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FHL2 (four and a half LIM domains 2)

Written2009-05Marie Lin, William Cheung
Department of Chemistry, The University of Hong Kong, Hong Kong, PR. China

(Note : for Links provided by Atlas : click)

Identity

Alias_symbol (synonym)SLIM3
DRAL
Other aliasAAG11
FHL-2
HGNC (Hugo) FHL2
LocusID (NCBI) 2274
Atlas_Id 44092
Location 2q12.1  [Link to chromosome band 2q12]
Location_base_pair Starts at 105360826 and ends at 105399118 bp from pter ( according to hg19-Feb_2009)  [Mapping FHL2.png]
Local_order 91kb telomeric to transforming growth factor, beta receptor associated protein 1 (TGFBRAP1).
Fusion genes
(updated 2017)
Data from Atlas, Mitelman, Cosmic Fusion, Fusion Cancer, TCGA fusion databases with official HUGO symbols (see references in chromosomal bands)
FHL2 (2q12.1) / RPL31 (2q11.2)FHL2 (2q12.1) / TNKS1BP1 (11q12.1)

DNA/RNA

 
  Chromosomal location of FHL2 gene (upper panel) and genomic organization of four FHL2 transcript variants.
Description Human FHL2 gene spans around 80kb of genomic DNA on the chromosome 2q12-q14 in telomere-to-centromere orientation. FHL2 promoter contains putative transcription factor binding sites for SRF (serum response factor), NKX2-5, MEF-2, E2F and AP-1 (activator protein-1).
Transcription Four transcript variants of FHL2 genes have been reported in Entrez Gene (NCBI). These alternative spliced transcripts are 1.55-1.91 kb in length, and differ in the 5'-UTR only.
Pseudogene No pseudogenes for FHL2 are known.

Protein

Description The open reading frame encodes a 279 amino acid protein with an estimated molecular weight of 32.2kDa. FHL2 protein constitutes four and a half N-terminal LIM domains. The four complete LIM domains extend from amino acid 40-92, 100-153, 162-217 and 220-275.
Expression In human tissues, FHL2 expression is the most abundant in adult heart and ovary, and of low level in brain, lung, liver, kidney and intestine. FHL2 is initially identified as a downregulated gene in human rhabdomyosarcoma cells. However, elevated FHL2 expression is detected in other cancers, including hepatocellular carcinoma, glioblastoma, breast, prostate, ovarian, and gastrointestinal cancers.
Localisation Cytoplasm and nucleus.
Function At tissue level, FHL2 plays important roles in the development of cardiac circulatory system and placenta. It also induces osteoblast and myoblast differentiation. At cellular level, FHL2 participates in various processes, including cell survival, adhesion, motility, transcription and signal transduction. At molecular level, the LIM domains of FHL2 are double zinc finger motifs that physically interact with partner proteins to modulate RNA splicing, DNA replication and repair. It also functions as a transcriptional co-activator for androgen receptor, AP-1, CREB (cAMP response element binding protein), CREM (cAMP response element modulator), BRCA1 (breast cancer 1), WT-1 (wilms' tumor), and NF-kB (nuclear factor-kB). Moreover, FHL2 is a transcriptional co-suppressor for ERK2 (extracellular signal regulated kinase 2), SRF and FOXO1 (forkhead box O1).
Homology FHL2 belongs to the four-and-a-half-LIM-only protein family, which includes FHL1, FHL2, FHL3, FHL4 and FHL5 (ACT). Human FHL2 amino acid sequence is 48.2% identical with FHL1, 53.4% with FHL3, 48.4% with mouse FHL4, and 59.1% with FHL5. Orthologs of human FHL2 are found in macaque, mouse, rat, bovine, dog, chicken, frog, zebrafish, amphioxis, drosophila and C. elegans.

Mutations

Somatic G142A missense mutation, corresponding to Gly48Ser within the first LIM domain, is identified in heterozygous state in a 49-years-old female dilated cardiomyopathy (DCM) patient. This mutation abrogates the binding of FHL2 with titin/connectin, and in turn impairs the abnormal recruitment of metabolic enzymes to cardiac sarcomere (Arimura et al., 2007).

Implicated in

Note
  
Entity Rhabdomyosarcoma
Note FHL2 expression is downregulated in rhabdomyosarcoma cells relative to normal myoblasts (Genini et al., 1997).
  
