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

Research output: Contribution to journalArticle

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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)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 identifiesSODDas a novel regulator of PI3K/Akt signaling to the actin cytoskeleton.

Original languageEnglish
Pages (from-to)29758-29770
Number of pages13
JournalJournal of Biological Chemistry
Volume286
Issue number34
DOIs
Publication statusPublished - Aug 26 2011

Fingerprint

1-Phosphatidylinositol 4-Kinase
Inositol
Phosphatidylinositols
Actin Cytoskeleton
Phosphoric Monoester Hydrolases
Muscle
Actins
Skeletal Muscle
Phosphotransferases
Kidney
Cell Movement
Fibroblasts
Epidermal Growth Factor
Chemical activation
Polyphosphates
Phosphorylation
Macrophages
Protein-Serine-Threonine Kinases
Stress Fibers
Cell Polarity

All Science Journal Classification (ASJC) codes

  • Biochemistry
  • Cell Biology
  • Molecular Biology

Cite this

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. / 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.

In: Journal of Biological Chemistry, Vol. 286, No. 34, 26.08.2011, p. 29758-29770.

Research output: Contribution to journalArticle

Rahman, P, Huysmans, RD, Wiradjaja, F, Gurung, R, Ooms, LM, Sheffield, DA, Dyson, JM, Layton, MJ, Sriratana, A, Takada, H, Tiganis, T & Mitchell, CA 2011, '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', Journal of Biological Chemistry, vol. 286, no. 34, pp. 29758-29770. https://doi.org/10.1074/jbc.M111.263103
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. / 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. In: Journal of Biological Chemistry. 2011 ; Vol. 286, No. 34. pp. 29758-29770.
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AU - Gurung, Rajendra

AU - Ooms, Lisa M.

AU - Sheffield, David A.

AU - Dyson, Jennifer M.

AU - Layton, Meredith J.

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