{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,23]],"date-time":"2026-09-23T16:14:23Z","timestamp":1790180063469,"version":"4.1.0"},"reference-count":70,"publisher":"Springer Science and Business Media LLC","issue":"1","license":[{"start":{"date-parts":[[2016,11,24]],"date-time":"2016-11-24T00:00:00Z","timestamp":1479945600000},"content-version":"tdm","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"},{"start":{"date-parts":[[2016,11,24]],"date-time":"2016-11-24T00:00:00Z","timestamp":1479945600000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0"}],"content-domain":{"domain":["link.springer.com"],"crossmark-restriction":false},"short-container-title":["Nat Commun"],"abstract":"<jats:title>Abstract<\/jats:title><jats:p>Vascular permeability and neovascularization are implicated in many diseases including retinopathies and diabetic wound healing. Robo4 is an endothelial-specific transmembrane receptor that stabilizes the vasculature, as shown in <jats:italic>Robo4<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice that develop hyperpermeability, but how Robo4 signals remained unclear. Here we show that <jats:italic>Robo4<\/jats:italic> deletion enhances permeability and revascularization in oxygen-induced retinopathy (OIR) and accelerates cutaneous wound healing. To determine Robo4 signalling pathways, we generated transgenic mice expressing a truncated Robo4 lacking the cytoplasmic domain (Robo4\u0394CD). Robo4\u0394CD expression is sufficient to prevent permeability, and inhibits OIR revascularization and wound healing in <jats:italic>Robo4<\/jats:italic><jats:sup><jats:italic>\u2212\/\u2212<\/jats:italic><\/jats:sup> mice. Mechanistically, Robo4 does not affect Slit2 signalling, but Robo4 and Robo4\u0394CD counteract Vegfr2-Y949 (Y951 in human VEGFR2) phosphorylation by signalling through the endothelial UNC5B receptor. We conclude that Robo4 inhibits angiogenesis and vessel permeability independently of its cytoplasmic domain, while activating VEGFR2-Y951 via ROBO4 inhibition might accelerate tissue revascularization in retinopathy of prematurity and in diabetic patients.<\/jats:p>","DOI":"10.1038\/ncomms13517","type":"journal-article","created":{"date-parts":[[2016,11,24]],"date-time":"2016-11-24T10:25:19Z","timestamp":1479983119000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":60,"title":["The Robo4 cytoplasmic domain is dispensable for vascular permeability and neovascularization"],"prefix":"10.1038","volume":"7","author":[{"given":"Feng","family":"Zhang","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Claudia","family":"Prahst","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Thomas","family":"Mathivet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Laurence","family":"Pibouin-Fragner","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-4637-5655","authenticated-orcid":false,"given":"Jiasheng","family":"Zhang","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Gael","family":"Genet","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Raymond","family":"Tong","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-3829-2577","authenticated-orcid":false,"given":"Alexandre","family":"Dubrac","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Anne","family":"Eichmann","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2016,11,24]]},"reference":[{"key":"BFncomms13517_CR1","doi-asserted-by":"publisher","first-page":"547","DOI":"10.1006\/geno.2002.6745","volume":"79","author":"L Huminiecki","year":"2002","unstructured":"Huminiecki, L., Gorn, M., Suchting, S., Poulsom, R. & Bicknell, R. Magic roundabout is a new member of the roundabout receptor family that is endothelial specific and expressed at sites of active angiogenesis. Genomics 79, 547\u2013552 (2002).","journal-title":"Genomics"},{"key":"BFncomms13517_CR2","doi-asserted-by":"publisher","first-page":"251","DOI":"10.1016\/S0012-1606(03)00258-6","volume":"261","author":"KW Park","year":"2003","unstructured":"Park, K. W. et al. Robo4 is a vascular-specific receptor that inhibits endothelial migration. Dev. Biol. 261, 251\u2013267 (2003).","journal-title":"Dev. Biol."