  
Entity Hepatocellular carcinoma
Note In 8 of 10 human liver tumors samples, FHL2 mRNA expression is higher than that in matched nontumor livers (Wei et al., 2003). In contrast, it is recently reported that FHL2 protein is downregulated in liver tumors, as compared with matched nontumor liver tissues. In addition, FHL2 inhibits hepatoma cell growth in vitro and in nude mice (Ding et al., 2009).
  
  
Entity Ovarian cancer
Note FHL2 protein expression is upregulated in epithelial ovarian cancer, as compared with matched normal tissues (Gabriel et al., 2004).
  
  
Entity Breast cancer
Note FHL2 is overexpressed in human mammary carcinoma samples, compared with normal breast tissues. FHL2 induces the expression of cell cycle inhibitor p21Cip1/Waf1 in MDA-MB 231 breast cancer cells (Martin et al., 2007).
Prognosis Patients with tumors expressing low amounts of FHL2 were characterized by a significantly better survival compared to those with high intratumoral FHL2 expression (Gabriel et al., 2006).
  
  
Entity Prostate cancer
Note FHL2 expression is downregulated by 2- to 4-fold in primary prostate cancer relatively to normal tissues for five pairs of samples (Kinoshita et al., 2005). Another study reports that FHL2 expression is increased in prostate adenocarcinoma cells when compared with benign epithelial cells. It might be the subcellular localization of FHL2 that governs the progression of prostate cancer (Muller et al., 2002). Androgen-induced FHL2 expression is mediated by SRF (Heemers et al., 2007).
Prognosis Nuclear, but not cytoplasmic expression of FHL2 significantly correlates with the recurrence of prostate cancer (Kahl el al., 2006).
  
  
Entity Gastrointestinal cancer
Note FHL2 expression is upregulated in gastric and colon cancer, compared with matched normal tissues. Suppression of FHL2 induces gastric and colon cell differentiation, and inhibits cell proliferation and expression of oncogenes (survivin, cox-2, hTERT and c-jun) in vitro. Antisense FHL2 also inhibits tumorigenesis of colon cancer cells in xenograft nude mice model (Wang et al., 2007).
  
  
Entity Glioma
Note The mRNA level of FHL2 is elevated in both low (3 of 6) and high (11 of 13) grade glioma patient samples. FHL2 induces glioblastoma cell proliferation and migration in vitro, and promotes tumorigenesis in glioblastoma xenograft nude mice model. Overexpression of FHL2 decreases mRNA levels of p53 and its downstream proapoptotic genes, and enhances promoter activities of AP-1, human telomerase reverse transcriptase and survivin genes (Li et al., 2008).
  

Bibliography

Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy.
Arimura T, Hayashi T, Matsumoto Y, Shibata H, Hiroi S, Nakamura T, Inagaki N, Hinohara K, Takahashi M, Manatsu SI, Sasaoka T, Izumi T, Bonne G, Schwartz K, Kimura A.
Biochem Biophys Res Commun. 2007 May 25;357(1):162-7. Epub 2007 Mar 30.
PMID 17416352
 
Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart.
Chan KK, Tsui SK, Lee SM, Luk SC, Liew CC, Fung KP, Waye MM, Lee CY.
Gene. 1998 Apr 14;210(2):345-50.
PMID 9573400
 
Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway.
Ding L, Wang Z, Yan J, Yang X, Liu A, Qiu W, Zhu J, Han J, Zhang H, Lin J, Cheng L, Qin X, Niu C, Yuan B, Wang X, Zhu C, Zhou Y, Li J, Song H, Huang C, Ye Q.
J Clin Invest. 2009 Feb;119(2):349-61. doi: 10.1172/JCI35930. Epub 2009 Jan 12.
PMID 19139564
 
Expression of the transcriptional coregulator FHL2 in human breast cancer: a clinicopathologic study.
Gabriel B, Fischer DC, Orlowska-Volk M, zur Hausen A, Schule R, Muller JM, Hasenburg A.
J Soc Gynecol Investig. 2006 Jan;13(1):69-75.
PMID 16378916
 
Focal adhesion kinase interacts with the transcriptional coactivator FHL2 and both are overexpressed in epithelial ovarian cancer.
Gabriel B, Mildenberger S, Weisser CW, Metzger E, Gitsch G, Schule R, Muller JM.
Anticancer Res. 2004 Mar-Apr;24(2B):921-7.
PMID 15161045
 
