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Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P2 and PI(3)P in a curved vesicle triggers actin polymerization. At clathrin-coated pits, PI(3)P is produced by the INPP4A hydrolysis of PI(3,4)P2, and this is necessary for actin-driven endocytosis. Both Cdc42\u22c5guanosine triphosphate and SNX9 activate N-WASP\u2013WIP- and Arp2\/3-mediated actin nucleation. Membrane curvature, PI(4,5)P2, and PI(3)P signals are needed for SNX9 assembly via its PX\u2013BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P2 alone. INPP4A activity is stimulated by high membrane curvature and synergizes with SNX9 BAR domain binding in a process we call curvature cascade amplification. We show that the SNX9-driven actin comets that arise on human disease\u2013associated oculocerebrorenal syndrome of Lowe (OCRL) deficiencies are reduced by inhibiting PI(3)P production, suggesting PI(3)P kinase inhibitors as a therapeutic strategy in Lowe syndrome.<\/jats:p>","DOI":"10.1083\/jcb.201704061","type":"journal-article","created":{"date-parts":[[2017,9,18]],"date-time":"2017-09-18T11:00:10Z","timestamp":1505732410000},"page":"3745-3765","update-policy":"https:\/\/doi.org\/10.1083\/jcb.crossmarkpolicy","source":"Crossref","is-referenced-by-count":94,"title":["Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature"],"prefix":"10.1083","volume":"216","author":[{"given":"Frederic","family":"Daste","sequence":"first","affiliation":[{"name":"Wellcome Trust\/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Astrid","family":"Walrant","sequence":"additional","affiliation":[{"name":"Wellcome Trust\/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-5538-4406","authenticated-orcid":true,"given":"Mikkel R.","family":"Holst","sequence":"additional","affiliation":[{"name":"Integrative Medical Biology, Ume\u00e5 University, Ume\u00e5, Sweden 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0001-7986-4917","authenticated-orcid":true,"given":"Jonathan R.","family":"Gadsby","sequence":"additional","affiliation":[{"name":"Wellcome Trust\/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Julia","family":"Mason","sequence":"additional","affiliation":[{"name":"Wellcome Trust\/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Ji-Eun","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Cambridge, England, UK 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Daniel","family":"Brook","sequence":"additional","affiliation":[{"name":"Wellcome Trust\/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Marcel","family":"Mettlen","sequence":"additional","affiliation":[{"name":"University of Texas Southwestern Medical Center, Dallas, TX 4"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Elin","family":"Larsson","sequence":"additional","affiliation":[{"name":"Integrative Medical Biology, Ume\u00e5 University, Ume\u00e5, Sweden 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Steven F.","family":"Lee","sequence":"additional","affiliation":[{"name":"Department of Chemistry, University of Cambridge, Cambridge, England, UK 2"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Richard","family":"Lundmark","sequence":"additional","affiliation":[{"name":"Integrative Medical Biology, Ume\u00e5 University, Ume\u00e5, Sweden 3"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-9978-1382","authenticated-orcid":true,"given":"Jennifer L.","family":"Gallop","sequence":"additional","affiliation":[{"name":"Wellcome Trust\/Cancer Research UK Gurdon Institute and Department of Biochemistry, University of Cambridge, Cambridge, England, UK 1"}],"role":[{"vocabulary":"crossref","role":"author"}]}],"member":"291","published-online":{"date-parts":[[2017,9,18]]},"reference":[{"key":"2023072318000607800_bib1","doi-asserted-by":"publisher","first-page":"1039","DOI":"10.1038\/ncb1918","article-title":"Differential requirements for actin during yeast and mammalian endocytosis","volume":"11","author":"Aghamohammadzadeh","year":"2009","journal-title":"Nat. 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