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J. Biol. Chem. 286 (34): 29758-29770

© 2011 by The American Society for Biochemistry and Molecular Biology, Inc.

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*Formula

Parvin Rahman{ddagger}, Richard D. Huysmans{ddagger}, Fenny Wiradjaja{ddagger}, Rajendra Gurung{ddagger}, Lisa M. Ooms{ddagger}, David A. Sheffield{ddagger}, Jennifer M. Dyson{ddagger}, Meredith J. Layton{ddagger}, Absorn Sriratana{ddagger}, Hidetoshi Takada§, Tony Tiganis{ddagger}1, , and Christina A. Mitchell{ddagger}2

From the {ddagger}Department of Biochemistry and Molecular Biology, Monash University, Clayton, 3800 Victoria, Australia and
the §Campbell Family Institute of Breast Cancer Research, Ontario Cancer Institute, University Health Network and Department of Medical Biophysics, University of Toronto, Toronto, Ontario M5G 2C1, Canada

ABSTRACT Back to Top

Abstract: 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.

Key Words: Akt PKB • Cell Migration • Phosphatidylinositol 3-Kinase • Phosphatidylinositol Phosphatase • Phosphatidylinositol Signaling • Signal Transduction • Silencer of Death Domains (SODD) • Skeletal Muscle and Kidney Enriched Inositol Phosphatase (SKIP) • Actin Cytoskeleton • Inositol Polyphosphate 5-Phosphatase

Received for publication May 20, 2011. Revision received June 28, 2011.

FOOTNOTES Back to Top

1 An NHMRC Principal Research Fellow.

2 To whom correspondence should be addressed. Fax: 61-399029435; E-mail: christina.mitchell{at}monash.edu.

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