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

	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.

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.
	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.

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