protein stability.

    Evidence Co-IP, in vitro ubiquitination with linkage-specific and lysine mutants, half-life measurements and TGF-β reporters

    PMID:23212909 PMID:26973248

    Open questions at the time
    • Generality of FHL2 as a ubiquitination scaffold across substrates untested
    • How FHL2 selects substrate-ligase pairs unknown
  13. 2016 High

    Showing matrix-stiffness- and FAK-phosphorylation-dependent shuttling that drives p21 expression unified FHL2's adhesion and nuclear roles into a mechanotransduction circuit controlling growth.

    Evidence Live-cell imaging on variable-stiffness substrates, FAK inhibition and FHL2 tyrosine mutagenesis, RNA Pol II colocalization and p21 readouts, later extended to 3D dormancy/chemoresistance

    PMID:27742790 PMID:39504377

    Open questions at the time
    • Identity of the FAK-phosphorylated tyrosine residue and import receptor not fully defined
    • p53-independent route to p21 mechanistically incomplete
  14. 2021 High

    Identifying FHL2 anchoring of mitochondria to F-actin via O-GlcNAcylated TRAK revealed a metabolic-sensing cytoskeletal function distinct from transcription.

    Evidence Co-IP with O-GlcNAc-TRAK, live mitochondrial-motility imaging, F-actin disruption and forced mitochondrial targeting under glucose manipulation in neurons and other cells

    PMID:34342639

    Open questions at the time
    • How FHL2 reads O-GlcNAc status mechanistically unknown
    • Physiological consequence of arrested mitochondrial transport in vivo untested

Open questions

Synthesis pass · forward-looking unresolved questions
  • How a single LIM-only adaptor integrates competing inputs to choose among its many partners and switch between coactivation, corepression, ubiquitination-scaffolding and cytoskeletal anchoring remains the central unresolved question.
  • No structural model explaining context-dependent partner selection
  • Quantitative rules governing localization (adhesion vs nucleus vs mitochondria) not established
  • Many partner interactions rest on single-lab Co-IP/Y2H without reciprocal in vivo validation

Mechanism profile

Synthesis pass · controlled-vocabulary classification · explore literature graph →
Molecular activity
GO:0140110 transcription regulator activity 8 GO:0060090 molecular adaptor activity 4 GO:0098772 molecular function regulator activity 4 GO:0008092 cytoskeletal protein binding 3
Localization
GO:0005634 nucleus 6 GO:0005856 cytoskeleton 4 GO:0005829 cytosol 3 GO:0005739 mitochondrion 2
Pathway
R-HSA-74160 Gene expression (Transcription) 6 R-HSA-162582 Signal Transduction 5 R-HSA-392499 Metabolism of proteins 5 R-HSA-1266738 Developmental Biology 4 R-HSA-1640170 Cell Cycle 3
Partners
ARCTNNB1EGFRERK2SPHK1SRFTRAF6TRAK
Complex memberships
Patched-DRAL-TUCAN/NALP1-caspase-9 complexcardiac sarcomere (Z-disc/titin)focal adhesionβ-catenin/CBP-p300 coactivator complex

