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Symbol FHL2 contributors: mct/pgu - updated : 04-10-2023
HGNC name four and a half LIM domains 2
HGNC id 3703
Corresponding disease
CMD1H cardiomyopathy, dilated 1H
Location 2q12.2      Physical location : 105.977.284 - 106.055.230
Synonym name
  • down-regulated in rhabdomyosarcoma LIM protein
  • skeletal muscle lim protein 3
  • aging associated gene 11
  • LIM domain protein DRAL
  • Synonym symbol(s) DRAL, SLIM3, AAG11, FHL-2
    TYPE functioning gene
    STRUCTURE 80.82 kb     8 Exon(s)
    10 Kb 5' upstream gene genomic sequence study
    regulatory sequence Promoter
    text structure
  • a functional promoter region upstream of the transcription start site
  • MAPPING cloned Y linked   status confirmed
    TRANSCRIPTS type messenger
    text produces transcripts by different 5prime exons, which may be responsible for tissue-specific regulation (PMID: 21540083)
    identificationnb exonstypebpproduct
    ProteinkDaAAspecific expressionYearPubmed
    6 - 1735 32 279 - 2011 21540083
    6 - 1727 32 279 - 2011 21540083
    7 - 1552 32 279 - 2011 21540083
    8 - 1907 32 279 - 2011 21540083
    7 - 1503 32 279 - 2011 21540083
    5 - 4375 - 165 - 2011 21540083
    8 - 4690 - 171 - 2011 21540083
    6 - 1798 32 279 - 2011 21540083
    6 - 4517 32 279 - 2011 21540083
    6 - 4521 - 165 - 2011 21540083
    7 - 1582 32 279 - 2011 21540083
    Type restricted
       expressed in (based on citations)
    SystemOrgan level 1Organ level 2Organ level 3Organ level 4LevelPubmedSpeciesStageRna symbol
    Cardiovascularheart   highly Homo sapiens
    Digestiveintestinesmall intestine  lowly
     intestinelarge intestinecolon lowly
    Reproductivefemale systemovary  highly
     male systemtestis  lowly
     male systemprostate  lowly
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Muscularcardiacmyocardium   Homo sapiens
    Muscularsmooth    Homo sapiens
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    cell lineage
    cell lines
    at STAGE
    physiological period embryo, pregnancy
    Text placenta, kidney
  • four and a half LIM domains, each of which are composed of two zinc finger structures
  • N-terminal half LIM domain followed by four complete LIM domains
  • four and a half LIM domains, which share primary sequence pattern of cysteine and histidine with the RING domain, but are devoid of E3 ubiquitin ligase activity
  • C terminal NXXY motif
    interspecies homolog to murine Fhl2 (92.1pc)
    homolog to rattus Fhl2 (91.4pc)
    CATEGORY adaptor , regulatory , signaling
    SUBCELLULAR LOCALIZATION     intracellular
    text localize in Z-disc
    basic FUNCTION
  • tissue specific coactivator of the androgen receptor, recruited to adhesion complexes FHL2/alpha and beta integrin chains
  • negative regulator of E4F1
  • having repressor function in cardiomyocytes through its ability to inhibit MAPK1/2 transcriptional coupling
  • acting as a specific adaptor protein to couple metabolic enzymes to sites of high energy consumption in the cardiac sarcomere
  • playing a role in heart muscle differentiation and in maintenance of the heart phenotype
  • being an antiosteoclastogenic molecule exerting its effect by attenuating TRAF6-mediated TNFRSF11A signaling
  • can act on different aspects of the cell cycle program to finely regulate cell proliferation
  • may function as a molecular transmitter linking various signaling pathways to transcriptional regulation
  • role in bundling of focal adhesion structures, in integrin-mediated ERK activation, and subsequently in proper allocation of matrix proteins on the cell surface
  • may regulate phosphatidylinositol 3-kinase/Akt via direct suppression of the SK1-S1P pathway in endothelial cells
  • prevents the formation of ID2-E47 heterodimer by binding to ID2, thus releasing E47 to DNA and restoring its transcriptional activity
  • association of FHL2 with NR4A1 plays a pivotal role in vascular disease
  • represses the transcriptional activity of NR4A1 through interaction with the N-terminal and DBD of NR4A1 and enhances smooth muscle cell growth
  • is a positive regulator of NFKB1 activity in liver regeneration and carcinogenesis
  • importance of FHL2 in both hepatocytes and hepatic immune cells
  • FHL1 and FHL2 are novel cardiac PRKD1 partners, which differentially facilitate PRKD1 activation and HDAC5 phosphorylation by distinct neurohormonal stimuli, but are unlikely to regulate MEF2A-driven transcriptional reprogramming
  • FHL2 is regulated under the control of a tissue-specific promoter in hematopoietic cells and it is downregulated by DNA hypermethylation in the leukemia cell line and primary leukemia cells
  • FHL2 downregulation has likely a role in the pathogenesis of myeloid malignancies
  • is a master cytokine in many biological processes, including tissue homeostasis, epithelial-to-mesenchymal transition, and wound repair
