| EGFL7 | |||||||||||||||||||||||||||||||||||||||||||||||||||
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| Aliases | EGFL7 , NEU1, VE-STATIN, ZNEU1, EGF like domain multiple 7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 608582 MGI: 2449923 HomoloGene: 9427 GeneCards: EGFL7 | ||||||||||||||||||||||||||||||||||||||||||||||||||
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EGF-like domain-containing protein 7 is a protein that in humans is encoded by the EGFL7 gene. [5] Intron 7 of EGFL7 hosts the miR-126 microRNA gene.
Epidermal Growth Factor like domain 7 (Egfl7) also known as Vascular Endothelial-statin (VE-statin) codes for a gene mostly expressed in endothelial cells. [6] [7] [8] The egfl7 gene is located on chromosomes 9 and 2 in human and mouse, respectively, and is structured in 11 exons and introns, including intron-1a and 1b which are alternatively transcribed from two different promoters. [6] These transcripts vary only in the first exon and code for the same protein which is initiated in the third exon [6] The seventh intron of the egfl7 gene contains a miRNA site for miR-126 and miR-126. [9]
The Egfl7 protein (29 kDa) is composed of several putative domains: a putative cleavable signal peptide at the N-terminal end, an EMI domain, found on extracellular matrix proteins, [10] two EGF-like domains and a leucine and valine rich C-terminal region. The first EGF-like domain has a region similar to the DSL (Delta/Serrate/Lag-2) domain found in ligands of the Notch receptors family, [11] the second EGF-like domain is predicted to bind Ca2+. The Eglf7 protein is secreted and associates with the blood vessel extracellular matrix. [6] [7] [8] [12]
Endothelial cell lines naturally express egfl7, on the contrary to non-endothelial cells. [6] [8] In endothelial cells, expression is controlled by the Erg and GATA2 transcription factors and, indirectly by Fli-1. [13] The expression pattern of the egfl7 gene is conserved across species. [7] Egfl7 is expressed in endothelial progenitors and in endothelial cells during embryonic and neonatal development. Expression is down-regulated in adults but is still detectable in blood vessels of lung, heart and kidney. [6] [7] [8] An up-regulation of egfl7 is observed in endothelial cells during vascular remodelling tissues, such as in reproductive organs during pregnancy, in regenerating endothelium following arterial injury, in atherosclerotic plaques, and in growing tumours. [6] [7] [14] Expression of egfl7 has also been reported in primordial germ cells and in adult ovaries and testes [15] and in neurons. [16]
Expression of egfl7 is endothelial cell-specific in physiological conditions, however it is aberrantly expressed by tumour cells in human cancers. In colorectal cancer, high levels of egfl7 correspond to tumours with higher pathologic stages and to the presence of lymph node metastases. [17] Egfl7 is also over-expressed by tumour cells in human hepatocellular carcinoma and overexpression is significantly higher in tumours with multiple nodules, without capsules and with vein invasion. Levels of egfl7 are thus correlated with markers of metastasis and with poor prognosis. [18] In glioma, egfl7 expression levels correlate with tumour grade. There is a correlation between expression of egfl7, cell proliferation and micro-vessel density. [19]
Silencing (knockdown) of the egfl7 gene in the zebrafish inhibits vascular tubulogenesis and embryos have little or no blood circulation. They show pericardial oedema and haemorrhage. Their main blood vessels have no lumen. [7] Although an initial gene inactivation report showed that mice which did not express egfl7 had various vascular defects, [20] the observed phenotypes were later attributed to the concomitant inactivation of the miR-126 locus. [9] [21] To date, there is no phenotype associated with the loss of egfl7 in mice. Egfl7 knockout mice are phenotypically normal, viable and fertile, they have a normal vascular system. [9] Over-expression of egfl7 specifically in endothelial cells in mice induces embryonic lethality with head haemorrhages, cardiac defects and head and yolk sac vasculature defects. [22] In vitro, Egfl7 inhibits the formation of cord-like structure in embryonic bodies. [23]