Evidence

Reading pass · 56 per-paper findings extracted from the source corpus
Year Finding Method Journal Conf PMIDs
2000 FHL2 (identical to DRAL) is a tissue-specific coactivator of the androgen receptor (AR): it binds specifically to AR in vitro and in vivo, and in an agonist- and AF-2-dependent manner selectively increases AR transcriptional activity but not that of other nuclear receptors. FHL2 colocalizes with AR in the nucleus of heart myocardium and prostate epithelial cells and coactivates the AR target gene probasin. In vitro binding assays, co-immunoprecipitation, transient transfection reporter assays, immunofluorescence/colocalization The EMBO journal High 10654935
2002 FHL2/DRAL acts as a scaffold anchoring metabolic enzymes (creatine kinase, adenylate kinase, phosphofructokinase) to the cardiac sarcomere by binding to two distinct sites on titin: the N2B region (I-band) and the is2 region (M-band titin), thereby targeting high-energy-consuming sites in cardiomyocytes. Yeast two-hybrid, co-immunoprecipitation, GST pull-down, immunofluorescence colocalization Journal of cell science High 12432079
2002 Sphingosine-1-phosphate (SPP) stimulation of the Rho signaling pathway induces translocation of FHL2 from the cytoplasm to the nucleus in a Rho GTPase- and Rho-kinase-dependent manner (but not via Cdc42, Rac1, or Ras), leading to activation of FHL2- and androgen receptor-dependent target genes. Subcellular fractionation, immunofluorescence localization, dominant-negative GTPase overexpression, Rho-kinase inhibitor treatment, reporter assays The EMBO journal High 11847121
2000 FHL2/DRAL binds to the cytoplasmic domains of several integrin alpha (α3A, α3B, α7A) and beta subunits; specific binding requires the membrane-proximal region of alpha subunits or the C-terminal NXXY motif of beta subunits. FHL2 is recruited to cell adhesion complexes and different LIM domain combinations mediate distinct protein interactions. Yeast two-hybrid, overexpression co-immunoprecipitation, deletion mutagenesis, immunofluorescence in adhesion complexes The Journal of biological chemistry High 10906324
2002 FHL2 interacts with β-catenin (requiring armadillo repeats 1+ in mammalian cells and all four LIM domains of FHL2), acts as a muscle cell-specific repressor of LEF/TCF target genes, and promotes myogenic differentiation by accelerating myotube formation and muscle-specific protein expression in C2C12 myoblasts. Yeast two-hybrid, in vitro binding, co-immunoprecipitation, TCF/LEF reporter assay, Xenopus axis duplication assay, stable C2C12 cell lines The Journal of cell biology High 12370240
2002 FHL2 acts as a coactivator of β-catenin, interacting with armadillo repeats 1–9 of β-catenin and cooperating to activate TCF/LEF-dependent transcription from cyclin D1 and IL-8 promoters. This coactivator function is promoter-context dependent. Yeast two-hybrid, co-immunoprecipitation, deletion mutagenesis, TCF/LEF reporter assays in kidney and colon cell lines The Journal of biological chemistry High 12466281
2003 FHL2 is a serum-inducible transcriptional coactivator of AP-1: it associates with both Jun and Fos in vitro and in vivo, powerfully stimulates Fos/Jun-dependent transcription, and its nuclear localization is controlled by a CRM1-dependent active nuclear export mechanism. In vitro pull-down, co-immunoprecipitation, reporter assays, leptomycin B treatment (CRM1 inhibition), immunofluorescence Proceedings of the National Academy of Sciences of the United States of America High 12644711
2004 FHL2 interacts with activated ERK2 (preferentially the phosphorylated form) in cardiomyocytes at the Z-line, requiring at least two LIM domains. FHL2 inhibits ERK2 nuclear residence, thereby blocking ERK-dependent transcriptional activation of ELK-1, GATA4, and the ANF promoter, and partially antagonizes cardiac hypertrophic responses. Yeast two-hybrid with cardiac cDNA library, co-immunoprecipitation, immunofluorescence colocalization, reporter assays, dominant-active MEK-1/GATA4 overexpression, LIM domain deletion mutagenesis Molecular and cellular biology High 14729955
2004 FHL2 is a direct SRF target gene regulated by RhoA activation, and FHL2 protein physically interacts with SRF. FHL2 selectively antagonizes RhoA/MAL-dependent induction of smooth muscle genes (but not immediate-early or cardiac genes) by competing with the coactivator MAL/MRTF-A for SRF binding, constituting an autoregulatory feedback loop. Expression profiling, ChIP (SRF binding to Fhl2 promoter), co-immunoprecipitation (FHL2-SRF), ChIP (FHL2 at SM gene promoters), competitive binding assays Molecular cell High 15610731