},{"key":"BFncomms13517_CR3","doi-asserted-by":"publisher","first-page":"25","DOI":"10.1097\/NEN.0000000000000146","volume":"74","author":"H Cai","year":"2015","unstructured":"Cai, H. et al. Roundabout 4 regulates blood-tumor barrier permeability through the modulation of ZO-1, Occludin, and Claudin-5 expression. J. Neuropathol. Exp. Neurol. 74, 25\u201337 (2015).","journal-title":"J. Neuropathol. Exp. Neurol."},{"key":"BFncomms13517_CR4","doi-asserted-by":"publisher","first-page":"574261","DOI":"10.1155\/2014\/574261","volume":"2014","author":"M Nafar","year":"2014","unstructured":"Nafar, M. et al. The novel diagnostic biomarkers for focal segmental glomerulosclerosis. Int. J. Nephrol. 2014, 574261 (2014).","journal-title":"Int. J. Nephrol."},{"key":"BFncomms13517_CR5","doi-asserted-by":"publisher","first-page":"1712","DOI":"10.1161\/01.RES.0000269779.10644.dc","volume":"100","author":"Y Okada","year":"2007","unstructured":"Okada, Y. et al. A three-kilobase fragment of the human Robo4 promoter directs cell type-specific expression in endothelium. Circ. Res. 100, 1712\u20131722 (2007).","journal-title":"Circ. Res."},{"key":"BFncomms13517_CR6","doi-asserted-by":"publisher","first-page":"1571","DOI":"10.1042\/BST20110746","volume":"39","author":"X Zhuang","year":"2011","unstructured":"Zhuang, X., Cross, D., Heath, V. L. & Bicknell, R. Shear stress, tip cells and regulators of endothelial migration. Biochem. Soc. Trans. 39, 1571\u20131575 (2011).","journal-title":"Biochem. Soc. Trans."},{"key":"BFncomms13517_CR7","doi-asserted-by":"publisher","first-page":"2336","DOI":"10.1182\/blood-2008-01-135079","volume":"112","author":"Y Okada","year":"2008","unstructured":"Okada, Y. et al. A GABP-binding element in the Robo4 promoter is necessary for endothelial expression in vivo. Blood 112, 2336\u20132339 (2008).","journal-title":"Blood"},{"key":"BFncomms13517_CR8","doi-asserted-by":"publisher","first-page":"987","DOI":"10.1016\/j.bbrc.2015.10.029","volume":"467","author":"Y Okada","year":"2015","unstructured":"Okada, Y. et al. Expression of the Robo4 receptor in endothelial cells is regulated by two AP-1 protein complexes. Biochem. Biophys. Res. Commun. 467, 987\u2013991 (2015).","journal-title":"Biochem. Biophys. Res. Commun."},{"key":"BFncomms13517_CR9","doi-asserted-by":"publisher","first-page":"2804","DOI":"10.1182\/blood-2012-12-468363","volume":"121","author":"M Yoshikawa","year":"2013","unstructured":"Yoshikawa, M. et al. Robo4 is an effective tumor endothelial marker for antibody-drug conjugates based on the rapid isolation of the anti-Robo4 cell-internalizing antibody. Blood 121, 2804\u20132813 (2013).","journal-title":"Blood"},{"key":"BFncomms13517_CR10","doi-asserted-by":"publisher","first-page":"e50849","DOI":"10.1371\/journal.pone.0050849","volume":"7","author":"Y Goto-Koshino","year":"2012","unstructured":"Goto-Koshino, Y. et al. Robo4 plays a role in bone marrow homing and mobilization, but is not essential in the long-term repopulating capacity of hematopoietic stem cells. PLoS ONE 7, e50849 (2012).","journal-title":"PLoS ONE"},{"key":"BFncomms13517_CR11","doi-asserted-by":"publisher","first-page":"72","DOI":"10.1016\/j.stem.2010.11.030","volume":"8","author":"S Smith-Berdan","year":"2011","unstructured":"Smith-Berdan, S. et al. Robo4 cooperates with CXCR4 to specify hematopoietic stem cell localization to bone marrow niches. Cell Stem Cell 8, 72\u201383 (2011).","journal-title":"Cell Stem