  • is a transcriptional cofactor that plays the role of coactivator or corepressor, depending on the cell and promoter contexts
  • multifunctional adaptor protein that can interact with cell surface receptors, cytosolic adaptor and structural proteins, kinases, and nuclear transcription factors
  • FHL2 seems to be involved in numerous steps of these extremely complex and multidirectional but tightly regulated tissue remodeling processes, supporting tissue repair and coordinating inflammation
  • FHL2 is a scaffold protein involved in regulating vSMC function and inflammation
  • anchors mitochondria to actin and adapts mitochondrial dynamics to glucose supply
  • FHL2 gene is consistently found as one of the top hyper-methylated genes upon aging
  • is an anti-hypertrophic adaptor protein that regulates cardiac myocyte signalling and function
  • CELLULAR PROCESS nucleotide, transcription, regulation
    integrin signaling pathway
    a component component of focal adhesion structures
    small molecule
  • coactivator of androgen receptor
  • interacting with the DNA replication regulatory protein CDC47 (MCM7)
  • interacting with MAPK2 through two LIM domains
  • inhibited the ability of activated ERK2 to reside within the nucleus, thus blocking ERK-dependent transcriptional responsiveness of ELK-1, GATA4, and the atrial natriuretic factor promoter)
  • binding with NP220
  • interacting with hydrophilic loop of PSEN2
  • interacting and corepressing ZNF145
  • bound to two distinct sites on titin
  • interacting with CCND1 (critical for cyclin D1 activation and cell growth, regulate the activity of the cyclin D1 promoter through its implication in acetylation of transcription factors and histones)
  • interacting with ZNF638, E4F1 and all members of the Id faily (Id1-4)
  • potential KCNH2 partner (interacts with and regulates the KCNH2 channel)
  • FHL1, FHL2, and FHL3 physically and functionally interact with SMAD2, SMAD3, and SMAD4, important regulators of cancer development and progression, in a TGF-beta-independent manner
  • repressor of ID2
  • FOXK1 interacting protein (FHL2, in a dose-dependent fashion, promotes FOXK1 transcriptional repression of FOXO4 activity)
  • FHL2 is a novel regulator of CCL19-induced dendritic cell (DC) migration
  • represses NR4A1 transcriptional activity in a dose-dependent manner
  • directly interacts with HIF1A to repress transcriptional activity
  • FHL2 controls the osteogenic differentiation of mesenchymal stromal cells (MSC), bone formation and bone mass through modulation of WNT molecules, WNT10B, WNT3A, WNT5A
  • binds and synergistically cooperates with RNF111 to activate SMAD3/SMAD4-dependent transcription
  • is important regulator of RNF111 ubiquitination and TGFB signal transduction
  • FHL2 enhanced TRAF6 activity in transcriptional activation of NFKB1 targets by stabilizing the protein
  • TRAF6 is a binding partner of FHL2 and an important component of the Toll-like receptor-NFKB1 pathway
  • is transcriptionally regulated by diverse types of transcription factors, for example, TP53, serum response factor (SRF), and specificity protein 1 (Sp1)
  • exhibits specific interaction with proteins exhibiting diverse functions, including transmembrane receptors, transcription factors and transcription co-regulators, enzymes, and structural proteins
  • is a critical regulator of TGFB1 expression
  • FHL2, via modulating CTNNB1 signalling, may implicate in regulation of TGFB1-mediated tubular epithelial-to-mesenchymal transition (EMT)
  • FHL2 decreases the inflammatory response of vascular smooth muscle cells (vSMCs) through inhibition of the NFKB1-signalling pathway
  • CMYA5 is a novel FHL2 interaction partner in cardiac myocytes
  • direct interaction of the two adaptor proteins FHL2 and CMYA5 in cardiac myocytes, which might impact subcellular compartmentation of CMYA5
  • cell & other
    Other up-regulated during retinoic acid-induced differenciation of neuroblastoma cells reducing the transcrptional and cell cycle promoting functions of ID2
    corresponding disease(s) CMD1H
    Other morbid association(s)
    TypeGene ModificationChromosome rearrangementProtein expressionProtein Function
    tumoral     --low  
    in rhabdomyosarcoma
    constitutional       loss of function
    leads to impaired assembly of extracellular matrix proteins on the cell surface and to impaired bundling of focal adhesions
    tumoral       gain of function
    in colorectal cancer (CRC) compared with matched normal tissues
    Variant & Polymorphism
    Candidate gene
    Therapy target
    FOXK1 and FHL2 may serve as putative targets in the combined therapy of colorectal cancer
  • up-regulation of Fhl2 may contribute to the antihypertrophic phenotype that is observed in cardiac-specific Rock2-deficient mice