2004 FHL2 physically interacts with CBP/p300 (predominantly through the CH3 domain of CBP/p300) and forms a ternary complex with β-catenin and CBP/p300 in the nucleus. FHL2 and CBP/p300 synergistically enhance β-catenin/TCF-mediated transcription, and FHL2 significantly increases p300-mediated acetylation of β-catenin in vivo. Co-immunoprecipitation, deletion mutagenesis, TCF/LEF reporter assays, FHL2-/- fibroblasts reconstitution, in vivo acetylation assay Molecular and cellular biology High 15572674
2005 FHL2 suppresses FOXO1 transcriptional activity and FOXO1-induced apoptosis in prostate cancer cells by enhancing the interaction of FOXO1 with SIRT1 and promoting SIRT1-mediated deacetylation of FOXO1. This interaction occurs in the nucleus and is enhanced by lysophosphatidic acid. Co-immunoprecipitation, deacetylation assay, reporter assays for FOXO1 target genes, apoptosis assay, nuclear co-localization The EMBO journal High 15692560
2005 FHL2 interacts with TRAF6 and inhibits TRAF6-induced NF-κB activity in osteoclast precursors. FHL2 deficiency enhances TRAF6/RANK association, delays cytoskeletal organization, accelerates osteoclast maturation, and results in hyperresorptive osteoclasts. FHL2 thus acts as an antiosteoclastogenic molecule by attenuating TRAF6-mediated RANK signaling. Co-immunoprecipitation (FHL2-TRAF6), NF-κB reporter assay, FHL2-/- osteoclasts, RANKL-treated mice, FHL2 overexpression, bone resorption assay The Journal of clinical investigation High 16184196
2006 FHL2 is an inhibitor of sphingosine kinase-1 (SK1): it interacts with SK1 via at least 4 LIM domains (while the C-terminal portion of SK1 mediates binding), colocalizes with SK1 in the cytoplasm, and overexpression of FHL2 attenuates SK1 activity and its antiapoptotic effects. Endothelin-1 inhibits FHL2-SK1 association and increases SK1 activity in cardiomyocytes. Yeast two-hybrid with cardiac cDNA library, co-immunoprecipitation, colocalization, SK1 enzyme activity assay, apoptosis assay, LIM domain deletion analysis Circulation research High 16888242
2007 FHL2 deficiency impairs cutaneous wound healing: Fhl2-null mice show impaired wound healing rescued by transgenic Fhl2 expression. Mechanistically, Fhl2-deficient fibroblasts show severely impaired collagen contraction and cell migration, reduced α-smooth muscle actin expression, and reduced p130Cas expression. The S1P/RhoA signaling cascade triggers FHL2 nuclear translocation in mesenchymal cells. Fhl2-knockout and Fhl2 transgenic mice, wound healing assay, collagen contraction assay, cell migration assay, western blotting, immunofluorescence The Journal of cell biology High 17420295
2008 FHL2 promotes osteoblast differentiation from mesenchymal stem cells through activation of Wnt/β-catenin signaling: FHL2 interacts with β-catenin, potentiates its nuclear translocation and TCF/LEF transcription, and increases Runx2 and alkaline phosphatase expression. This pathway is blocked by DKK1 and by a dominant-negative Runx2. shRNA knockdown, gain-of-function overexpression, co-immunoprecipitation (FHL2-β-catenin), nuclear translocation assay, TCF/LEF reporter, DKK1 inhibition, dominant-negative Runx2 FASEB journal High 18653765
2008 FHL2 stabilizes myocardin and MRTF-A proteins (by increasing their half-life via a proteasome-dependent mechanism) and interacts with SRF, myocardin, and MRTF factors by GST pull-down and co-immunoprecipitation. FHL2 enhances myocardin/MRTF-A-dependent transactivation of smooth muscle gene promoters. FHL2 also attenuates RhoA/MRTF-B effects, possibly through decreased MRTF-B nuclear localization. Yeast two-hybrid, GST pull-down, co-immunoprecipitation, reporter assays, proteasome inhibitor treatment (MG-132, lactacystin), protein stability pulse-chase, ubiquitin immunoprecipitation American journal of physiology. Heart and circulatory physiology High 18586895
2009 In the absence of Sonic Hedgehog, Patched (Ptc) interacts with DRAL/FHL2, which is required for Ptc pro-apoptotic activity. DRAL recruits a caspase-activating complex containing TUCAN/NALP1 and caspase-9, and Ptc triggers caspase-9 activation and cell death through this DRAL-dependent mechanism in both immortalized cells and during neural tube development in chick embryos. Co-immunoprecipitation (Ptc-DRAL), functional apoptosis assays, caspase-9 activation assay, DRAL knockdown/overexpression, chick neural tube in vivo experiments Nature cell biology High 19465923