Cell"},{"key":"BFncomms13517_CR12","doi-asserted-by":"publisher","first-page":"675","DOI":"10.4161\/cc.11.4.19146","volume":"11","author":"S Smith-Berdan","year":"2012","unstructured":"Smith-Berdan, S., Schepers, K., Ly, A., Passegue, E. & Forsberg, E. C. Dynamic expression of the Robo ligand Slit2 in bone marrow cell populations. Cell Cycle 11, 675\u2013682 (2012).","journal-title":"Cell Cycle"},{"key":"BFncomms13517_CR13","doi-asserted-by":"publisher","first-page":"255","DOI":"10.1016\/j.stemcr.2014.12.013","volume":"4","author":"S Smith-Berdan","year":"2015","unstructured":"Smith-Berdan, S., Nguyen, A., Hong, M. A. & Forsberg, E. C. ROBO4-mediated vascular integrity regulates the directionality of hematopoietic stem cell trafficking. Stem Cell Rep. 4, 255\u2013268 (2015).","journal-title":"Stem Cell Rep."},{"key":"BFncomms13517_CR14","doi-asserted-by":"publisher","first-page":"121","DOI":"10.1096\/fj.04-1991fje","volume":"19","author":"S Suchting","year":"2005","unstructured":"Suchting, S., Heal, P., Tahtis, K., Stewart, L. M. & Bicknell, R. Soluble Robo4 receptor inhibits in vivo angiogenesis and endothelial cell migration. FASEB J. 19, 121\u2013123 (2005).","journal-title":"FASEB J."},{"key":"BFncomms13517_CR15","first-page":"683025","volume":"2014","author":"SS Yadav","year":"2014","unstructured":"Yadav, S. S. & Narayan, G. Role of ROBO4 signalling in developmental and pathological angiogenesis. Biomed. Res. Int. 2014, 683025 (2014).","journal-title":"Biomed. Res. Int."},{"key":"BFncomms13517_CR16","doi-asserted-by":"publisher","first-page":"83","DOI":"10.1007\/s10456-014-9448-z","volume":"18","author":"X Zhuang","year":"2015","unstructured":"Zhuang, X. et al. Robo4 vaccines induce antibodies that retard tumor growth. Angiogenesis 18, 83\u201395 (2015).","journal-title":"Angiogenesis"},{"key":"BFncomms13517_CR17","doi-asserted-by":"publisher","first-page":"448","DOI":"10.1038\/nm1742","volume":"14","author":"CA Jones","year":"2008","unstructured":"Jones, C. A. et al. Robo4 stabilizes the vascular network by inhibiting pathologic angiogenesis and endothelial hyperpermeability. Nat. Med. 14, 448\u2013453 (2008).","journal-title":"Nat. Med."},{"key":"BFncomms13517_CR18","doi-asserted-by":"publisher","first-page":"33","DOI":"10.1016\/j.devcel.2010.12.001","volume":"20","author":"AW Koch","year":"2011","unstructured":"Koch, A. W. et al. Robo4 maintains vessel integrity and inhibits angiogenesis by interacting with UNC5B. Dev. Cell 20, 33\u201346 (2011).","journal-title":"Dev. Cell"},{"key":"BFncomms13517_CR19","doi-asserted-by":"publisher","first-page":"10520","DOI":"10.1073\/pnas.1001896107","volume":"107","author":"R Marlow","year":"2010","unstructured":"Marlow, R. et al. Vascular Robo4 restricts proangiogenic VEGF signaling in breast. Proc. Natl Acad. Sci. USA 107, 10520\u201310525 (2010).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms13517_CR20","first-page":"101","volume":"35","author":"LE Smith","year":"1994","unstructured":"Smith, L. E. et al. Oxygen-induced retinopathy in the mouse. Invest. Ophthalmol. Vis. Sci. 35, 101\u2013111 (1994).","journal-title":"Invest. Ophthalmol. Vis. Sci."},{"key":"BFncomms13517_CR21","doi-asserted-by":"publisher","first-page":"1565","DOI":"10.1038\/nprot.2009.187","volume":"4","author":"KM Connor","year":"2009","unstructured":"Connor, K. M. et al. Quantification of oxygen-induced retinopathy in the mouse: a model of vessel loss, vessel regrowth and pathological angiogenesis. Nat. Protoc. 4, 1565\u20131573 (2009).","journal-title":"Nat. Protoc."