EFEMP1 (EGF containing fibulin-like extracellular matrix protein 1)

2012-09-01   Yi-Hong Zhou 

The University of California, Irvine, USA

Identity

HGNC
LOCATION
2p16.1
LOCUSID
ALIAS
DHRD,DRAD,FBLN3,FBNL,FIBL-3,MLVT,MTLV,S1-5
FUSION GENES

DNA/RNA

Atlas Image
Figure 1. A. Three transcripts were reported in Genebank for variant 1 (NM_004105), variant 2 (NM_001039348), and variant 3 (NM_001039349). NM_004105 has been permanently suppressed because currently there is insufficient support for the transcript. Variant 3 originates from alternative splicing of exon 2 in variant 2. B. Primers used to detect methylation of EFEMP1 promoter in cancer. C. EFEMP1 proximal promoter and sequence upstream of translation start site. Three SP1-binding sites and an estrogen response element (ERE) binding site are underscored, CG residues are marked in green, exons in uppercase, and MSP/BGS primer locations in boldface with sequences shown in B.

Transcription

The EFEMP1 coding region extends over a genomic interval of 56485 bp and comprises 10 exons. EFEMP1 proximal promoter lacks TATA or CAAT regulatory boxes and is rich with CG residues. EFEMP1 expression is repressed by promoter methylation in several cancer types and cancer cell lines. Primers used to detect EFEMP1 promoter methylation are show in figures 1B and 1C.

Proteins

Note

The two transcription variants encode the same EFEMP1 protein of 493-amino acids with a molecular mass of ~ 55 kDa. Consecutive exons from 4 to 9 encode tandem arrays of epidermal growth-factor (EGF)-like domains. There is no EFEMP1 ortholog in non-mammalian species, indicating its recent evolution in higher vertebrates with intragenic exon duplications. There are 92-94% similarity at protein level among EFEMP1 of human, rat and mouse.
Atlas Image
Figure 2. Domain structures of EFEMP1 and modular gene structure for EGF-like domains based on variant 2. DSL, Delta-Serrate-Lag (DSL) motif is a motif unique to Delta/Serrate/LAG-2 proteins in addition to repeated copies of EGF motif (Lissemore and Starmer, 1999).

Description

EFEMP1 belongs to seven-member family of secreted glycoproteins characterized by a N-terminal signal peptide, a tandem repeat of EGF-like domains and a unique C-terminal fibulin-type module.

Expression

EFEMP1 is broadly expressed throughout the body during development and in adult tissues. It is highly expressed by epithelial and endothelial cells.

Localisation

Extracellular matrix.

Function

EFEMP1 is one member of fibulins that serve to modulate cellular behavior and functions by connecting and integrating multiple partner molecules in extracellular compartment. EFEMP1 is likely to contribute the integrity of basement membrane zones and anchor other extracellular matrix structures such as elastic fibers to basement membranes. Studies based on Efemp1 knock-out mouse implicate EFEMP1 function in withholding tissue integrity by stimulating the expression of Timp1 and Timp3 and inhibiting the expression and activities of matrix metalloproteinase Mmp2, and Mmp9 (Rahn et al., 2009). EFEMP1 interacts with TIMP3 (Klenotic et al., 2004) and hepatitis B virus X antigen (Sun et al., 1998). EFEMP1 suppresses endothelial cell spouting and antagonizes angiogenesis in vivo (Albig et al., 2006). EFEMP1 interacts with EGFR (Camaj et al., 2009). However, opposing effects from EFEMP1 on EGFR-AKT signaling activity were reported in different cancer cells, to promote (Camaj et al., 2009) or suppress (Hu et al., 2011; Hwang et al., 2010; Kim et al., 2012) cancer cell migration/invasion and/or in vivo tumor growth. A Delta-Serrate-Lag motif in EGF-like module with insertion has been revealed to be responsible for EFEMP1-mediated activation of Notch signaling in glioma cells (Hu et al., 2012).