2009 FHL2 suppresses VEGF-induced PI3K/Akt activation in endothelial cells by directly binding to and inhibiting sphingosine kinase-1 (SK1), thereby blocking SK1-mediated S1P production and downstream Akt/eNOS phosphorylation. VEGF stimulation decreases FHL2-SK1 association. FHL2 mRNA injection into Xenopus embryos inhibits vascular network development. Immunoprecipitation, immunostaining, SK1 activity assay, PI3K activity assay, Akt/eNOS phosphorylation western blot, siRNA knockdown, Xenopus in vivo assay Arteriosclerosis, thrombosis, and vascular biology High 19325137
2000 DRAL/FHL2 expression is transcriptionally upregulated by p53 (both by transient p53 expression in rhabdomyosarcoma cells and by ionizing radiation of wild-type cells), identifying DRAL as a p53-responsive gene. Ectopic DRAL expression efficiently triggers apoptosis. Endogenous DRAL localizes to cytoplasm, nucleus, focal contacts, Z-discs, and (to a lesser extent) M-bands in cardiac myofibrils. p53 transient transfection, ionizing radiation, RT-PCR for DRAL mRNA, promoter analysis (p53 sites), ectopic expression + apoptosis assay, immunofluorescence localization The Journal of cell biology High 11062252
2002 FHL2 interacts with PLZF (promyelocytic leukemia zinc finger protein) in vitro and in vivo and acts as a corepressor, augmenting PLZF-mediated transcriptional repression. This is the first reported FHL protein functioning as a corepressor. Inducible yeast two-hybrid, in vitro binding, co-immunoprecipitation, reporter assays for PLZF-mediated repression The Journal of biological chemistry Medium 12145280
2002 FHL2 interacts with presenilin 2 (PS2) but not presenilin 1 (PS1) at a hydrophilic loop region (aa 269–298) of the PS2 N-terminal fragment. This interaction was confirmed by affinity column assay and co-immunoprecipitation from human lung fibroblasts. PS2 overexpression increases FHL2 in the membrane fraction. Yeast two-hybrid, affinity column assay, co-immunoprecipitation from MRC5 cells, fractionation Human molecular genetics Medium 11001931
2002 FHL2 interacts with IGFBP-5 but not IGFBP-3, -4, or -6 in vitro and by co-immunoprecipitation in U2 osteosarcoma cells. Both FHL2 and IGFBP-5 are present in the nucleus, suggesting FHL2 could mediate IGFBP-5 nuclear effects. Yeast two-hybrid, co-immunoprecipitation, in vitro binding with purified proteins, nuclear fractionation/immunofluorescence The Journal of biological chemistry Medium 11821401
2001 FHL2 is not required for normal cardiac development but modifies the hypertrophic response to β-adrenergic stimulation: FHL2-null mice show exaggerated cardiac hypertrophy (59% vs. 20% increase in heart weight/body weight) following chronic isoproterenol infusion. Homologous recombination knockout mice, isoproterenol chronic infusion, cardiac weight measurement Circulation High 11390345
2004 FHL2 and FHL3 interact with both alpha-7 (splice isoforms A and B) and beta-1 integrin subunits; the intact suprastructure of the whole FHL molecule is required (not single LIM domains). FHL2 and FHL3 (but not FHL1) colocalize with integrins at cell adhesion sites in cardiac and skeletal muscles, at the periphery of Z-discs, suggesting a role in mechanical stabilization. Yeast two-hybrid, GST pull-down, deletion mutagenesis, co-immunoprecipitation, immunofluorescence The Journal of biological chemistry Medium 15117962
2001 FHL2 localizes to focal adhesions in multiple cell lines and the second LIM domain (LIM2) is the principal determinant of focal adhesion localization. During myofibrillogenesis, FHL2 translocates from focal adhesions to Z-discs of terminally differentiated heart muscle. GFP-fusion protein imaging, colocalization with vinculin-CFP, site-directed mutagenesis of LIM domains, immunofluorescence during differentiation Cell motility and the cytoskeleton Medium 11124707
2002 FHL2 and FHL3 colocalize in mitochondria of C2C12 cells, as demonstrated by GFP two-fusion FRET assay showing direct protein-protein interaction at mitochondria. FHL3 LIM2 domain is essential for interaction with FHL2, while FHL3 LIM1 is essential for focal adhesion localization. Yeast two-hybrid, GFP-FRET (two-fusion FRET), site-directed mutagenesis, GFP live-cell imaging Journal of cellular biochemistry Medium 11135358
2002 FHL2 interacts with the cardiac slow delayed rectifier potassium channel subunit minK (KCNE1) and is required for generation of IKs current: in HEK293 cells (which lack endogenous FHL2), KvLQT1+minK co-expression only generates IKs when FHL2 is co-expressed; in CHO-K1 cells (which endogenously express FHL2), antisense-mediated depletion of FHL2 suppresses IKs. Yeast two-hybrid, GST pull-down, immunocytochemistry colocalization, electrophysiology (patch clamp), antisense knockdown Cardiovascular research High 12237170
