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We definitively illustrate the necessity for receptor activation in cellular transformation and the importance of implantation site and microenvironment in directing ependymoma development.<jats:italic>In vitro<\/jats:italic>assays of EphB2 overexpressing<jats:italic>Ink4a\/Arf<\/jats:italic><jats:sup>(\u2212\/\u2212)<\/jats:sup>STeNSCs showed no changes in their neural stem cell characteristics (stem cell marker expression and self-renewal) upon receptor activation, but EphB2 driven tumor cells were inhibited significantly in differentiation and exhibited increased tumorsphere formation and cellular proliferation in response to ephrin-B ligand mediated receptor activation. Additionally, we observed substantial differences in the phosphorylation state of several key proteins involved in Ras and p38 MAPK signaling when comparing EphB2 overexpressing<jats:italic>Ink4a\/Arf<\/jats:italic><jats:sup>(\u2212\/\u2212)<\/jats:sup>STeNSCs and tumor cells with relatively little change in total protein levels. We propose that EphB2 mediated ependymoma development is a multifactorial process requiring microenvironment directed receptor activation, resulting in changes in the phosphorylation status of key regulatory proteins, maintenance of a stem-like state and cellular proliferation.<\/jats:p>","DOI":"10.1038\/srep09248","type":"journal-article","created":{"date-parts":[[2015,3,24]],"date-time":"2015-03-24T05:56:19Z","timestamp":1427176579000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":16,"title":["EphB2 activation is required for ependymoma development as well as inhibits differentiation and promotes proliferation of the transformed cell"],"prefix":"10.1038","volume":"5","author":[{"given":"Phylip","family":"Chen","sequence":"first","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Nathan","family":"Rossi","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Samuel","family":"Priddy","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Christopher R.","family":"Pierson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Adam W.","family":"Studebaker","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Robert A.","family":"Johnson","sequence":"additional","affiliation":[],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"297","published-online":{"date-parts":[[2015,3,24]]},"reference":[{"key":"BFsrep09248_CR1","doi-asserted-by":"publisher","first-page":"745","DOI":"10.1016\/S0092-8674(01)00496-2","volume":"106","author":"LE Wybenga-Groot","year":"2001","unstructured":"Wybenga-Groot, L. 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