Homology

EFEMP1 shares homology with the other members of fibulin family on (EGF)-like domains and fibulin-type module.

Mutations

Germinal

A single mutation of EFEMP1 gene at R345W was identified in patients with Malattia Leventinese (ML) and Doyne honeycombe retinal dystrophy (DHRD) (Stone et al., 1999). Severe atropy of the retina was observed in patients with this mutation, including absence of photoreceptor and RPE cells, and large fibrous scars in the macular region. This mutation was reported to cause protein misfolding, so that it is secreted inefficiently and retained within cells (Marmorstein et al., 2002). Comparison of pathological features of Efemp1 knockout and R345W knock-in mice suggests R345W mutation in causing macular degeneration is not due to loss of EFEMP1, so it is likely that the mutation has an added detrimental effect that alters Bruchs membrane to a greater extent than other structures (Fu et al., 2007; McLaughlin et al., 2007).

Implicated in

Entity name
Brain cancer
Note
EFEMP1 was found to be highly expressed in malignant gliomas and in glioma cells with activation of Notch signaling (Hu et al., 2012; Hu et al., 2009). However, EFEMP1 expression is positively associated with survival of patients with the highest grade of glioma - glioblastoma multiforme (GBM) and consistently, EFEMP1 was shown to suppress highly proliferative GBM cell growth in vivo by attenuation of EGFR-AKT signaling activities and VEGFA-induced angiogenesis (Hu et al., 2011). Along with activation of Notch pathway, EFEMP1 was shown to enhance migration/invasion and growth in vivo by glioma cells high in Notch signaling and stem-like feature (Hu et al., 2012). The contradictory roles of EFEMP1 to the growth of different glioma cells suggest EFEMP1 context-dependent function, thus could be an interesting gene to study glioma initiation, progression and tumor heterogeneity.
Entity name
Breast cancer
Note
Hypermethylation of EFEMP1 promoter was found to be the major cause of EFEMP1 expression down-regulation in 50-60% sporadic breast cancer (SBC). Tumor suppressive function of EFEMP1 is implicated in SBC by a favorable prognosis effect of EFEMP1 expression to survival, particularly node-positive patients who received adjuvant anthracycline-based chemotherapy, but not in those treated by either cyclophosphamide-methotrexate-5-fluorouracil (CMF) or tamoxifen (Sadr-Nabavi et al., 2009).
Entity name
Cervical cancer
Note
EFEMP1 protein expression was found to be significantly higher in cervical carcinoma with lymph node metastasis and correlates with poor patient survival (En-lin et al., 2010). Tumor-promoting effect of EFEMP1 in cervical cancer is supported by its function in promoting growth in vivo and in vitro invasion by cervical cancer cell line Hela (Song et al., 2011).
Entity name
Colorectal cancer
Note
Hypermethylation of EFEMP1 promoter was reported in 38,8% colorectal cancer (CRC), which is correlated with downregulation of EFEMP1 expression and cancer progression to advanced pathological stage with lymph node metastasis. Tumor suppressive function of EFEMP1 is implicated in CRC by a favorable prognosis effect of EFEMP1 expression to overall survival and disease-free survival (Tong et al., 2011).
Entity name
Liver cancer
Note
Hypermethylation of EFEMP1 promoter was reported in 50% hepatocellular carcinoma (HCC), which is correlated with downregulation of EFEMP1 expression. Tumor suppressive function of EFEMP1 is implicated in liver cancer by unfavorable prognosis from promoter methylation of EFEMP1 (Nomoto et al., 2010).
Entity name
Lung cancer
Note
Hypermethylation of EFEMP1 promoter was independently reported by two laboratories in 36% and 43% of non-small cell lung carcinoma (NSCLC), while it was rarely found in the matched normal samples (Wang et al., 2010; Yue et al., 2007; Zhang et al., 2011). It is correlated with downregulation of EFEMP1 expression and cancer progression to advanced pathological stage and lymph node metastasis. Tumor suppressive function of EFEMP1 in lung cancer cell is demonstrated by its suppression effect on anchorage independent growth and in vitro invasion via suppression the expression of matrix metalloproteinase, including MMP2, MMP7, and MMP9 (Kim et al., 2012).
Entity name
Nasopharyngeal carcinoma
Note
Hypermethylation of EFEMP1 promoter has been revealed in nasopharyngeal carcinoma (NPC) tumours compared with normal tissues. Downregulation of EFEMP1 expression was found in NPC at advanced lymph node-metastasis stages and a poor 5-year survival rate. Tumor suppressive function of EFEMP1 in NPC is revealed by suppressing migration and invasion of NPC-derived cells and correspondingly decreasing the AKT phosphorylation (Hwang et al., 2010).
Entity name
Pancreatic cancer
Note
EFEMP1 was reported to bind EGFR and activate MAPK and AKT pathways in pancreatic carcinoma cells and promote in vivo tumor growth with a stimulation of VEGFA production by tumors (Camaj et al., 2009; Seeliger et al., 2009).
Entity name
Prostate cancer
Note
Hypermethylation of EFEMP1 promoter was reported in 95,3% of prostate cancer (PCa) but 13,4% of benign prostate hyperplasia (BPH), and EFEMP1 expression was significantly higher in tissue samples from patients with BPH than in those with PCa (Kim et al., 2011).
Entity name
Werner syndrome
Note
S1-5 mRNA is overexpressed in Werner syndrome and senescent human diploid fibroblasts (Lecka-Czernik et al., 1995).
Entity name
Adult height
Note
The EFEMP1 locus is one of 20 loci identified in a genome-wide association analysis that influence adult height (Okada et al., 2010).