2002 FHL2 interacts with the WT1 transcription factor and coactivates WT1-mediated transcription, including synergistic induction of MIS gene expression by WT1/SF1 and coactivation of the DAX1 promoter by WT1. In vitro interaction assays, co-immunoprecipitation, reporter assays, coexpression studies Biochimica et biophysica acta Medium 12151099
2002 FHL2 interacts with the DNA-binding nuclear protein hNP220 via LIM domains 2, 3, and 4, and this interaction occurs in the nucleus as shown by two-fusion FRET assay. Yeast two-hybrid, GFP/BFP fusion protein FRET in nucleus, domain deletion analysis Journal of cellular biochemistry Medium 11813260
2003 BRCA1 interacts with FHL2 through its second BRCT domain, while the last three LIM domains of FHL2 are required for the interaction with BRCA1. 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, BRCA1 mutant analysis FEBS letters Medium 14550570
2004 Focal adhesion kinase (FAK/pp125FAK) forms a protein complex with FHL2 in human ovarian carcinoma cells, as demonstrated by co-immunoprecipitation. Co-immunoprecipitation, immunohistochemistry Anticancer research Low 15161045
2006 FHL2 interacts with ADAM-17 (the metalloprotease responsible for ectodomain shedding) at amino acids 721–739 of ADAM-17, via the actin cytoskeleton. FHL2 regulates ADAM-17 surface localization and activity: FHL2-deficient macrophages show more ADAM-17 at the surface but reduced ADAM-17 substrate release under PMA stimulation. Yeast two-hybrid, co-immunoprecipitation, colocalization, surface ADAM-17 quantification in FHL2-/- macrophages, shedding assay Journal of cellular physiology Medium 16619241
2006 FHL2 interacts with E4F1 (full-length p120 form but not truncated p50 form) in the nuclear compartment, and this interaction inhibits E4F1's capacity to block cell proliferation and repress transcription. FHL2 expression reduces nuclear E4F1-p53 complexes. UV-light induces nuclear accumulation of FHL2 and endogenous E4F1-FHL2 complex formation. In vitro binding, co-immunoprecipitation (in vivo), nuclear fractionation, reporter assays, cell proliferation assay, UV treatment Oncogene Medium 16652157
2008 FHL2 deficiency in mesenchymal stem cells impairs assembly of extracellular matrix proteins on the cell surface and impairs bundling of focal adhesions. This is accompanied by increased FAK phosphorylation at Y925 and enhanced ERK activation upon cell adhesion. Inhibition of MAPK activity restores matrix organization in FHL2-null cells. FHL2-knockout MSCs vs. wild-type, rescue with recombinant FHL2, FAK/ERK phosphorylation western blot, MAPK inhibitor treatment, ECM assembly assay FASEB journal Medium 18356303
2009 FHL2 directly interacts with all four Id family proteins (Id1–4) via an N-terminal loop-helix structure conserved in Id proteins, and antagonizes the inhibitory effect of Id proteins on E47-mediated transcription by competing with E47 for Id2 binding, releasing E47 to bind DNA and restore transcriptional activity. Co-immunoprecipitation, deletion mutagenesis, competitive binding assay, E47-reporter assay, FHL2 and Id overexpression in neuroblastoma cells Nucleic acids research Medium 19417068
2011 FHL2 physically interacts with Snail1 (reciprocal co-immunoprecipitation), promotes Snail1 nuclear accumulation, and negatively regulates E-cadherin transcription by decreasing transcriptional activity at E-box sites in the E-cadherin promoter. Reciprocal co-immunoprecipitation, immunofluorescence (Snail1 localization), dual luciferase reporter with E-cadherin promoter constructs including E-box mutations, siRNA knockdown European journal of cancer Medium 20801642
2011 FHL2 is a co-repressor of the NR4A nuclear receptor Nur77: each of the four LIM domains of FHL2 can bind Nur77 (with both the N-terminal domain and DNA-binding domain of Nur77 involved), and FHL2 inhibits Nur77 transcriptional activity and its association with DNA (ChIP). FHL2 overexpression increases smooth muscle cell growth while knockdown reduces DNA synthesis. Yeast two-hybrid, co-immunoprecipitation, deletion mutagenesis, reporter assay, ChIP (enolase3 promoter), shRNA knockdown, DNA synthesis assay The Journal of biological chemistry High 22049082
2012 FHL2 directly binds calcineurin in cardiomyocytes (co-immunoprecipitation at the sarcomere, enhanced by endothelin-1) and acts as an endogenous agonist-dependent suppressor of calcineurin, inhibiting calcineurin-NFAT signaling and NFAT target gene expression. FHL2 loss amplifies isoproterenol-induced NFAT target gene induction and hypertrophic growth. Co-immunoprecipitation, immunofluorescence colocalization, FHL2-/- mice, siRNA knockdown, NFAT reporter assay (RCAN1, IL-2 promoters), cardiomyocyte cross-sectional area measurement, cyclosporine inhibition Molecular and cellular biology High 22851699