},{"key":"BFncomms13517_CR22","doi-asserted-by":"publisher","first-page":"2047","DOI":"10.4161\/cc.20535","volume":"11","author":"GX Ruan","year":"2012","unstructured":"Ruan, G. X. & Kazlauskas, A. VEGF-A engages at least three tyrosine kinases to activate PI3K\/Akt. Cell Cycle 11, 2047\u20132048 (2012).","journal-title":"Cell Cycle"},{"key":"BFncomms13517_CR23","doi-asserted-by":"publisher","first-page":"2342","DOI":"10.1038\/sj.emboj.7600709","volume":"24","author":"T Matsumoto","year":"2005","unstructured":"Matsumoto, T. et al. VEGF receptor-2 Y951 signaling and a role for the adapter molecule TSAd in tumor angiogenesis. EMBO J. 24, 2342\u20132353 (2005).","journal-title":"EMBO J."},{"key":"BFncomms13517_CR24","doi-asserted-by":"publisher","first-page":"1363","DOI":"10.1084\/jem.20111343","volume":"209","author":"Z Sun","year":"2012","unstructured":"Sun, Z. et al. VEGFR2 induces c-Src signaling and vascular permeability in vivo via the adaptor protein TSAd. J. Exp. Med. 209, 1363\u20131377 (2012).","journal-title":"J. Exp. Med."},{"key":"BFncomms13517_CR25","doi-asserted-by":"publisher","first-page":"11017","DOI":"10.1038\/ncomms11017","volume":"7","author":"X Li","year":"2016","unstructured":"Li, X. et al. VEGFR2 pY949 signalling regulates adherens junction integrity and metastatic spread. Nat. Commun. 7, 11017 (2016).","journal-title":"Nat. Commun."},{"key":"BFncomms13517_CR26","doi-asserted-by":"publisher","first-page":"1325","DOI":"10.1038\/ncb1976","volume":"11","author":"CA Jones","year":"2009","unstructured":"Jones, C. A. et al. Slit2-Robo4 signalling promotes vascular stability by blocking Arf6 activity. Nat. Cell Biol. 11, 1325\u20131331 (2009).","journal-title":"Nat. Cell Biol."},{"key":"BFncomms13517_CR27","doi-asserted-by":"publisher","first-page":"795","DOI":"10.1016\/S0092-8674(00)80590-5","volume":"96","author":"K Brose","year":"1999","unstructured":"Brose, K. et al. Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell 96, 795\u2013806 (1999).","journal-title":"Cell"},{"key":"BFncomms13517_CR28","doi-asserted-by":"publisher","first-page":"205","DOI":"10.1016\/S0092-8674(00)80915-0","volume":"92","author":"T Kidd","year":"1998","unstructured":"Kidd, T. et al. Roundabout controls axon crossing of the CNS midline and defines a novel subfamily of evolutionarily conserved guidance receptors. Cell 92, 205\u2013215 (1998).","journal-title":"Cell"},{"key":"BFncomms13517_CR29","doi-asserted-by":"publisher","first-page":"785","DOI":"10.1016\/S0092-8674(00)80589-9","volume":"96","author":"T Kidd","year":"1999","unstructured":"Kidd, T., Bland, K. S. & Goodman, C. S. Slit is the midline repellent for the robo receptor in Drosophila. Cell 96, 785\u2013794 (1999).","journal-title":"Cell"},{"key":"BFncomms13517_CR30","doi-asserted-by":"publisher","first-page":"124","DOI":"10.1016\/j.yjmcc.2013.09.005","volume":"64","author":"JD Paul","year":"2013","unstructured":"Paul, J. D. et al. SLIT3-ROBO4 activation promotes vascular network formation in human engineered tissue and angiogenesis in vivo. J. Mol. Cell. Cardiol. 64, 124\u2013131 (2013).","journal-title":"J. Mol. Cell. Cardiol."},{"key":"BFncomms13517_CR31","doi-asserted-by":"publisher","first-page":"445","DOI":"10.1097\/MNH.0b013e32836235f4","volume":"22","author":"DA Yuen","year":"2013","unstructured":"Yuen, D. A. & Robinson, L. A. Slit2-Robo signaling: a novel regulator of vascular injury. Curr. Opin. Nephrol. Hypertens. 22, 445\u2013451 (2013).","journal-title":"Curr. Opin. Nephrol. Hypertens."},{"key":"BFncomms13517_CR32","doi-asserted-by":"publisher","first-page":"483","DOI":"10.1038\/nm.3849","volume":"21","author":"N Rama","year":"2015","unstructured":"Rama, N. et al. Slit2 signaling through Robo1 and Robo2 is required for retinal neovascularization. Nat. Med. 21, 483\u2013491 (2015).","journal-title":"Nat. Med."},{"key":"BFncomms13517_CR33","doi-asserted-by":"publisher","first-page":"465","DOI":"10.1161\/CIRCRESAHA.112.277426","volume":"112","author":"MT Mommersteeg","year":"2013","unstructured":"Mommersteeg, M. T. et al. Slit-roundabout signaling regulates the development of the cardiac systemic venous return and pericardium. Circ. Res. 112, 465\u2013475 (2013).","journal-title":"Circ. Res."