In vitro, the Egfl7 protein inhibits human aortic smooth muscle cells migration stimulated by PDGF-BB but has no effects on cell proliferation, suggesting that Egfl7 plays a role in vessel maturation. In contrast, Egfl7 produced in conditioned medium is a chemo-attractant for rat vascular smooth muscle cells, mouse endothelial cells and for primary mouse embryonic fibroblasts in vitro. [14] In vitro, egfl7 knockdown in HUVEC inhibits migration, probably by blocking the Notch pathway, [22] although other groups reported that Egfl7 has no effect on HUVEC migration. [6] [7] [14] [20] Suppression of egfl7 expression inhibits the migration of hepatocellular carcinoma cells through an EGFR/FAK pathway. In vivo, egfl7 knockdown expression in hepatocellular carcinoma cells decreases the number of intra-hepatic and pulmonary metastases. [18] In mice, inhibition of egfl7 in hepatocellular carcinoma cells decrease tumour growth and micro-vessel density. [18] Over-expression of Egfl7 in tumour cells implanted in mice increases tumour growth and metastasis. Within the tumours, Egfl7 increases micro-vessel density, hypoxia, necrosis and vascular permeability. [24]
Egfl7 is a natural negative regulator of vascular elastogenesis. It interacts with and inhibits the catalytic activity of LOX, preventing the crosslink of tropoelastin molecules into mature insoluble elastin. [12]
Egfl7 interacts with the four Notch receptors, with Dll4, but not with jagged1. Moreover, recombinant Egfl7 competes with jagged1 or jagged2 proteins for their interaction with Notch1. Egfl7 knockdown stimulates the Notch pathway and Egfl7 over-expression inhibits the Notch pathway in HUVEC and neural stem cells. [16] [22]
Treatment with Egfl7 inhibits the hypoxia/re-oxygenation-induced ICAM-1 expression, NF-κB nuclear translocation and decrease of IκBα expression in human coronary artery endothelial cells (HCAEC). [25] HCAEC treatment with recombinant egfl7 protein inhibits neutrophils adhesion onto HCAEC and NF-κB DNA-binding activity induced by calcineurin inhibition, a cornerstone of immuno-suppressive therapy after heart transplantation. [26] Egfl7 promotes tumour escape from immunity by repressing leukocyte adhesion molecules of tumor blood vessel endothelial cells. [24] Endothelial cells from mice tumours over-expressing Egfl7 express much less ICAM-1, VCAM-1 and E-selectin than control tumours. Consequently, tumours over-expressing Egfl7 are much less infiltrated by immune cells. In vitro, egfl7 knockdown in HUVEC promotes expression of ICAM-1, VCAM-1 and E-selectin, and enhances the adhesion of Jurkat cells on these cells.
The Notch signaling pathway is a highly conserved cell signaling system present in most animals. Mammals possess four different notch receptors, referred to as NOTCH1, NOTCH2, NOTCH3, and NOTCH4. The notch receptor is a single-pass transmembrane receptor protein. It is a hetero-oligomer composed of a large extracellular portion, which associates in a calcium-dependent, non-covalent interaction with a smaller piece of the notch protein composed of a short extracellular region, a single transmembrane-pass, and a small intracellular region.
The epidermal growth factor receptor is a transmembrane protein that is a receptor for members of the epidermal growth factor family of extracellular protein ligands.
E-selectin, also known as CD62 antigen-like family member E (CD62E), endothelial-leukocyte adhesion molecule 1 (ELAM-1), or leukocyte-endothelial cell adhesion molecule 2 (LECAM2), is a selectin cell adhesion molecule expressed only on endothelial cells activated by cytokines. Like other selectins, it plays an important part in inflammation. In humans, E-selectin is encoded by the SELE gene.
Receptor tyrosine kinases (RTKs) are the high-affinity cell surface receptors for many polypeptide growth factors, cytokines, and hormones. Of the 90 unique tyrosine kinase genes identified in the human genome, 58 encode receptor tyrosine kinase proteins. Receptor tyrosine kinases have been shown not only to be key regulators of normal cellular processes but also to have a critical role in the development and progression of many types of cancer. Mutations in receptor tyrosine kinases lead to activation of a series of signalling cascades which have numerous effects on protein expression. Receptor tyrosine kinases are part of the larger family of protein tyrosine kinases, encompassing the receptor tyrosine kinase proteins which contain a transmembrane domain, as well as the non-receptor tyrosine kinases which do not possess transmembrane domains.
Neuropilin is a protein receptor active in neurons.
Heparin-binding EGF-like growth factor (HB-EGF) is a member of the EGF family of proteins that in humans is encoded by the HBEGF gene.
Epiregulin (EPR) is a protein that in humans is encoded by the EREG gene.