2012 FHL2 activates NF-κB signaling by stabilizing TRAF6 protein (interaction confirmed by co-immunoprecipitation), thereby enhancing TRAF6-dependent NF-κB target gene transcription. FHL2-/- macrophages show reduced TNF and IL-6 production after LPS stimulation, and FHL2-/- mice show delayed liver regeneration after hepatectomy. Co-immunoprecipitation (FHL2-TRAF6), siRNA knockdown in 293-hTLR4 cells, FHL2-/- macrophages, partial hepatectomy in FHL2-/- mice, NF-κB reporter assay, cytokine measurement Molecular and cellular biology High 23775124
2012 FHL2 activates TGF-β signaling by binding Arkadia (a RING ubiquitin E3 ligase) and inhibiting K27-linked polyubiquitination of Arkadia, thereby increasing Arkadia protein stability and enabling Arkadia-induced Smad3/Smad4-dependent transcription. Co-immunoprecipitation, in vitro ubiquitination assay, RING domain mutation, lysine mutants of Arkadia, FHL2 siRNA knockdown, TGF-β reporter assay, protein half-life measurement The Journal of biological chemistry High 23212909
2012 ROCK2 deficiency in cardiomyocytes leads to increased FHL2 expression, and FHL2-mediated inhibition of SRF and ERK contributes to the antihypertrophic phenotype. Knockdown of FHL2 in ROCK2-deficient cardiomyocytes or placing ROCK2+/- mice on FHL2+/- background restored the hypertrophic response to angiotensin II. Cardiac-specific ROCK2 knockout mice, FHL2 haploinsufficiency genetic epistasis, siRNA knockdown of FHL2 in cardiomyocytes, cardiac hypertrophy measurements, SRF/ERK activity assays FASEB journal High 23271052
2016 FHL2 shuttling between focal adhesions and the nucleus is mechanosensitive and depends on matrix stiffness. On soft surfaces or after force loss, FHL2 moves from focal adhesions to the nucleus (RNA Pol II sites) and increases p21 gene expression to inhibit cell growth. This shuttling requires phosphorylation of FHL2 by focal adhesion kinase (FAK) at a specific tyrosine residue. Live-cell fluorescence imaging on substrates of varying stiffness, force manipulation, FAK inhibition/mutagenesis, tyrosine mutagenesis of FHL2, RNA Pol II co-localization, p21 reporter/expression assay Proceedings of the National Academy of Sciences of the United States of America High 27742790
2016 FHL2 serves as a scaffold protein facilitating MDM2-mediated ubiquitination and proteasomal degradation of IER3: FHL2 binds to both IER3 and MDM2, forming a ternary complex, and enables efficient MDM2-mediated polyubiquitination of IER3 at lysine 60. Co-immunoprecipitation, ubiquitination assay, proteasome inhibitor treatment, lysine-60 mutagenesis, reporter assay, FHL2/MDM2 siRNA knockdown, immunohistochemistry Oncogene High 26973248
2021 FHL2 anchors mitochondria to F-actin and arrests mitochondrial movement in response to increased glucose influx. FHL2 associates with O-GlcNAcylated TRAK (Milton), drives F-actin accumulation around mitochondria, and tethers mitochondria to F-actin. Disruption of F-actin restores mitochondrial movement arrested by TRAK O-GlcNAcylation or forced FHL2 targeting to mitochondria. Co-immunoprecipitation (FHL2-O-GlcNAc TRAK), live-cell mitochondrial motility imaging, F-actin disruption (cytochalasin D), forced mitochondrial targeting of FHL2, glucose manipulation, neurons and non-neuronal cells The Journal of cell biology High 34342639
2010 FHL2 interacts with Foxk1 and, in a dose-dependent manner, promotes Foxk1-mediated transcriptional repression of Foxo4 activity in myogenic progenitor cells. FHL2 knockdown causes cell cycle arrest, and FHL2-null mice show perturbed skeletal muscle regeneration. Yeast two-hybrid, transcriptional reporter assay (Foxk1-Foxo4), FHL2 knockdown (siRNA), FHL2-null mouse histology, immunohistochemistry Stem cells Medium 20013826
2012 FHL2 interacts with NR5A nuclear receptors (LRH-1 and SF-1) via a single LIM domain (while determinants in both the LBD and DBD of NR5A proteins are important) and functions as a transcriptional coactivator to enhance inhibin-α and P450scc gene expression in granulosa cells. FHL2 also interacts with CREB and augments NR5A/forskolin-synergistic activation of inhibin gene expression. Yeast two-hybrid (human ovary library), in vitro interaction assays, siRNA knockdown in primary granulosa cells, reporter assay (inhibin-α promoter), deletion mutagenesis Molecular endocrinology Medium 22734036