},{"key":"BFncomms13517_CR34","doi-asserted-by":"publisher","first-page":"61","DOI":"10.1186\/1471-2121-9-61","volume":"9","author":"S Kaur","year":"2008","unstructured":"Kaur, S. et al. Silencing of directional migration in roundabout4 knockdown endothelial cells. BMC Cell Biol. 9, 61 (2008).","journal-title":"BMC Cell Biol."},{"key":"BFncomms13517_CR35","doi-asserted-by":"publisher","first-page":"513","DOI":"10.1096\/fj.07-098269","volume":"23","author":"H Sheldon","year":"2009","unstructured":"Sheldon, H. et al. Active involvement of Robo1 and Robo4 in filopodia formation and endothelial cell motility mediated via WASP and other actin nucleation-promoting factors. FASEB J. 23, 513\u2013522 (2009).","journal-title":"FASEB J."},{"key":"BFncomms13517_CR36","doi-asserted-by":"publisher","first-page":"14923","DOI":"10.1073\/pnas.0705310104","volume":"104","author":"C Morlot","year":"2007","unstructured":"Morlot, C. et al. Structural insights into the Slit-Robo complex. Proc. Natl Acad. Sci. USA 104, 14923\u201314928 (2007).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms13517_CR37","doi-asserted-by":"publisher","first-page":"16226","DOI":"10.1074\/jbc.M800688200","volume":"283","author":"N Fukuhara","year":"2008","unstructured":"Fukuhara, N., Howitt, J. A., Hussain, S. A. & Hohenester, E. Structural and functional analysis of slit and heparin binding to immunoglobulin-like domains 1 and 2 of Drosophila Robo. J. Biol. Chem. 283, 16226\u201316234 (2008).","journal-title":"J. Biol. Chem."},{"key":"BFncomms13517_CR38","doi-asserted-by":"publisher","first-page":"39693","DOI":"10.1074\/jbc.M609384200","volume":"281","author":"SA Hussain","year":"2006","unstructured":"Hussain, S. A. et al. A molecular mechanism for the heparan sulfate dependence of slit-robo signaling. J. Biol. Chem. 281, 39693\u201339698 (2006).","journal-title":"J. Biol. Chem."},{"key":"BFncomms13517_CR39","doi-asserted-by":"publisher","first-page":"1258","DOI":"10.1016\/j.neuron.2014.11.004","volume":"84","author":"P Zelina","year":"2014","unstructured":"Zelina, P. et al. Signaling switch of the axon guidance receptor Robo3 during vertebrate evolution. Neuron 84, 1258\u20131272 (2014).","journal-title":"Neuron"},{"key":"BFncomms13517_CR40","doi-asserted-by":"publisher","first-page":"19","DOI":"10.1016\/S1535-6108(03)00164-8","volume":"4","author":"B Wang","year":"2003","unstructured":"Wang, B. et al. Induction of tumor angiogenesis by Slit-Robo signaling and inhibition of cancer growth by blocking Robo activity. Cancer Cell 4, 19\u201329 (2003).","journal-title":"Cancer Cell"},{"key":"BFncomms13517_CR41","doi-asserted-by":"publisher","first-page":"4300","DOI":"10.1182\/blood-2008-12-193326","volume":"114","author":"B Zhang","year":"2009","unstructured":"Zhang, B. et al. Repulsive axon guidance molecule Slit3 is a novel angiogenic factor. Blood 114, 4300\u20134309 (2009).","journal-title":"Blood"},{"key":"BFncomms13517_CR42","doi-asserted-by":"publisher","first-page":"5669","DOI":"10.1182\/blood-2009-01-196485","volume":"113","author":"C Urbich","year":"2009","unstructured":"Urbich, C. et al. HDAC5 is a repressor of angiogenesis and determines the angiogenic gene expression pattern of endothelial cells. Blood 113, 5669\u20135679 (2009).","journal-title":"Blood"},{"key":"BFncomms13517_CR43","doi-asserted-by":"publisher","first-page":"404","DOI":"10.1128\/MCB.00667-10","volume":"31","author":"CM Dunaway","year":"2011","unstructured":"Dunaway, C. M. et al. Cooperative signaling between Slit2 and Ephrin-A1 regulates a balance between angiogenesis and angiostasis. Mol. Cell. Biol. 31, 404\u2013416 (2011).","journal-title":"Mol. Cell. Biol."