Atlas of Genetics and Cytogenetics in Oncology and Haematology EFEMP 1 ( EGF containing fibulin-like extracellular matrix protein 1 )

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 growthfactor (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. Description


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).
Variant 3 originates from alternative splicing of exon 2 in variant 2. 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 fibulintype module.
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 Bruch's membrane to a greater extent than other structures (Fu et al., 2007;McLaughlin et al., 2007).

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.

Note
Hypermethylation of EFEMP1 promoter was found to be the major cause of EFEMP1 expression downregulation 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).

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).

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).

Figure 2 .Figure 3 .
Figure 2. Primers used to detect methylation of EFEMP1 promoter in cancer.

Figure 4 .
Figure 4. 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).