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FLASH GENE
Symbol FHL2 contributors: mct/pgu - updated : 26-08-2016
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
    DNA
    TYPE functioning gene
    STRUCTURE 77.95 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
    Physical map
    IL1RL1 2q12 interleukin 1 receptor-like 1 IL18R1 2q12 interleukin 18 receptor 1 IL18RAP 2p24.3-p24.1 interleukin 18 receptor accessory protein LOC389015 2 similar to Sodium/hydrogen exchanger 4 (Na(+)/H(+) exchanger 4) (NHE-4) SLC9A2 2q11.2 solute carrier family 9 (sodium/hydrogen exchanger), isoform 2 MGC11332 2q12.1 hypothetical protein MGC11332 FLJ30294 2q12.1 hypothetical protein FLJ30294 LOC130822 2q12.1 similar to cytokine receptor-like factor 3; cytokine receptor-like molecule 9; cytokine receptor related protein 4 LOC391413 2 similar to Adenosylhomocysteinase (S-adenosyl-L-homocysteine hydrolase) (AdoHcyase) LOC391414 2 similar to high mobility group protein homolog HMG4 POU3F3 3p14.2 POU domain, class 3, transcription factor 3 MRPS9 2q12.1 mitochondrial ribosomal protein S9 GPR45 2q11.2-q12 G protein-coupled receptor 45 TGFBRAP1 2q12.1 transforming growth factor, beta receptor associated protein 1 MGC5509 2q12.2 hypothetical protein MGC5509 FHL2 2q12-q13 four and a half LIM domains 2 NCK2 2q12 NCK adaptor protein 2 ECRG4 2q12.2 esophageal cancer related gene 4 protein UXS1 2q12.1 UDP-glucuronate decarboxylase 1 LOC391415 2 similar to ribosomal protein S21; 40S ribosomal protein S21 LOC391416 2 similar to hypothetical protein MGC4614 LOC389016 2 similar to RAN-binding protein 2-like 1 isoform 1; sperm membrane protein BS-63; RAN-binding protein 2-like 1 LOC391417 2 similar to anaphase-promoting complex 1 (meiotic checkpoint regulator) CD8B2 2q12 CD8 antigen, beta polypeptide 2, pseudogene (p37) LOC389017 2 similar to Elongation factor 1-alpha 1 (EF-1-alpha-1) (Elongation factor 1 A-1) (eEF1A-1) (Elongation factor Tu) (EF-Tu) LOC389018 2 similar to Elongation factor 1-alpha 1 (EF-1-alpha-1) (Elongation factor 1 A-1) (eEF1A-1) (Elongation factor Tu) (EF-Tu) ST6GalII 2q11.2-q12.1 beta-galactoside alpha-2,6-sialyltransferase II LOC339819 2q12.3 similar to protein phosphatase 1, regulatory (inhibitor) subunit 2 DKFZp686P0288 2q12.3 similar to Ran-binding protein 2 SLC5A7 2q12 solute carrier family 5 (choline transporter), member 7 LOC391418 2 similar to phenol sulfotransferase SULT1C1 2q11.1-q11.2 sulfotransferase family, cytosolic, 1C, member 1
    RNA
    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
    EXPRESSION
    Type restricted
       expressed in (based on citations)
    organ(s)
    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
    tissue
    SystemTissueTissue level 1Tissue level 2LevelPubmedSpeciesStageRna symbol
    Connectivebone   
    Muscularcardiacmyocardium   Homo sapiens
    Muscularsmooth    Homo sapiens
    Muscularstriatumcardiac  
    cells
    SystemCellPubmedSpeciesStageRna symbol
    Cardiovascularendothelial cell Homo sapiens
    cell lineage
    cell lines
    fluid/secretion
    at STAGE
    physiological period embryo, pregnancy
    Text placenta, kidney
    PROTEIN
    PHYSICAL PROPERTIES
    STRUCTURE
    motifs/domains
  • four cysteine-rich LIM/double zinc finger motifs
  • 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
  • HOMOLOGY
    interspecies homolog to murine Fhl2 (92.1pc)
    homolog to rattus Fhl2 (91.4pc)
    Homologene
    FAMILY
    CATEGORY adaptor , regulatory , signaling
    SUBCELLULAR LOCALIZATION     intracellular
    intracellular,cytoplasm,cytoskeleton
    intracellular,nucleus,chromatin/chromosome
    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
  • 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
  • CELLULAR PROCESS nucleotide, transcription, regulation
    PHYSIOLOGICAL PROCESS
    PATHWAY
    metabolism
    signaling
    integrin signaling pathway
    a component component of focal adhesion structures
    INTERACTION
    DNA
    RNA
    small molecule
    protein
  • 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
  • cell & other
    REGULATION
    Other up-regulated during retinoic acid-induced differenciation of neuroblastoma cells reducing the transcrptional and cell cycle promoting functions of ID2
    ASSOCIATED DISORDERS
    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
    Susceptibility
    Variant & Polymorphism
    Candidate gene
    Marker
    Therapy target
    ANIMAL & CELL MODELS
  • up-regulation of Fhl2 may contribute to the antihypertrophic phenotype that is observed in cardiac-specific Rock2-deficient mice