},{"key":"BFncomms13517_CR44","doi-asserted-by":"publisher","first-page":"1409","DOI":"10.1242\/dev.060046","volume":"138","author":"JE Fish","year":"2011","unstructured":"Fish, J. E. et al. A Slit\/miR-218\/Robo regulatory loop is required during heart tube formation in zebrafish. Development 138, 1409\u20131419 (2011).","journal-title":"Development"},{"key":"BFncomms13517_CR45","doi-asserted-by":"publisher","first-page":"1336","DOI":"10.1161\/CIRCRESAHA.110.227926","volume":"107","author":"EM Small","year":"2010","unstructured":"Small, E. M., Sutherland, L. B., Rajagopalan, K. N., Wang, S. & Olson, E. N. MicroRNA-218 regulates vascular patterning by modulation of Slit-Robo signaling. Circ. Res. 107, 1336\u20131344 (2010).","journal-title":"Circ. Res."},{"key":"BFncomms13517_CR46","doi-asserted-by":"publisher","first-page":"2433","DOI":"10.1101\/gad.437807","volume":"21","author":"B Larrivee","year":"2007","unstructured":"Larrivee, B. et al. Activation of the UNC5B receptor by Netrin-1 inhibits sprouting angiogenesis. Genes Dev. 21, 2433\u20132447 (2007).","journal-title":"Genes Dev."},{"key":"BFncomms13517_CR47","doi-asserted-by":"publisher","first-page":"172","DOI":"10.1016\/j.ydbio.2008.03.023","volume":"318","author":"K Bouvree","year":"2008","unstructured":"Bouvree, K. et al. Netrin-1 inhibits sprouting angiogenesis in developing avian embryos. Dev. Biol. 318, 172\u2013183 (2008).","journal-title":"Dev. Biol."},{"key":"BFncomms13517_CR48","doi-asserted-by":"publisher","first-page":"614","DOI":"10.1016\/j.devcel.2009.02.006","volume":"16","author":"M Castets","year":"2009","unstructured":"Castets, M. et al. Inhibition of endothelial cell apoptosis by netrin-1 during angiogenesis. Dev. Cell 16, 614\u2013620 (2009).","journal-title":"Dev. Cell"},{"key":"BFncomms13517_CR49","doi-asserted-by":"publisher","first-page":"179","DOI":"10.1038\/nature03080","volume":"432","author":"X Lu","year":"2004","unstructured":"Lu, X. et al. The netrin receptor UNC5B mediates guidance events controlling morphogenesis of the vascular system. Nature 432, 179\u2013186 (2004).","journal-title":"Nature"},{"key":"BFncomms13517_CR50","doi-asserted-by":"publisher","first-page":"128","DOI":"10.1073\/pnas.0403198102","volume":"102","author":"JF Sun","year":"2005","unstructured":"Sun, J. F. et al. Microvascular patterning is controlled by fine-tuning the Akt signal. Proc. Natl Acad. Sci. USA 102, 128\u2013133 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms13517_CR51","doi-asserted-by":"publisher","first-page":"692","DOI":"10.1016\/j.molcel.2009.02.016","volume":"33","author":"R Wang","year":"2009","unstructured":"Wang, R. et al. Autoinhibition of UNC5b revealed by the cytoplasmic domain structure of the receptor. Mol. Cell 33, 692\u2013703 (2009).","journal-title":"Mol. Cell"},{"key":"BFncomms13517_CR52","doi-asserted-by":"publisher","first-page":"41573","DOI":"10.1074\/jbc.R300026200","volume":"278","author":"JG Donaldson","year":"2003","unstructured":"Donaldson, J. G. Multiple roles for Arf6: sorting, structuring, and signaling at the plasma membrane. J. Biol. Chem. 278, 41573\u201341576 (2003).","journal-title":"J. Biol. Chem."},{"key":"BFncomms13517_CR53","doi-asserted-by":"publisher","first-page":"2722","DOI":"10.1038\/emboj.2013.212","volume":"32","author":"A Vehlow","year":"2013","unstructured":"Vehlow, A. et al. Endophilin, Lamellipodin, and Mena cooperate to regulate F-actin-dependent EGF-receptor endocytosis. EMBO J. 32, 2722\u20132734 (2013).","journal-title":"EMBO J."},{"key":"BFncomms13517_CR54","doi-asserted-by":"publisher","first-page":"2001","DOI":"10.1242\/jcs.081182","volume":"124","author":"M Galovic","year":"2011","unstructured":"Galovic, M., Xu, D., Areces, L. B., van der Kammen, R. & Innocenti, M. Interplay between N-WASP and CK2 optimizes clathrin-mediated endocytosis of EGFR. J. Cell Sci. 124, 2001\u20132012 (2011).","journal-title":"J. Cell Sci."