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Phosphatidic acid regulation of PIPKI is critical for actin cytoskeletal reorganization.

ABSTRACT: Type I phosphatidylinositol-4-phosphate 5-kinase (PIPKI) is the main enzyme generating the lipid second messenger phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], which has critical functions in many cellular processes, such as cytoskeletal reorganization, membrane trafficking, and signal transduction. All three members of the PIPKI family are activated by phosphatidic acid (PA). However, how PA regulates the activity and functions of PIPKI have not been fully elucidated. In this study, we identify a PA-binding site on PIPKI?. Mutation of this site inhibited the PA-stimulated activity and membrane localization of PIPKI? as well as the formation of actin comets and foci induced by PIPKI?. We also demonstrate that phospholipase D (PLD) generates a pool of PA involved in PIPKI? regulation by showing that PLD inhibitors blocked the membrane localization of PIPKI? and its ability to induce actin cytoskeletal reorganization. Targeting the PIPKI? PA-binding-deficient mutant to membranes by a membrane localization sequence failed to restore the actin reorganization activity of PIPKI?, suggesting that PA binding is not only involved in recruiting PIPKI? to membranes but also may induce a conformational change. Taken together, these results reveal a new molecular mechanism through which PA regulates PIPKI and provides direct evidence that PA is important for the localization and functions of PIPKI in intact cells.

SUBMITTER: Roach AN

PROVIDER: S-EPMC3494241 | biostudies-literature | 2012 Dec

REPOSITORIES: biostudies-literature

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Phosphatidic acid regulation of PIPKI is critical for actin cytoskeletal reorganization.

Roach Akua N AN Wang Ziqing Z Wu Ping P Zhang Feng F Chan Robin B RB Yonekubo Yoshiya Y Di Paolo Gilbert G Gorfe Alemayehu A AA Du Guangwei G

Journal of lipid research 20120918 12

Type I phosphatidylinositol-4-phosphate 5-kinase (PIPKI) is the main enzyme generating the lipid second messenger phosphatidylinositol-4,5-bisphosphate [PI(4,5)P2], which has critical functions in many cellular processes, such as cytoskeletal reorganization, membrane trafficking, and signal transduction. All three members of the PIPKI family are activated by phosphatidic acid (PA). However, how PA regulates the activity and functions of PIPKI have not been fully elucidated. In this study, we ide ...[more]

PMID: 22991193

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Phosphatidic acid regulation of PIPKI is critical for actin cytoskeletal reorganization.

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Phosphatidic acid regulation of PIPKI is critical for actin cytoskeletal reorganization.

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