Subtractive cloning and characterization of DRAL, a novel LIM-domain protein down-regulated in rhabdomyosarcoma.
Genini M, Schwalbe P, Scholl FA, Remppis A, Mattei MG, Schafer BW.
DNA Cell Biol. 1997 Apr;16(4):433-42.
PMID 9150430
 
Androgen induction of the androgen receptor coactivator four and a half LIM domain protein-2: evidence for a role for serum response factor in prostate cancer.
Heemers HV, Regan KM, Dehm SM, Tindall DJ.
Cancer Res. 2007 Nov 1;67(21):10592-9.
PMID 17975004
 
The multifunctional roles of the four-and-a-half-LIM only protein FHL2.
Johannessen M, Moller S, Hansen T, Moens U, Van Ghelue M.
Cell Mol Life Sci. 2006 Feb;63(3):268-84. (REVIEW)
PMID 16389449
 
Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence.
Kahl P, Gullotti L, Heukamp LC, Wolf S, Friedrichs N, Vorreuther R, Solleder G, Bastian PJ, Ellinger J, Metzger E, Schule R, Buettner R.
Cancer Res. 2006 Dec 1;66(23):11341-7.
PMID 17145880
 
Differently regulated androgen receptor transcriptional complex in prostate cancer compared with normal prostate.
Kinoshita M, Nakagawa T, Shimizu A, Katsuoka Y.
Int J Urol. 2005 Apr;12(4):390-7.
PMID 15948728
 
The biological relevance of FHL2 in tumour cells and its role as a putative cancer target.
Kleiber K, Strebhardt K, Martin BT.
Anticancer Res. 2007 Jan-Feb;27(1A):55-61. (REVIEW)
PMID 17352216
 
The four-and-a-half-LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities.
Li M, Wang J, Ng SS, Chan CY, Chen AC, Xia HP, Yew DT, Wong BC, Chen Z, Kung HF, Lin MC.
Glia. 2008 Sep;56(12):1328-38.
PMID 18615633
 
FHL2 regulates cell cycle-dependent and doxorubicin-induced p21Cip1/Waf1 expression in breast cancer cells.
Martin BT, Kleiber K, Wixler V, Raab M, Zimmer B, Kaufmann M, Strebhardt K.
Cell Cycle. 2007 Jul 15;6(14):1779-88.
PMID 17682292
 
The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus.
Muller JM, Metzger E, Greschik H, Bosserhoff AK, Mercep L, Buettner R, Schule R.
EMBO J. 2002 Feb 15;21(4):736-48.
PMID 11847121
 
Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis.
Wang J, Yang Y, Xia HH, Gu Q, Lin MC, Jiang B, Peng Y, Li G, An X, Zhang Y, Zhuang Z, Zhang Z, Kung HF, Wong BC.
Gastroenterology. 2007 Mar;132(3):1066-76. Epub 2006 Dec 3.
PMID 17383428
 
Identification of the LIM protein FHL2 as a coactivator of beta-catenin.
Wei Y, Renard CA, Labalette C, Wu Y, Levy L, Neuveut C, Prieur X, Flajolet M, Prigent S, Buendia MA.
J Biol Chem. 2003 Feb 14;278(7):5188-94. Epub 2002 Dec 3.
PMID 12466281
 

Citation

This paper should be referenced as such :
Lin, M ; Cheung, W
FHL2 (four, a half LIM domains 2)
Atlas Genet Cytogenet Oncol Haematol. 2010;14(4):383-385.
Free journal version : [ pdf ]   [ DOI ]
On line version : http://AtlasGeneticsOncology.org/Genes/FHL2ID44092ch2q12.html


Other Leukemias implicated (Data extracted from papers in the Atlas) [ 1 ]
  t(11;11)(q14;q23) KMT2A/PICALM::inv(11)(q14q23) KMT2A/PICALM


