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Rahman, Parvin; Huysmans, Richard D.; Wiradjaja, Fenny; Gurung, Rajendra; Ooms, Lisa M.; Sheffield, David A.; Dyson, Jennifer M.; Layton, Meredith J.; Sriratana, Absorn; Takada, Hidetoshi; Tiganis, Tony; Mitchell, Christina A.
Journal of biological chemistry/The Journal of biological chemistry, 08/2011, Letnik: 286, Številka: 34Journal Article
Phosphoinositide 3-kinase (PI3K) regulates cell polarity and migration by generating phosphatidylinositol 3,4,5-trisphosphate (PI(3,4,5)P3) at the leading edge of migrating cells. The serine-threonine protein kinase Akt binds to PI(3,4,5)P3, resulting in its activation. Active Akt promotes spatially regulated actin cytoskeletal remodeling and thereby directed cell migration. The inositol polyphosphate 5-phosphatases (5-ptases) degrade PI(3,4,5)P3 to form PI(3,4)P2, which leads to diminished Akt activation. Several 5-ptases, including SKIP and SHIP2, inhibit actin cytoskeletal reorganization by opposing PI3K/Akt signaling. In this current study, we identify a molecular co-chaperone termed silencer of death domains (SODD/BAG4) that forms a complex with several 5-ptase family members, including SKIP, SHIP1, and SHIP2. The interaction between SODD and SKIP exerts an inhibitory effect on SKIP PI(3,4,5)P3 5-ptase catalytic activity and consequently enhances the recruitment of PI(3,4,5)P3-effectors to the plasma membrane. In contrast, SODD−/− mouse embryonic fibroblasts exhibit reduced Akt-Ser473 and -Thr308 phosphorylation following EGF stimulation, associated with increased SKIP PI(3,4,5)P3-5-ptase activity. SODD−/− mouse embryonic fibroblasts exhibit decreased EGF-stimulated F-actin stress fibers, lamellipodia, and focal adhesion complexity, a phenotype that is rescued by the expression of constitutively active Akt1. Furthermore, reduced cell migration was observed in SODD−/− macrophages, which express the three 5-ptases shown to interact with SODD (SKIP, SHIP1, and SHIP2). Therefore, this study identifies SODD as a novel regulator of PI3K/Akt signaling to the actin cytoskeleton.
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JCR | SNIP | JCR | SNIP | JCR | SNIP | JCR | SNIP |
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in: SICRIS
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