},{"key":"BFncomms13517_CR55","doi-asserted-by":"publisher","first-page":"1499","DOI":"10.1016\/j.cellsig.2015.03.006","volume":"27","author":"T Gryaznova","year":"2015","unstructured":"Gryaznova, T. et al. Intersectin adaptor proteins are associated with actin-regulating protein WIP in invadopodia. Cell Signal. 27, 1499\u20131508 (2015).","journal-title":"Cell Signal."},{"key":"BFncomms13517_CR56","doi-asserted-by":"publisher","first-page":"e111459","DOI":"10.1371\/journal.pone.0111459","volume":"9","author":"A Burke-Gaffney","year":"2014","unstructured":"Burke-Gaffney, A., Svermova, T., Mumby, S., Finney, S. J. & Evans, T. W. Raised plasma Robo4 and cardiac surgery-associated acute kidney injury. PLoS ONE 9, e111459 (2014).","journal-title":"PLoS ONE"},{"key":"BFncomms13517_CR57","doi-asserted-by":"publisher","first-page":"a006502","DOI":"10.1101\/cshperspect.a006502","volume":"2","author":"S Koch","year":"2012","unstructured":"Koch, S. & Claesson-Welsh, L. Signal transduction by vascular endothelial growth factor receptors. Cold Spring Harb. Perspect Med. 2, a006502 (2012).","journal-title":"Cold Spring Harb. Perspect Med."},{"key":"BFncomms13517_CR58","doi-asserted-by":"publisher","first-page":"1076","DOI":"10.1073\/pnas.0404984102","volume":"102","author":"Y Sakurai","year":"2005","unstructured":"Sakurai, Y., Ohgimoto, K., Kataoka, Y., Yoshida, N. & Shibuya, M. Essential role of Flk-1 (VEGF receptor 2) tyrosine residue 1173 in vasculogenesis in mice. Proc. Natl Acad. Sci. USA 102, 1076\u20131081 (2005).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms13517_CR59","doi-asserted-by":"publisher","first-page":"28","DOI":"10.1016\/j.molmed.2007.11.005","volume":"14","author":"V Bennett","year":"2008","unstructured":"Bennett, V. & Healy, J. Organizing the fluid membrane bilayer: diseases linked to spectrin and ankyrin. Trends Mol. Med. 14, 28\u201336 (2008).","journal-title":"Trends Mol. Med."},{"key":"BFncomms13517_CR60","doi-asserted-by":"publisher","first-page":"387","DOI":"10.1038\/sj.onc.1210635","volume":"27","author":"S Cuenin","year":"2008","unstructured":"Cuenin, S., Tinel, A., Janssens, S. & Tschopp, J. p53-induced protein with a death domain (PIDD) isoforms differentially activate nuclear factor-kappaB and caspase-2 in response to genotoxic stress. Oncogene 27, 387\u2013396 (2008).","journal-title":"Oncogene"},{"key":"BFncomms13517_CR61","doi-asserted-by":"publisher","first-page":"122","DOI":"10.1038\/79102","volume":"26","author":"Y Lin","year":"2000","unstructured":"Lin, Y., Ma, W. & Benchimol, S. Pidd, a new death-domain-containing protein, is induced by p53 and promotes apoptosis. Nat. Genet. 26, 122\u2013127 (2000).","journal-title":"Nat. Genet."},{"key":"BFncomms13517_CR62","doi-asserted-by":"publisher","first-page":"533","DOI":"10.1016\/j.cell.2007.01.019","volume":"128","author":"HH Park","year":"2007","unstructured":"Park, H. H. et al. Death domain assembly mechanism revealed by crystal structure of the oligomeric PIDDosome core complex. Cell 128, 533\u2013546 (2007).","journal-title":"Cell"},{"key":"BFncomms13517_CR63","doi-asserted-by":"publisher","first-page":"833","DOI":"10.1038\/386833a0","volume":"386","author":"ED Leonardo","year":"1997","unstructured":"Leonardo, E. D. et al. Vertebrate homologues of C. elegans UNC-5 are candidate netrin receptors. Nature 386, 833\u2013838 (1997).","journal-title":"Nature"},{"key":"BFncomms13517_CR64","doi-asserted-by":"publisher","first-page":"150","DOI":"10.1038\/nn.2256","volume":"12","author":"LT MacNeil","year":"2009","unstructured":"MacNeil, L. T., Hardy, W. R., Pawson, T., Wrana, J. L. & Culotti, J. G. UNC-129 regulates the balance between UNC-40 dependent and independent UNC-5 signaling pathways. Nat. Neurosci. 