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Drugs that reduce mTOR activity are only partially successful in the treatment of TSC, suggesting that mTOR-independent pathways play a role in disease development. Here, kinome profiles of wild-type and<jats:italic>Tsc2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>mouse embryonic fibroblasts (MEFs) were generated, revealing a prominent role for PAK2 in signal transduction downstream of TSC1\/2. Further investigation showed that the effect of the TSC1\/2 complex on PAK2 is mediated through RHEB, but is independent of mTOR and p21RAC. We also demonstrated that PAK2 over-activation is likely responsible for the migratory and cell cycle abnormalities observed in<jats:italic>Tsc2<\/jats:italic><jats:sup>\u2212\/\u2212<\/jats:sup>MEFs. Finally, we detected high levels of PAK2 activation in giant cells in the brains of TSC patients. These results show that PAK2 is a direct effector of TSC1-TSC2-RHEB signaling and a new target for rational drug therapy in TSC.<\/jats:p>","DOI":"10.1038\/srep14534","type":"journal-article","created":{"date-parts":[[2015,9,28]],"date-time":"2015-09-28T09:21:29Z","timestamp":1443432089000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":40,"title":["PAK2 is an effector of TSC1\/2 signaling independent of mTOR and a potential therapeutic target for Tuberous Sclerosis Complex"],"prefix":"10.1038","volume":"5","author":[{"given":"Maria M.","family":"Alves","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Gwenny M.","family":"Fuhler","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Karla C.S.","family":"Queiroz","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jetse","family":"Scholma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Susan","family":"Goorden","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jasper","family":"Anink","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"C.","family":"Arnold Spek","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marianne","family":"Hoogeveen-Westerveld","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Marco J.","family":"Bruno","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Mark","family":"Nellist","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ype","family":"Elgersma","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Eleonora","family":"Aronica","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Maikel P.","family":"Peppelenbosch","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2015,9,28]]},"reference":[{"key":"BFsrep14534_CR1","doi-asserted-by":"publisher","first-page":"221","DOI":"10.1177\/088307389200700219","volume":"7","author":"ES Roach","year":"1992","unstructured":"Roach, E. 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