External links

Nomenclature
HGNC (Hugo)FHL2   3703
LRG (Locus Reference Genomic)LRG_740
Cards
AtlasFHL2ID44092ch2q12
Entrez_Gene (NCBI)FHL2  2274  four and a half LIM domains 2
AliasesAAG11; DRAL; FHL-2; SLIM-3; 
SLIM3
GeneCards (Weizmann)FHL2
Ensembl hg19 (Hinxton)ENSG00000115641 [Gene_View]
Ensembl hg38 (Hinxton)ENSG00000115641 [Gene_View]  chr2:105360826-105399118 [Contig_View]  FHL2 [Vega]
ICGC DataPortalENSG00000115641
TCGA cBioPortalFHL2
AceView (NCBI)FHL2
Genatlas (Paris)FHL2
WikiGenes2274
SOURCE (Princeton)FHL2
Genetics Home Reference (NIH)FHL2
Genomic and cartography
GoldenPath hg38 (UCSC)FHL2  -     chr2:105360826-105399118 -  2q12.2   [Description]    (hg38-Dec_2013)
GoldenPath hg19 (UCSC)FHL2  -     2q12.2   [Description]    (hg19-Feb_2009)
EnsemblFHL2 - 2q12.2 [CytoView hg19]  FHL2 - 2q12.2 [CytoView hg38]
Mapping of homologs : NCBIFHL2 [Mapview hg19]  FHL2 [Mapview hg38]
OMIM602633   
Gene and transcription
Genbank (Entrez)###############################################################################################################################################################################################################################################################
RefSeq transcript (Entrez)NM_001039492 NM_001318894 NM_001318895 NM_001318896 NM_001318897 NM_001318898 NM_001318899 NM_001450 NM_201555 NM_201556 NM_201557
RefSeq genomic (Entrez)
Consensus coding sequences : CCDS (NCBI)FHL2
Cluster EST : UnigeneHs.443687 [ NCBI ]
CGAP (NCI)Hs.443687
Alternative Splicing GalleryENSG00000115641
Gene ExpressionFHL2 [ NCBI-GEO ]   FHL2 [ EBI - ARRAY_EXPRESS ]   FHL2 [ SEEK ]   FHL2 [ MEM ]
Gene Expression Viewer (FireBrowse)FHL2 [ Firebrowse - Broad ]
SOURCE (Princeton)Expression in : [Datasets]   [Normal Tissue Atlas]  [carcinoma Classsification]  [NCI60]
GenevestigatorExpression in : [tissues]  [cell-lines]  [cancer]  [perturbations]  
BioGPS (Tissue expression)2274
GTEX Portal (Tissue expression)FHL2
Human Protein AtlasENSG00000115641-FHL2 [pathology]   [cell]   [tissue]
Protein : pattern, domain, 3D structure
UniProt/SwissProtQ14192   [function]  [subcellular_location]  [family_and_domains]  [pathology_and_biotech]  [ptm_processing]  [expression]  [interaction]
NextProtQ14192  [Sequence]  [Exons]  [Medical]  [Publications]
With graphics : InterProQ14192
Splice isoforms : SwissVarQ14192
PhosPhoSitePlusQ14192
Domaine pattern : Prosite (Expaxy)LIM_DOMAIN_1 (PS00478)    LIM_DOMAIN_2 (PS50023)   
Domains : Interpro (EBI)Znf_LIM   
Domain families : Pfam (Sanger)LIM (PF00412)   
Domain families : Pfam (NCBI)pfam00412   
Domain families : Smart (EMBL)LIM (SM00132)  
Conserved Domain (NCBI)FHL2
DMDM Disease mutations2274
Blocks (Seattle)FHL2
PDB (SRS)1X4K    1X4L    2D8Z    2MIU   
PDB (PDBSum)1X4K    1X4L    2D8Z    2MIU   
PDB (IMB)1X4K    1X4L    2D8Z    2MIU   
PDB (RSDB)1X4K    1X4L    2D8Z    2MIU   
Structural Biology KnowledgeBase1X4K    1X4L    2D8Z    2MIU   
SCOP (Structural Classification of Proteins)1X4K    1X4L    2D8Z    2MIU   
CATH (Classification of proteins structures)1X4K    1X4L    2D8Z    2MIU   
SuperfamilyQ14192
Human Protein Atlas [tissue]ENSG00000115641-FHL2 [tissue]
Peptide AtlasQ14192
HPRD04026
IPIIPI00743342   IPI00398431   IPI00396967   IPI00916700   IPI00985309   
Protein Interaction databases
DIP (DOE-UCLA)Q14192
IntAct (EBI)Q14192
FunCoupENSG00000115641
BioGRIDFHL2
STRING (EMBL)FHL2
ZODIACFHL2
Ontologies - Pathways
QuickGOQ14192
