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SHIP2 is a phosphoinositide-metabolizing enzyme, which dephosphorylates PI(3,4,5)P<jats:sub>3<\/jats:sub> resulting to PI(3,4)P<jats:sub>2<\/jats:sub>, and it has been recently shown that A\u03b2 directly increases the activity of SHIP2. Here we monitored, utilizing fluorescent SHIP2 biosensor, real-time increase of PI(3,4)P<jats:sub>2<\/jats:sub>-containing vesicles in HT22 cells treated with A\u03b2. Interestingly, PI(3,4)P<jats:sub>2<\/jats:sub> is accumulated at late endosomes and lysosomal vesicles. We further discovered that ARAP3 can be attracted to PI(3,4)P<jats:sub>2<\/jats:sub>-positive mature endosomes via its PH domain and this facilitates the degradation of ARAP3. The reduced level of ARAP3 then causes RhoA hyperactivation and filamentous actin, which are critical for neurodegeneration in AD. These results provide a novel molecular link between A\u03b2 and actin disruption through dysregulated phosphoinositide metabolism, and the SHIP2-PI(3,4)P<jats:sub>2<\/jats:sub>-ARAP3-RhoA signaling pathway can be considered as new therapeutic targets for synaptic dysfunctions in Alzheimer\u2019s disease.<\/jats:p>","DOI":"10.1038\/s41598-019-51914-2","type":"journal-article","created":{"date-parts":[[2019,10,30]],"date-time":"2019-10-30T20:29:48Z","timestamp":1572467388000},"update-policy":"https:\/\/doi.org\/10.1007\/springer_crossmark_policy","source":"Crossref","is-referenced-by-count":19,"title":["A\u03b2 modulates actin cytoskeleton via SHIP2-mediated phosphoinositide metabolism"],"prefix":"10.1038","volume":"9","author":[{"given":"Hae Nim","family":"Lee","sequence":"first","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Kyoung Mi","family":"Sim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hyunbin","family":"Kim","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jeongmin","family":"Ju","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Ae Nim","family":"Pae","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jae-Bong","family":"Park","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Hoon","family":"Ryu","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Jihye","family":"Seong","sequence":"additional","affiliation":[],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"297","published-online":{"date-parts":[[2019,10,29]]},"reference":[{"key":"51914_CR1","doi-asserted-by":"publisher","first-page":"651","DOI":"10.1038\/nature05185","volume":"443","author":"G Di Paolo","year":"2006","unstructured":"Di Paolo, G. & De Camilli, P. Phosphoinositides in cell regulation and membrane dynamics. Nature 443, 651\u2013657, https:\/\/doi.org\/10.1038\/nature05185 (2006).","journal-title":"Nature"},{"key":"51914_CR2","doi-asserted-by":"publisher","first-page":"233","DOI":"10.1038\/nature12360","volume":"499","author":"Y Posor","year":"2013","unstructured":"Posor, Y. et al. Spatiotemporal control of endocytosis by phosphatidylinositol-3,4-bisphosphate. Nature 499, 233\u2013237, https:\/\/doi.org\/10.1038\/nature12360 (2013).","journal-title":"Nature"},{"key":"51914_CR3","doi-asserted-by":"publisher","first-page":"794","DOI":"10.1016\/j.bbalip.2014.09.014","volume":"1851","author":"Y Posor","year":"2015","unstructured":"Posor, Y., Eichhorn-Grunig, M. & Haucke, V. Phosphoinositides in endocytosis. 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