Betacellulin is a protein that in humans is encoded by the BTC gene located on chromosome 4 at locus 4q13-q21. Betacellulin was initially identified as a mitogen. Betacellulin, is a part of an Epidermal Growth Factor (EGF) family and functions as a ligand for the epidermal growth factor receptor (EGFR). As the role a EGFR, betacellulin is manifested by different form of muscles and tissues, it also has a great effect of nitrogen that is used for retinal pigment epithelial cells and vascular smooth muscle cells. While many studies attest a role for betacellulin in the differentiation of pancreatic β-cells, the last decade witnessed the association of betacellulin with many additional biological processes, ranging from reproduction to the control of neural stem cells. Betacellulin is a member of the EGF family of growth factors. It is synthesized primarily as a transmembrane precursor, which is then processed to mature molecule by proteolytic events.
T-cadherin, also known as cadherin 13, H-cadherin (heart), and CDH13, is a unique member of the cadherin superfamily of proteins because it lacks the transmembrane and cytoplasmic domains common to all other cadherins and is instead anchored to the cell's plasma membrane by the GPI anchor.
SHC-transforming protein 1 is a protein that in humans is encoded by the SHC1 gene. SHC has been found to be important in the regulation of apoptosis and drug resistance in mammalian cells.
Cadherin-5, or VE-cadherin, also known as CD144, is a type of cadherin. It is encoded by the human gene CDH5.
Proprotein convertase subtilisin/kexin type 9 (PCSK9) is an enzyme encoded by the PCSK9 gene in humans on chromosome 1. It is the 9th member of the proprotein convertase family of proteins that activate other proteins. Similar genes (orthologs) are found across many species. As with many proteins, PCSK9 is inactive when first synthesized, because a section of peptide chains blocks their activity; proprotein convertases remove that section to activate the enzyme. The PCSK9 gene also contains one of 27 loci associated with increased risk of coronary artery disease.
Homeobox protein Hox-A5 is a protein that in humans is encoded by the HOXA5 gene.
Hematopoietically-expressed homeobox protein HHEX is a protein that in humans is encoded by the HHEX gene and also known as Proline Rich Homeodomain protein PRH.
Mitogen-activated protein kinase kinase kinase kinase 4 (MAP4K4) – also known as hepatocyte progenitor kinase-like/germinal center kinase-like kinase (HGK) and Nck-interacting kinase (NIK) – is an enzyme, specifically a serine/threonine (S/T) kinase encoded by the MAP4K4 gene in humans.
Angiogenic factor with G patch and FHA domains 1 is a protein that in humans is encoded by the AGGF1 gene.
Slit is a family of secreted extracellular matrix proteins which play an important signalling role in the neural development of most bilaterians. While lower animal species, including insects and nematode worms, possess a single Slit gene, humans, mice and other vertebrates possess three Slit homologs: Slit1, Slit2 and Slit3. Human Slits have been shown to be involved in certain pathological conditions, such as cancer and inflammation.
Angiogenesis is the process of forming new blood vessels from existing blood vessels, formed in vasculogenesis. It is a highly complex process involving extensive interplay between cells, soluble factors, and the extracellular matrix (ECM). Angiogenesis is critical during normal physiological development, but it also occurs in adults during inflammation, wound healing, ischemia, and in pathological conditions such as rheumatoid arthritis, hemangioma, and tumor growth. Proteolysis has been indicated as one of the first and most sustained activities involved in the formation of new blood vessels. Numerous proteases including matrix metalloproteinases (MMPs), a disintegrin and metalloproteinase domain (ADAM), a disintegrin and metalloproteinase domain with throbospondin motifs (ADAMTS), and cysteine and serine proteases are involved in angiogenesis. This article focuses on the important and diverse roles that these proteases play in the regulation of angiogenesis.
In molecular biology mir-126 is a short non-coding RNA molecule. MicroRNAs function to regulate the expression levels of other genes by several pre- and post-transcription mechanisms.
A disintegrin and metalloproteinase with thrombospondin motifs 7 (ADAMTS7) is an enzyme that in humans is encoded by the ADAMTS7 gene on chromosome 15. It is ubiquitously expressed in many tissues and cell types. This enzyme catalyzes the degradation of cartilage oligomeric matrix protein (COMP) degradation. ADAMTS7 has been associated with cancer and arthritis in multiple tissue types. The ADAMTS7 gene also contains one of 27 SNPs associated with increased risk of coronary artery disease.