Ontology : AmiGOnegative regulation of transcription from RNA polymerase II promoter  osteoblast differentiation  transcription coactivator activity  protein binding  nucleus  nucleoplasm  focal adhesion  transcription, DNA-templated  transcription factor binding  zinc ion binding  response to hormone  Z disc  androgen receptor signaling pathway  M band  identical protein binding  negative regulation of apoptotic process  positive regulation of transcription, DNA-templated  androgen receptor binding  atrial cardiac muscle cell development  ventricular cardiac muscle cell development  heart trabecula formation  
Ontology : EGO-EBInegative regulation of transcription from RNA polymerase II promoter  osteoblast differentiation  transcription coactivator activity  protein binding  nucleus  nucleoplasm  focal adhesion  transcription, DNA-templated  transcription factor binding  zinc ion binding  response to hormone  Z disc  androgen receptor signaling pathway  M band  identical protein binding  negative regulation of apoptotic process  positive regulation of transcription, DNA-templated  androgen receptor binding  atrial cardiac muscle cell development  ventricular cardiac muscle cell development  heart trabecula formation  
Pathways : BIOCARTAHypoxia and p53 in the Cardiovascular system [Genes]   
Pathways : KEGGOsteoclast differentiation   
REACTOMEQ14192 [protein]
REACTOME PathwaysR-HSA-1989781 [pathway]   
NDEx NetworkFHL2
Atlas of Cancer Signalling NetworkFHL2
Wikipedia pathwaysFHL2
Orthology - Evolution
OrthoDB2274
GeneTree (enSembl)ENSG00000115641
Phylogenetic Trees/Animal Genes : TreeFamFHL2
HOVERGENQ14192
HOGENOMQ14192
Homologs : HomoloGeneFHL2
Homology/Alignments : Family Browser (UCSC)FHL2
Gene fusions - Rearrangements
Tumor Fusion PortalFHL2
Polymorphisms : SNP and Copy number variants
NCBI Variation ViewerFHL2 [hg38]
dbSNP Single Nucleotide Polymorphism (NCBI)FHL2
dbVarFHL2
ClinVarFHL2
1000_GenomesFHL2 
Exome Variant ServerFHL2
ExAC (Exome Aggregation Consortium)ENSG00000115641
GNOMAD BrowserENSG00000115641
Genetic variants : HAPMAP2274
Genomic Variants (DGV)FHL2 [DGVbeta]
DECIPHERFHL2 [patients]   [syndromes]   [variants]   [genes]  
CONAN: Copy Number AnalysisFHL2 
Mutations
ICGC Data PortalFHL2 
TCGA Data PortalFHL2 
Broad Tumor PortalFHL2
OASIS PortalFHL2 [ Somatic mutations - Copy number]
Somatic Mutations in Cancer : COSMICFHL2  [overview]  [genome browser]  [tissue]  [distribution]  
Mutations and Diseases : HGMDFHL2
LOVD (Leiden Open Variation Database)Whole genome datasets
LOVD (Leiden Open Variation Database)LOVD - Leiden Open Variation Database
LOVD (Leiden Open Variation Database)LOVD 3.0 shared installation
BioMutasearch FHL2
DgiDB (Drug Gene Interaction Database)FHL2
DoCM (Curated mutations)FHL2 (select the gene name)
CIViC (Clinical Interpretations of Variants in Cancer)FHL2 (select a term)
intoGenFHL2
NCG5 (London)FHL2
Cancer3DFHL2(select the gene name)
Impact of mutations[PolyPhen2] [SIFT Human Coding SNP] [Buck Institute : MutDB] [Mutation Assessor] [Mutanalyser]
Diseases
OMIM602633   
Orphanet635   
DisGeNETFHL2
MedgenFHL2
Genetic Testing Registry FHL2
NextProtQ14192 [Medical]
TSGene2274
GENETestsFHL2
Target ValidationFHL2
Huge Navigator FHL2 [HugePedia]
snp3D : Map Gene to Disease2274
BioCentury BCIQFHL2
ClinGenFHL2
Clinical trials, drugs, therapy
Chemical/Protein Interactions : CTD2274
Chemical/Pharm GKB GenePA164
Clinical trialFHL2
Miscellaneous
canSAR (ICR)FHL2 (select the gene name)
Probes
Litterature
PubMed138 Pubmed reference(s) in Entrez
GeneRIFsGene References Into Functions (Entrez)
CoreMineFHL2
EVEXFHL2
GoPubMedFHL2
iHOPFHL2
REVIEW articlesautomatic search in PubMed
Last year publicationsautomatic search in PubMed

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indexed on : Tue Nov 21 14:50:40 CET 2017

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