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LL5 directs the translocation of Filamin A and SHIP2 to sites of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) accumulation, and PtdIns(3,4,5)P3 localization is mutually modified by co-recruited SHIP2

Takabayashi, Tetsuji and Xie, Min-Jue and Takeuchi, Seiji and Kawasaki, Motomi and Yagi, Hideshi and Okamoto, Masayuki and Rahman, Mohammad Tariqur and Malik, Fawzia and Kuroda, Kazuki and Kubota, Chikara and Fujieda, Shigeharu and Nagano, Takashi and Sato, Makoto (2010) LL5 directs the translocation of Filamin A and SHIP2 to sites of phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) accumulation, and PtdIns(3,4,5)P3 localization is mutually modified by co-recruited SHIP2. Journal of Biological Chemistry, 285 (21). pp. 16155-16165. ISSN 0021-9258 (P), 1083-351X (O)

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Abstract

Phosphatidylinositol 3,4,5-triphosphate (PtdIns(3,4,5)P3) accumulates at the leading edge of migrating cells and works, at least partially, as both a compass to indicate directionality and a hub for subsequent intracellular events. However, how PtdIns(3,4,5)P3 regulates the migratory machinery has not been fully elucidated. Here, we demonstrate a novel mechanism for efficient lamellipodium formation that depends on PtdIns(3,4,5)P3 and the reciprocal regulation of PtdIns(3,4,5)P3 itself. LL5β, whose subcellular localization is directed by membrane PtdIns(3,4,5)P3, recruits the actin-cross-linking protein Filamin A to the plasma membrane, where PtdIns(3,4,5)P3 accumulates, with the Filamin A-binding Src homology 2 domain-containing inositol polyphosphate 5-phosphatase 2 (SHIP2). A large and dynamic lamellipodium was formed in the presence of Filamin A and LL5β by the application of epidermal growth factor. Conversely, depletion of either Filamin A or LL5β or the overexpression of either an F-actin-cross-linking mutant of Filamin A or a mutant of LL5β without its PtdIns(3,4,5)P3-interacting region inhibited such events in COS-7 cells. Because F-actin initially polymerizes near the plasma membrane, it is likely that membrane-recruited Filamin A efficiently cross-links newly polymerized F-actin, leading to enhanced lamellipodium formation at the site of PtdIns(3,4,5)P3 accumulation. Moreover, we demonstrate that co-recruited SHIP2 dephosphorylates PtdIns(3,4,5)P3 at the same location.

Item Type: Article (Journal)
Additional Information: 5128/12444
Subjects: R Medicine > RC Internal medicine > RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
Kulliyyahs/Centres/Divisions/Institutes: Kulliyyah of Science > Department of Biotechnology
Depositing User: Dr Mohammad Tariqur Rahman
Date Deposited: 23 Dec 2011 14:51
Last Modified: 23 Dec 2011 19:01
URI: http://irep.iium.edu.my/id/eprint/12444

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