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

• Main Authors: Takabayashi, Tetsuji, Xie, Min-Jue, Takeuchi, Seiji, Kawasaki, Motomi, Yagi, Hideshi, Okamoto, Masayuki, Rahman, Mohammad Tariqur, Malik, Fawzia, Kuroda, Kazuki, Kubota, Chikara, Fujieda, Shigeharu, Nagano, Takashi, Sato, Makoto
• Format: Article
• Language: English
• Published: American Society for Biochemistry and Molecular Biology Inc. 2010
• Subjects: RC0321 Neuroscience. Biological psychiatry. Neuropsychiatry
• Online Access: http://irep.iium.edu.my/12444/1/LL5B_Direct_the_translocation_of_filamin_A_sites.pdf; http://irep.iium.edu.my/12444/; http://dx.doi.org/10.1074/jbc.M109.081901
• Institution: Universiti Islam Antarabangsa Malaysia

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.