2014 FHL2 interacts with liver X receptor isoforms (LXRα and LXRβ) by co-immunoprecipitation, enhances LXRE-dependent transcription, and increases LXRβ association with the ABCG1 promoter (ChIP). FHL2 deficiency in smooth muscle cells reduces LXR target gene expression and attenuates cholesterol efflux to ApoA-1 and HDL. Co-immunoprecipitation, LXRE reporter assay, ChIP (ABCG1 promoter), FHL2-KO SMC transcriptome, cholesterol efflux assay Molecular and cellular biology High 25332231
2018 FHL2 physically interacts with wild-type EGFR and EGFRvIII in GBM cells, increases EGFR/EGFRvIII protein levels by enhancing protein stability (not mRNA), and knockdown of FHL2 reduces EGFR/EGFRvIII protein and phosphorylation levels of EGFR and AKT. Co-immunoprecipitation, western blot for protein levels vs. mRNA, FHL2 siRNA knockdown, FHL2-null astrocytes + FHL2 reintroduction, in vivo tumor growth assay Oncogene Medium 29321665
2018 PARP12 interacts with FHL2 (confirmed by protein affinity purification) and regulates FHL2 protein stability: PARP12 deficiency decreases FHL2 protein levels by promoting FHL2 ubiquitination. This regulation is independent of PARP12 enzymatic activity (mono-ADP-ribosylation of FHL2 not detected in vitro or in vivo). Protein affinity purification (Co-IP), ubiquitination assay, in vitro ADP-ribosylation assay (negative result for FHL2), western blot for FHL2 levels in PARP12-deficient cells Cell death & disease Medium 30154409
2024 In dormancy-inducing stiff 3D matrices, FHL2 undergoes stiffness-dependent nuclear localization leading to p53-independent high p21(Cip1/Waf1) nuclear expression, and cells in these matrices become sensitive to chemotherapy upon FHL2 knockdown, identifying a FHL2-p21 signaling axis in mechanically-induced dormancy. 3D engineered matrices of varying stiffness, immunofluorescence (FHL2 nuclear localization), p21 expression analysis, FHL2 siRNA knockdown + chemotherapy sensitivity assay, validation in murine and human tissue Science advances Medium 39504377
2000 FHL2 interacts with hCDC47 (MCM7), a DNA replication regulatory protein, via the second and third LIM domains together with the first half LIM domain of FHL2, as shown by yeast two-hybrid and in vitro interaction studies. Yeast two-hybrid library screen, in vitro interaction assay, LIM domain deletion analysis Journal of cellular biochemistry Low 10649446
2002 TUCAN/CARDINAL (a CARD-domain protein) associates with DRAL/FHL2; TUCAN/CARDINAL suppresses NF-κB activity while DRAL expression enhances NF-κB activation, suggesting they participate in a regulatory mechanism coordinating NF-κB-controlled cellular responses. Co-immunoprecipitation (TUCAN-DRAL), NF-κB reporter assay, overexpression FEBS letters Low 12067710
2020 FHL2 inhibits ovulation by interacting with androgen receptor (AR) to act as its co-regulator suppressing C/EBPβ expression, and by binding to ERK1/2 to inhibit its phosphorylation in granulosa cells. FHL2 overexpression in rat ovaries via lentiviral injection causes acyclicity and polycystic ovary morphology. Co-immunoprecipitation (FHL2-AR, FHL2-ERK1/2), siRNA knockdown in KGN cells, lentiviral overexpression in rat ovaries, phospho-ERK1/2 western blot, C/EBPβ reporter, ovulation assay EBioMedicine Medium 32028069
2016 FHL2 functions as a co-activator of NFκB and AP-1 to regulate AKT1 gene transcription in granulosa cell tumors, as shown by co-immunoprecipitation and chromatin immunoprecipitation. FHL2-mediated GCT cell growth and viability occurs through AKT1 expression, and constitutively active AKT1 rescues FHL2 knockdown-induced growth arrest. Co-immunoprecipitation, ChIP (FHL2 on AKT1 promoter), reporter assay, FHL2 knockdown + AKT1 rescue, in vivo tumor model Cell death & disease Medium 27415427
2010 FHL2 regulates cyclin D1 expression and cell proliferation: FHL2 is associated with the cyclin D1 promoter at TCF/CRE sites (by ChIP), FHL2 deficiency greatly reduces cyclin D1 levels and proliferation in fibroblasts, reexpression of FHL2 restores cyclin D1 and proliferation, and ectopic cyclin D1 overrides growth inhibition in FHL2-null fibroblasts. ChIP (FHL2 on cyclin D1 promoter), FHL2-/- fibroblasts, FHL2 reexpression rescue, cyclin D1 overexpression rescue, cell proliferation assay, gene expression profiling The Journal of biological chemistry High 18378678
2010 FHL2 regulates IL-6 expression in skeletal muscle cells through stimulation of NF-κB and p38 MAPK signaling pathways. FHL2 overexpression increases IL-6 mRNA and protein secretion, while FHL2 siRNA knockdown significantly decreases IL-6 secretion in response to TNFα. FHL2 overexpression, siRNA knockdown, IL-6 promoter reporter assay, NF-κB reporter, p38 MAPK inhibitor, ELISA for IL-6 Cytokine Medium 22633286