Bibliography

Pubmed IDLast YearTitleAuthors
165105812006Fibulins 3 and 5 antagonize tumor angiogenesis in vivo.Albig AR et al
198043592009EFEMP1 binds the EGF receptor and activates MAPK and Akt pathways in pancreatic carcinoma cells.Camaj P et al
203781572010The expression of EFEMP1 in cervical carcinoma and its relationship with prognosis.En-lin S et al
176664042007The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice.Fu L et al
226652682012Fibulin-3 promotes glioma growth and resistance through a novel paracrine regulation of Notch signaling.Hu B et al
198875592009Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion.Hu B et al
219556182011EFEMP1 suppresses malignant glioma growth and exerts its action within the tumor extracellular compartment.Hu Y et al
209277792010Fibulin-3 is associated with tumour progression and a poor prognosis in nasopharyngeal carcinomas and inhibits cell migration and invasion via suppressed AKT activity.Hwang CF et al
219012482012Fibulin-3 promoter methylation alters the invasive behavior of non-small cell lung cancer cell lines via MMP-7 and MMP-2 regulation.Kim EJ et al
215718672011EFEMP1 as a novel DNA methylation marker for prostate cancer: array-based DNA methylation and expression profiling.Kim YJ et al
151237172004Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1). Implications for macular degenerations.Klenotic PA et al
77999181995An overexpressed gene transcript in senescent and quiescent human fibroblasts encoding a novel protein in the epidermal growth factor-like repeat family stimulates DNA synthesis.Lecka-Czernik B et al
101910751999Phylogenetic analysis of vertebrate and invertebrate Delta/Serrate/LAG-2 (DSL) proteins.Lissemore JL et al
122423462002Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration.Marmorstein LY et al
178729052007Lack of fibulin-3 causes early aging and herniation, but not macular degeneration in mice.McLaughlin PJ et al
198989002010Epidermal growth factor-containing fibulin-like extracellular matrix protein 1, EFEMP1, a novel tumor-suppressor gene detected in hepatocellular carcinoma using double combination array analysis.Nomoto S et al
201899362010A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci.Okada Y et al
190959642009Failure of pelvic organ support in mice deficient in fibulin-3.Rahn DD et al
191152042009Decreased expression of angiogenesis antagonist EFEMP1 in sporadic breast cancer is caused by aberrant promoter methylation and points to an impact of EFEMP1 as molecular biomarker.Sadr-Nabavi A et al
192087482009EFEMP1 expression promotes in vivo tumor growth in human pancreatic adenocarcinoma.Seeliger H et al
211635142011EFEMP1 expression promotes angiogenesis and accelerates the growth of cervical cancer in vivo.Song EL et al
103692671999A single EFEMP1 mutation associated with both Malattia Leventinese and Doyne honeycomb retinal dystrophy.Stone EM et al
94259421998Identification of a protein isolated from senescent human cells that binds to hepatitis B virus X antigen.Sun BS et al
217449992011Downregulation of fibulin-3 gene by promoter methylation in colorectal cancer predicts adverse prognosis.Tong JD et al
199133262010Aberrant promoter methylation of FBLN-3 gene and clinicopathological significance in non-small cell lung carcinoma.Wang R et al
176711142007Frequent inactivation of RAMP2, EFEMP1 and Dutt1 in lung cancer by promoter hypermethylation.Yue W et al
212559132011Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer.Zhang Y et al

