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EGFL7

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Template:PBB EGF-like domain-containing protein 7 is a protein that in humans is encoded by the EGFL7 gene.[1] Intron 7 of EGFL7 hosts the miR-126 microRNA gene.

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.[2][3][4] 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.[2] These transcripts vary only in the first exon and code for the same protein which is initiated in the third exon [2] The seventh intron of the egfl7 gene contains a miRNA site for miR-126 and miR-126.[5]

egfl7 gene

Protein structure and expression

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,[6] 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,[7] the second EGF-like domain is predicted to bind Ca2+. The Eglf7 protein is secreted and associates with the blood vessel extracellular matrix.[2][3][4][8]

Endothelial cell lines naturally express egfl7, on the contrary to non-endothelial cells.[2][4] In endothelial cells, expression is controlled by the Erg and GATA2 transcription factors and, indirectly by Fli-1.[9] The expression pattern of the egfl7 gene is conserved across species.[3] 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.[2][3][4] 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.[2][3][10] Expression of egfl7 has also been reported in primordial germ cells and in adult ovaries and testes[11] and in neurons.[12]

Expression in human tumours

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.[13] 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.[14] In glioma, egfl7 expression levels correlate with tumour grade. There is a correlation between expression of egfl7, cell proliferation and micro-vessel density.[15]

Function

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.[3] Although an initial gene inactivation report showed that mice which did not express egfl7 had various vascular defects,[16] the observed phenotypes were later attributed to the concomitant inactivation of the miR-126 locus.[5][17] 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.[5] 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.[18] In vitro, Egfl7 inhibits the formation of cord-like structure in embryonic bodies.[19]

Cellular migration

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.[10] In vitro, egfl7 knockdown in HUVEC inhibits migration, probably by blocking the Notch pathway,[18] although other groups reported that Egfl7 has no effect on HUVEC migration.[2][3][10][16] 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.[14] In mice, inhibition of egfl7 in hepatocellular carcinoma cells decrease tumour growth and micro-vessel density.[14] 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.[20]

Inhibition of elastogenesis

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.[8]

Inhibition of Notch pathway

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.[12][18]

Inhibition of leukocyte adhesion proteins

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).[21] 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.[22] Egfl7 promotes tumour escape from immunity by repressing leukocyte adhesion molecules of tumor blood vessel endothelial cells.[20] 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.