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 210 16389449
2002 The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus. The EMBO journal 164 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 150 18653765
2018 DNA methylation of the ELOVL2, FHL2, KLF14, C1orf132/MIR29B2C, and TRIM59 genes for age prediction from blood, saliva, and buccal swab samples. Forensic science international. Genetics 147 30300865
2004 The SRF target gene Fhl2 antagonizes RhoA/MAL-dependent activation of SRF. Molecular cell 137 15610731
2001 Cardiac-specific LIM protein FHL2 modifies the hypertrophic response to beta-adrenergic stimulation. Circulation 135 11390345
2004 Extracellular signal-regulated kinase 2 interacts with and is negatively regulated by the LIM-only protein FHL2 in cardiomyocytes. Molecular and cellular biology 131 14729955
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 126 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
2002 Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2). The Journal of biological chemistry 117 11821401
2009 The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex. Nature cell biology 112 19465923
1997 Subtractive cloning and characterization of DRAL, a novel LIM-domain protein down-regulated in rhabdomyosarcoma. DNA and cell biology 112 9150430
2004 Interaction and functional cooperation between the LIM protein FHL2, CBP/p300, and beta-catenin. Molecular and cellular biology 102 15572674
2012 FHL2 prevents cardiac hypertrophy in mice with cardiac-specific deletion of ROCK2. FASEB journal : official publication of the Federation of American Societies for Experimental Biology 96 23271052
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
2004 The LIM-only proteins FHL2 and FHL3 interact with alpha- and beta-subunits of the muscle alpha7beta1 integrin receptor. The Journal of biological chemistry 92 15117962
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
2005 FHL2 inhibits the activated osteoclast in a TRAF6-dependent manner. The Journal of clinical investigation 77 16184196
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 61 26548523
2014 FHL2 expression and variants in hypertrophic cardiomyopathy. Basic research in cardiology 61 25358972
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 60 27742790
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 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
2001 Protein-protein interaction of FHL3 with FHL2 and visualization of their interaction by green fluorescent proteins (GFP) two-fusion fluorescence resonance energy transfer (FRET). Journal of cellular biochemistry 57 11135358
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
2020 Identification of recurrent FHL2-GLI2 oncogenic fusion in sclerosing stromal tumors of the ovary. Nature communications 52 31896750
2021 FHL2 anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply. The Journal of cell biology 51 34342639
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
2020 Up-regulated FHL2 inhibits ovulation through interacting with androgen receptor and ERK1/2 in polycystic ovary syndrome. EBioMedicine 45 32028069
2019 miR-340-FHL2 axis inhibits cell growth and metastasis in ovarian cancer. Cell death & disease 45 31068580
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
2011 FHL2 protein is a novel co-repressor of nuclear receptor Nur77. The Journal of biological chemistry 42 22049082
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
2013 LIM-only protein FHL2 activates NF-κB signaling in the control of liver regeneration and hepatocarcinogenesis. Molecular and cellular biology 41 23775124
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
2018 PARP12 (ARTD12) suppresses hepatocellular carcinoma metastasis through interacting with FHL2 and regulating its stability. Cell death & disease 40 30154409
2008 The LIM-only protein FHL2 regulates cyclin D1 expression and cell proliferation. The Journal of biological chemistry 40 18378678
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 33 18586895
2012 The LIM-only protein FHL2 controls mesenchymal cell osteogenic differentiation and bone formation through Wnt5a and Wnt10b. Bone 32 23201222
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
2002 Interaction of the heart-specific LIM domain protein, FHL2, with DNA-binding nuclear protein, hNP220. Journal of cellular biochemistry 29 11813260
2017 FHL2 promotes tubular epithelial-to-mesenchymal transition through modulating β-catenin signalling. Journal of cellular and molecular medicine 28 29193729
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 28 23212909
2008 The four-and-a-half-LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities. Glia 28 18615633
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
2009 Enhanced expression of FHL2 leads to abnormal myelopoiesis in vivo. Leukemia 27 19369964
2015 FHL2: a scaffold protein of carcinogenesis, tumour-stroma interactions and treatment response. Histology and histopathology 26 26676939
2012 The LIM domain protein FHL2 interacts with the NR5A family of nuclear receptors and CREB to activate the inhibin-α subunit gene in ovarian granulosa cells. Molecular endocrinology (Baltimore, Md.) 26 22734036
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
2012 The LIM-only protein FHL2 regulates interleukin-6 expression through p38 MAPK mediated NF-κB pathway in muscle cells. Cytokine 25 22633286
2011 FHL2 expression in peritumoural fibroblasts correlates with lymphatic metastasis in sporadic but not in HNPCC-associated colon cancer. Laboratory investigation; a journal of technical methods and pathology 25 21826055
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
2024 Dormancy-inducing 3D engineered matrix uncovers mechanosensitive and drug-protective FHL2-p21 signaling axis. Science advances 22 39504377
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
2023 FHL2 deficiency impairs follicular development and fertility by attenuating EGF/EGFR/YAP signaling in ovarian granulosa cells. Cell death & disease 21 37015904
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
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
2023 FHL2 regulates microglia M1/M2 polarization after spinal cord injury via PARP14-depended STAT1/6 pathway. International immunopharmacology 18 37708708
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
2024 FHL2 expression by cancer-associated fibroblasts promotes metastasis and angiogenesis in lung adenocarcinoma. International journal of cancer 17 39244734
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

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