FHL2 (four and a half LIM domains 2)

2009-05-01   Marie Lin , William Cheung 

Department of Chemistry, The University of Hong Kong, Hong Kong, PR. China

Identity

HGNC
LOCATION
2q12.1
LOCUSID
ALIAS
AAG11,DRAL,FHL-2,SLIM-3,SLIM3
FUSION GENES

DNA/RNA

Atlas Image
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.

Proteins

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

Entity name
Rhabdomyosarcoma
Note
FHL2 expression is downregulated in rhabdomyosarcoma cells relative to normal myoblasts (Genini et al., 1997).
Entity name
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 name
Ovarian cancer
Note
FHL2 protein expression is upregulated in epithelial ovarian cancer, as compared with matched normal tissues (Gabriel et al., 2004).
Entity name
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 name
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 name
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 name
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

Pubmed IDLast YearTitleAuthors
174163522007Structural analysis of four and half LIM protein-2 in dilated cardiomyopathy.Arimura T et al
95734001998Molecular cloning and characterization of FHL2, a novel LIM domain protein preferentially expressed in human heart.Chan KK et al
191395642009Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway.Ding L et al
163789162006Expression of the transcriptional coregulator FHL2 in human breast cancer: a clinicopathologic study.Gabriel B et al
151610452004Focal adhesion kinase interacts with the transcriptional coactivator FHL2 and both are overexpressed in epithelial ovarian cancer.Gabriel B et al
91504301997Subtractive cloning and characterization of DRAL, a novel LIM-domain protein down-regulated in rhabdomyosarcoma.Genini M et al
179750042007Androgen 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 et al
163894492006The multifunctional roles of the four-and-a-half-LIM only protein FHL2.Johannessen M et al
171458802006Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence.Kahl P et al
159487282005Differently regulated androgen receptor transcriptional complex in prostate cancer compared with normal prostate.Kinoshita M et al
173522162007The biological relevance of FHL2 in tumour cells and its role as a putative cancer target.Kleiber K et al
186156332008The four-and-a-half-LIM protein 2 (FHL2) is overexpressed in gliomas and associated with oncogenic activities.Li M et al
176822922007FHL2 regulates cell cycle-dependent and doxorubicin-induced p21Cip1/Waf1 expression in breast cancer cells.Martin BT et al
118471212002The transcriptional coactivator FHL2 transmits Rho signals from the cell membrane into the nucleus.Müller JM et al
173834282007Suppression of FHL2 expression induces cell differentiation and inhibits gastric and colon carcinogenesis.Wang J et al
124662812003Identification of the LIM protein FHL2 as a coactivator of beta-catenin.Wei Y et al

Other Information

Locus ID:

NCBI: 2274
MIM: 602633
HGNC: 3703
Ensembl: ENSG00000115641

Variants:

dbSNP: 2274
ClinVar: 2274
TCGA: ENSG00000115641
COSMIC: FHL2

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000115641ENST00000322142Q14192
ENSG00000115641ENST00000322142Q6I9R8
ENSG00000115641ENST00000344213Q14192
ENSG00000115641ENST00000344213Q6I9R8
ENSG00000115641ENST00000358129Q14192
ENSG00000115641ENST00000393352Q14192
ENSG00000115641ENST00000393352Q6I9R8
ENSG00000115641ENST00000393353Q14192
ENSG00000115641ENST00000393353Q6I9R8
ENSG00000115641ENST00000408995Q14192
ENSG00000115641ENST00000408995Q6I9R8
ENSG00000115641ENST00000409177Q14192
ENSG00000115641ENST00000409177Q6I9R8
ENSG00000115641ENST00000409807Q14192
ENSG00000115641ENST00000409807Q6I9R8
ENSG00000115641ENST00000447958C9J3S8
ENSG00000115641ENST00000452732F8WDA8
ENSG00000115641ENST00000530340Q14192
ENSG00000115641ENST00000530340Q6I9R8
ENSG00000115641ENST00000607522U3KQT4

Expression (GTEx)

0
50
100
150
200
250

Pathways

PathwaySourceExternal ID
Osteoclast differentiationKEGGko04380
Osteoclast differentiationKEGGhsa04380
MetabolismREACTOMER-HSA-1430728
Metabolism of lipids and lipoproteinsREACTOMER-HSA-556833
Fatty acid, triacylglycerol, and ketone body metabolismREACTOMER-HSA-535734
Regulation of lipid metabolism by Peroxisome proliferator-activated receptor alpha (PPARalpha)REACTOMER-HSA-400206
PPARA activates gene expressionREACTOMER-HSA-1989781

Protein levels (Protein atlas)

Not detected
Low
Medium
High

PharmGKB

Entity IDNameTypeEvidenceAssociationPKPDPMIDs
PA449748gemcitabineChemicalMultilinkAnnotationassociated24444404

References

Pubmed IDYearTitleCitations
171458802006Androgen receptor coactivators lysine-specific histone demethylase 1 and four and a half LIM domain protein 2 predict risk of prostate cancer recurrence.150
156925602005Suppression of FOXO1 activity by FHL2 through SIRT1-mediated deacetylation.117
191395642009Human four-and-a-half LIM family members suppress tumor cell growth through a TGF-beta-like signaling pathway.59
124662812003Identification of the LIM protein FHL2 as a coactivator of beta-catenin.47
186537652008FHL2 mediates dexamethasone-induced mesenchymal cell differentiation into osteoblasts by activating Wnt/beta-catenin signaling-dependent Runx2 expression.44
194659232009The Patched dependence receptor triggers apoptosis through a DRAL-caspase-9 complex.43
155726742004Interaction and functional cooperation between the LIM protein FHL2, CBP/p300, and beta-catenin.42
151179622004The LIM-only proteins FHL2 and FHL3 interact with alpha- and beta-subunits of the muscle alpha7beta1 integrin receptor.32
235854792013RNA-binding protein PCBP2 modulates glioma growth by regulating FHL3.32
118214012002Insulin-like growth factor-binding protein 5 (IGFBP-5) interacts with a four and a half LIM protein 2 (FHL2).30

Citation

Marie Lin ; William Cheung

FHL2 (four and a half LIM domains 2)

Atlas Genet Cytogenet Oncol Haematol. 2009-05-01

Online version: http://atlasgeneticsoncology.org/gene/44092/fhl2