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Control of actin polymerization via the coincidence of phosphoinositides and high membrane curvature
Umeå University, Faculty of Medicine, Department of Integrative Medical Biology (IMB).
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2017 (English)In: Journal of Cell Biology, ISSN 0021-9525, E-ISSN 1540-8140, Vol. 216, no 11, p. 3745-3765Article in journal (Refereed) Published
Abstract [en]

The conditional use of actin during clathrin-mediated endocytosis in mammalian cells suggests that the cell controls whether and how actin is used. Using a combination of biochemical reconstitution and mammalian cell culture, we elucidate a mechanism by which the coincidence of PI(4,5)P-2 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)P-2, and this is necessary for actin-driven endocytosis. Both Cdc42.guanosine triphosphate and SNX9 activate N-WASP-WIP-and Arp2/3-mediated actin nucleation. Membrane curvature, PI(4,5)P-2, and PI(3) P signals are needed for SNX9 assembly via its PX-BAR domain, whereas signaling through Cdc42 is activated by PI(4,5)P-2 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-associated 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.

Place, publisher, year, edition, pages
ROCKEFELLER UNIV PRESS , 2017. Vol. 216, no 11, p. 3745-3765
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Cell Biology
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URN: urn:nbn:se:umu:diva-142260DOI: 10.1083/jcb.201704061ISI: 000414609700026OAI: oai:DiVA.org:umu-142260DiVA, id: diva2:1163207
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EU, Horizon 2020, 281971Available from: 2017-12-06 Created: 2017-12-06 Last updated: 2018-06-09Bibliographically approved

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Holst, Mikkel R.Larsson, ElinLundmark, Richard
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