Other Information

Locus ID:

NCBI: 2202
MIM: 601548
HGNC: 3218
Ensembl: ENSG00000115380

Variants:

dbSNP: 2202
ClinVar: 2202
TCGA: ENSG00000115380
COSMIC: EFEMP1

RNA/Proteins

Gene IDTranscript IDUniprot
ENSG00000115380ENST00000355426Q12805
ENSG00000115380ENST00000355426A0A0S2Z4F1
ENSG00000115380ENST00000394555Q12805
ENSG00000115380ENST00000394555A0A0S2Z4F1
ENSG00000115380ENST00000421664C9J8S9
ENSG00000115380ENST00000424207C9J4H7
ENSG00000115380ENST00000429909C9JQX7
ENSG00000115380ENST00000438672Q580Q6
ENSG00000115380ENST00000439193C9JPZ9
ENSG00000115380ENST00000440439C9J4J8
ENSG00000115380ENST00000452337C9JUM4
ENSG00000115380ENST00000634374A0A0U1RQV3
ENSG00000115380ENST00000635671A0A0U1RRL0

Expression (GTEx)

0
500
1000
1500

Pathways

PathwaySourceExternal ID
Extracellular matrix organizationREACTOMER-HSA-1474244
Elastic fibre formationREACTOMER-HSA-1566948
Molecules associated with elastic fibresREACTOMER-HSA-2129379

Protein levels (Protein atlas)

Not detected
Low
Medium
High

References

Pubmed IDYearTitleCitations
183919522008Genome-wide association analysis identifies 20 loci that influence adult height.322
122423462002Aberrant accumulation of EFEMP1 underlies drusen formation in Malattia Leventinese and age-related macular degeneration.74
203796142010Personalized smoking cessation: interactions between nicotine dose, dependence and quit-success genotype score.62
198875592009Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion.55
198875592009Fibulin-3 is uniquely upregulated in malignant gliomas and promotes tumor cell motility and invasion.55
151237172004Tissue inhibitor of metalloproteinases-3 (TIMP-3) is a binding partner of epithelial growth factor-containing fibulin-like extracellular matrix protein 1 (EFEMP1). Implications for macular degenerations.51
176664042007The R345W mutation in EFEMP1 is pathogenic and causes AMD-like deposits in mice.48
192660772009Genetic determinants of height growth assessed longitudinally from infancy to adulthood in the northern Finland birth cohort 1966.48
201899362010A genome-wide association study in 19 633 Japanese subjects identified LHX3-QSOX2 and IGF1 as adult height loci.47
192087482009EFEMP1 expression promotes in vivo tumor growth in human pancreatic adenocarcinoma.42

Citation

Yi-Hong Zhou

EFEMP1 (EGF containing fibulin-like extracellular matrix protein 1)

Atlas Genet Cytogenet Oncol Haematol. 2012-09-01

Online version: http://atlasgeneticsoncology.org/gene/49818/efemp1