References

  1. ^ "Entrez Gene: EGFL7 EGF-like-domain, multiple 7".
  2. ^ a b c d e f g h Soncin F, Mattot V, Lionneton F, Spruyt N, Lepretre F, Begue A, Stehelin D (November 2003). "VE-statin, an endothelial repressor of smooth muscle cell migration". EMBO J. 22 (21): 5700–11. doi:10.1093/emboj/cdg549. PMC 275406. PMID 14592969.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  3. ^ a b c d e f g Parker LH, Schmidt M, Jin SW, Gray AM, Beis D, Pham T, Frantz G, Palmieri S, Hillan K, Stainier DY, De Sauvage FJ, Ye W (April 2004). "The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation". Nature. 428 (6984): 754–8. doi:10.1038/nature02416. PMID 15085134.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  4. ^ a b c d Fitch MJ, Campagnolo L, Kuhnert F, Stuhlmann H (June 2004). "Egfl7, a novel epidermal growth factor-domain gene expressed in endothelial cells". Dev. Dyn. 230 (2): 316–24. doi:10.1002/dvdy.20063. PMC 1458501. PMID 15162510.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  5. ^ a b c Kuhnert F, Mancuso MR, Hampton J, Stankunas K, Asano T, Chen CZ, Kuo CJ (December 2008). "Attribution of vascular phenotypes of the murine Egfl7 locus to the microRNA miR-126". Development. 135 (24): 3989–93. doi:10.1242/dev.029736. PMID 18987025.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  6. ^ Doliana R, Bot S, Bonaldo P, Colombatti A (November 2000). "EMI, a novel cysteine-rich domain of EMILINs and other extracellular proteins, interacts with the gC1q domains and participates in multimerization". FEBS Lett. 484 (2): 164–8. doi:10.1016/S0014-5793(00)02140-2. PMID 11068053.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  7. ^ Fleming RJ (December 1998). "Structural conservation of Notch receptors and ligands". Semin. Cell Dev. Biol. 9 (6): 599–607. doi:10.1006/scdb.1998.0260. PMID 9918871.
  8. ^ a b Lelièvre E, Hinek A, Lupu F, Buquet C, Soncin F, Mattot V (June 2008). "VE-statin/egfl7 regulates vascular elastogenesis by interacting with lysyl oxidases". EMBO J. 27 (12): 1658–70. doi:10.1038/emboj.2008.103. PMC 2435125. PMID 18497746.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  9. ^ Le Bras A, Samson C, Trentini M, Caetano B, Lelievre E, Mattot V, Beermann F, Soncin F (2010). "VE-statin/egfl7 expression in endothelial cells is regulated by a distal enhancer and a proximal promoter under the direct control of Erg and GATA-2". PLoS ONE. 5 (8): e12156. doi:10.1371/journal.pone.0012156. PMC 2922337. PMID 20808444.{{cite journal}}: CS1 maint: multiple names: authors list (link) CS1 maint: unflagged free DOI (link)
  10. ^ a b c Campagnolo L, Leahy A, Chitnis S, Koschnick S, Fitch MJ, Fallon JT, Loskutoff D, Taubman MB, Stuhlmann H (July 2005). "EGFL7 is a chemoattractant for endothelial cells and is up-regulated in angiogenesis and arterial injury". Am. J. Pathol. 167 (1): 275–84. doi:10.1016/S0002-9440(10)62972-0. PMC 1451775. PMID 15972971.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  11. ^ Campagnolo L, Moscatelli I, Pellegrini M, Siracusa G, Stuhlmann H (July 2008). "Expression of EGFL7 in primordial germ cells and in adult ovaries and testes". Gene Expr. Patterns. 8 (6): 389–96. doi:10.1016/j.gep.2008.05.001. PMC 2569197. PMID 18556249.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  12. ^ a b Schmidt MH, Bicker F, Nikolic I, Meister J, Babuke T, Picuric S, Müller-Esterl W, Plate KH, Dikic I (July 2009). "Epidermal growth factor-like domain 7 (EGFL7) modulates Notch signalling and affects neural stem cell renewal". Nat. Cell Biol. 11 (7): 873–80. doi:10.1038/ncb1896. PMID 19503073.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  13. ^ Díaz R, Silva J, García JM, Lorenzo Y, García V, Peña C, Rodríguez R, Muñoz C, García F, Bonilla F, Domínguez G (September 2008). "Deregulated expression of miR-106a predicts survival in human colon cancer patients". Genes Chromosomes Cancer. 47 (9): 794–802. doi:10.1002/gcc.20580. PMID 18521848.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  14. ^ a b c Wu F, Yang LY, Li YF, Ou DP, Chen DP, Fan C (December 2009). "Novel role for epidermal growth factor-like domain 7 in metastasis of human hepatocellular carcinoma". Hepatology. 50 (6): 1839–50. doi:10.1002/hep.23197. PMID 19824075.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  15. ^ Huang CH, Li XJ, Zhou YZ, Luo Y, Li C, Yuan XR (November 2010). "Expression and clinical significance of EGFL7 in malignant glioma". J. Cancer Res. Clin. Oncol. 136 (11): 1737–43. doi:10.1007/s00432-010-0832-9. PMID 20213100.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  16. ^ a b Schmidt M, Paes K, De Mazière A, Smyczek T, Yang S, Gray A, French D, Kasman I, Klumperman J, Rice DS, Ye W (August 2007). "EGFL7 regulates the collective migration of endothelial cells by restricting their spatial distribution". Development. 134 (16): 2913–23. doi:10.1242/dev.002576. PMID 17626061.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  17. ^ Wang S, Aurora AB, Johnson BA, Qi X, McAnally J, Hill JA, Richardson JA, Bassel-Duby R, Olson EN (August 2008). "The endothelial-specific microRNA miR-126 governs vascular integrity and angiogenesis". Dev. Cell. 15 (2): 261–71. doi:10.1016/j.devcel.2008.07.002. PMC 2685763. PMID 18694565.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  18. ^ a b c Nichol D, Shawber C, Fitch MJ, Bambino K, Sharma A, Kitajewski J, Stuhlmann H (December 2010). "Impaired angiogenesis and altered Notch signaling in mice overexpressing endothelial Egfl7". Blood. 116 (26): 6133–43. doi:10.1182/blood-2010-03-274860. PMC 3031397. PMID 20947685.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  19. ^ Durrans A, Stuhlmann H (2010). "A role for Egfl7 during endothelial organization in the embryoid body model system". J Angiogenes Res. 2: 4. doi:10.1186/2040-2384-2-4. PMC 2834644. PMID 20298530.{{cite journal}}: CS1 maint: unflagged free DOI (link)
  20. ^ a b Delfortrie S, Pinte S, Mattot V, Samson C, Villain G, Caetano B, Lauridant-Philippin G, Baranzelli MC, Bonneterre J, Trottein F, Faveeuw C, Soncin F (December 2011). "Egfl7 promotes tumor escape from immunity by repressing endothelial cell activation". Cancer Res. 71 (23): 7176–86. doi:10.1158/0008-5472.CAN-11-1301. PMID 22037871.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  21. ^ Badiwala MV, Tumiati LC, Joseph JM, Sheshgiri R, Ross HJ, Delgado DH, Rao V (September 2010). "Epidermal growth factor-like domain 7 suppresses intercellular adhesion molecule 1 expression in response to hypoxia/reoxygenation injury in human coronary artery endothelial cells". Circulation. 122 (11 Suppl): S156–61. doi:10.1161/CIRCULATIONAHA.109.927715. PMID 20837907.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  22. ^ Badiwala MV, Guha D, Tumiati L, Joseph J, Ghashghai A, Ross HJ, Delgado DH, Rao V (September 2011). "Epidermal growth factor-like domain 7 is a novel inhibitor of neutrophil adhesion to coronary artery endothelial cells injured by calcineurin inhibition". Circulation. 124 (11 Suppl): S197–203. doi:10.1161/CIRCULATIONAHA.110.011734. PMID 21911813.{{cite journal}}: CS1 maint: multiple names: authors list (link)

Further reading

  • Lim J, Hao T, Shaw C, Patel AJ, Szabó G, Rual JF, Fisk CJ, Li N, Smolyar A, Hill DE, Barabási AL, Vidal M, Zoghbi HY (May 2006). "A protein-protein interaction network for human inherited ataxias and disorders of Purkinje cell degeneration". Cell. 125 (4): 801–14. doi:10.1016/j.cell.2006.03.032. PMID 16713569.{{cite journal}}: CS1 maint: multiple names: authors list (link)
  • Parker LH, Schmidt M, Jin SW, Gray AM, Beis D, Pham T, Frantz G, Palmieri S, Hillan K, Stainier DY, De Sauvage FJ, Ye W (April 2004). "The endothelial-cell-derived secreted factor Egfl7 regulates vascular tube formation". Nature. 428 (6984): 754–8. doi:10.1038/nature02416. PMID 15085134.{{cite journal}}: CS1 maint: multiple names: authors list (link)
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