Silencer of death domains (SODD) inhibits skeletal muscle and kidney enriched inositol 5-phosphatase (SKIP) and regulates phosphoinositide 3-kinase (PI3K)/Akt signaling to the actin cytoskeleton

Parvin Rahman, Richard Huysmans, Fenny Wiradjaja, Rajendra Gurung, Lisa Ooms, David Sheffield, Jennifer Dyson, Meredith Layton, Absorn Sriratana, Hidetoshi Takada, Tony Tiganis, Christina Anne Mitchell

Research output: Contribution to journalArticleResearchpeer-review

12 Citations (Scopus)

Abstract

Phosphoinositide 3-kinase (PI3K) regulates cell polarity and migration by generating PI(3,4,5)P(3) at the leading edge of migrating cells. The serine-threonine protein kinase Akt binds to PI(3,4,5)P(3) resulting in its activation. Active Akt promotes spatially regulated actin cytoskeletal remodelling and thereby directed cell migration. The inositol polyphosphate 5-phosphatases (5-ptase) degrade PI(3,4,5)P(3) to form PI(3,4)P(2), which leads to diminished Akt activation. Several 5-ptases, including SKIP and SHIP2 inhibit actin cytoskeletal reorganisation by opposing PI3K/Akt signalling. 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)P(3) 5-ptase catalytic activity, and consequently enhances the recruitment of PI(3,4,5)P(3)-effectors to the plasma membrane. In contrast, (-/-)SODD mouse embryonic fibroblasts (MEFs) exhibit reduced Akt-Ser(473) and -Thr(308) phosphorylation following EGF stimulation, associated with increased SKIP PI(3,4,5)P(3)-5-ptase activity. (-/-)SODD MEFs exhibit decreased EGF-stimulated F-actin stress fibers, lamellipodia and focal adhesion complexity, a phenotype that is rescued by 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 signalling to the actin cytoskeleton.
Original languageEnglish
Pages (from-to)29758 - 29770
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number34
DOIs
Publication statusPublished - 2011

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