12, 150\u2013155 (2009).","journal-title":"Nat. Neurosci."},{"key":"BFncomms13517_CR65","doi-asserted-by":"publisher","first-page":"12491","DOI":"10.1073\/pnas.0804008105","volume":"105","author":"E Lejmi","year":"2008","unstructured":"Lejmi, E. et al. Netrin-4 inhibits angiogenesis via binding to neogenin and recruitment of Unc5B. Proc. Natl Acad. Sci. USA 105, 12491\u201312496 (2008).","journal-title":"Proc. Natl Acad. Sci. USA"},{"key":"BFncomms13517_CR66","doi-asserted-by":"publisher","first-page":"5157","DOI":"10.1074\/jbc.M110.180919","volume":"286","author":"M Hagihara","year":"2011","unstructured":"Hagihara, M. et al. Neogenin, a receptor for bone morphogenetic proteins. J. Biol. Chem. 286, 5157\u20135165 (2011).","journal-title":"J. Biol. Chem."},{"key":"BFncomms13517_CR67","doi-asserted-by":"publisher","first-page":"2920","DOI":"10.1038\/emboj.2011.189","volume":"30","author":"S Yamagishi","year":"2011","unstructured":"Yamagishi, S. et al. FLRT2 and FLRT3 act as repulsive guidance cues for Unc5-positive neurons. EMBO J. 30, 2920\u20132933 (2011).","journal-title":"EMBO J."},{"key":"BFncomms13517_CR68","doi-asserted-by":"publisher","first-page":"370","DOI":"10.1016\/j.neuron.2014.10.008","volume":"84","author":"E Seiradake","year":"2014","unstructured":"Seiradake, E. et al. FLRT structure: balancing repulsion and cell adhesion in cortical and vascular development. Neuron 84, 370\u2013385 (2014).","journal-title":"Neuron"},{"key":"BFncomms13517_CR69","doi-asserted-by":"publisher","first-page":"4274","DOI":"10.1182\/blood-2011-03-339531","volume":"118","author":"F Zhang","year":"2011","unstructured":"Zhang, F. et al. Tetraspanin CD151 maintains vascular stability by balancing the forces of cell adhesion and cytoskeletal tension. Blood 118, 4274\u20134284 (2011).","journal-title":"Blood"},{"key":"BFncomms13517_CR70","doi-asserted-by":"publisher","first-page":"409","DOI":"10.1161\/CIRCULATIONAHA.115.017537","volume":"133","author":"A Dubrac","year":"2016","unstructured":"Dubrac, A. et al. Targeting NCK-mediated endothelial cell front-rear polarity inhibits neovascularization. Circulation 133, 409\u2013421 (2016).","journal-title":"Circulation"}],"container-title":["Nature Communications"],"original-title":[],"language":"en","link":[{"URL":"https:\/\/www.nature.com\/articles\/ncomms13517.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms13517","content-type":"text\/html","content-version":"vor","intended-application":"text-mining"},{"URL":"https:\/\/www.nature.com\/articles\/ncomms13517.pdf","content-type":"application\/pdf","content-version":"vor","intended-application":"similarity-checking"}],"deposited":{"date-parts":[[2023,1,4]],"date-time":"2023-01-04T09:38:32Z","timestamp":1672825112000},"score":1,"resource":{"primary":{"URL":"https:\/\/www.nature.com\/articles\/ncomms13517"}},"subtitle":[],"short-title":[],"issued":{"date-parts":[[2016,11,24]]},"references-count":70,"journal-issue":{"issue":"1","published-online":{"date-parts":[[2016,12,23]]}},"alternative-id":["BFncomms13517"],"URL":"https:\/\/doi.org\/10.1038\/ncomms13517","relation":{},"ISSN":["2041-1723"],"issn-type":[{"value":"2041-1723","type":"electronic"}],"subject":[],"published":{"date-parts":[[2016,11,24]]},"assertion":[{"value":"22 April 2016","order":1,"name":"received","label":"Received","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"11 October 2016","order":2,"name":"accepted","label":"Accepted","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"24 November 2016","order":3,"name":"first_online","label":"First Online","group":{"name":"ArticleHistory","label":"Article History"}},{"value":"The authors declare no competing financial interests.","order":1,"name":"Ethics","group":{"name":"EthicsHeading","label":"Competing interests"}}],"article-number":"13517"}}