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 D Huysmans,Fenny Wiradjaja,Rajendra Gurung,Lisa M Ooms,David A Sheffield,Jennifer M Dyson,Meredith J Layton,Absorn Sriratana,Hidetoshi Takada,Tony Tiganis,Christina A Mitchell

doi:10.1074/jbc.m111.263103

Parvin Rahman, Richard D Huysmans + Show 10 more

Open Access

https://doi.org/10.1074/jbc.m111.263103

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Abstract

Phosphoinositide 3-kinase (PI3K) regulates cell polarity and migration by generating phosphatidylinositol 3,4,5-trisphosphate (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 remodeling and thereby directed cell migration. The inositol polyphosphate 5-phosphatases (5-ptases) 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 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)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 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(-/-) 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.

Highlights

(NHMRC) Australia Grants 1010368 and 384137. □S The on-line version of this article contains supplemental Figs. 1–3. 1 An National Health and Medical Research Council (NHMRC) Principal Research Fellow. 2 To whom correspondence should be addressed
This study identifies silencer of death domains” (SODD) as a novel regulator of Phosphoinositide 3-kinase (PI3K)/ Akt signaling to the actin cytoskeleton
We identify that SKIP, SHIP1, and SHIP2 interact with a molecular co-chaperone designated “silencer of death domains” (SODD; called BAG4)

Summary

Introduction

(NHMRC) Australia Grants 1010368 and 384137. □S The on-line version of this article (available at http://www.jbc.org) contains supplemental Figs. 1–3. 1 An NHMRC Principal Research Fellow. 2 To whom correspondence should be addressed. Expression of FLAG-SODD reduced HA-SKIP PI[3,4,5]P3 5-ptase activity in SODDϪ/Ϫ MEFs by ϳ37% (n ϭ 4, p Ͻ 0.05) (Fig. 3F). PH-ARNO fluorescence relative to the cytosol of the same cell, revealed a ϳ25% increase in FLAG-SODD-expressing cells, relative to vector controls following 10-min EGF stimulation (Fig. 4B).

Results

Conclusion