title: 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.
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.
authors.affiliation: Department of Biochemistry and Molecular Biology, Monash University, Clayton, Victoria, Australia.
authors.forename: Parvin
authors.initials: P
authors.lastname: Rahman
authors.forename: Richard D
authors.initials: RD
authors.lastname: Huysmans
authors.forename: Fenny
authors.initials: F
authors.lastname: Wiradjaja
authors.forename: Rajendra
authors.initials: R
authors.lastname: Gurung
authors.forename: Lisa M
authors.initials: LM
authors.lastname: Ooms
authors.forename: David A
authors.initials: DA
authors.lastname: Sheffield
authors.forename: Jennifer M
authors.initials: JM
authors.lastname: Dyson
authors.forename: Meredith J
authors.initials: MJ
authors.lastname: Layton
authors.forename: Absorn
authors.initials: A
authors.lastname: Sriratana
authors.forename: Hidetoshi
authors.initials: H
authors.lastname: Takada
authors.forename: Tony
authors.initials: T
authors.lastname: Tiganis
authors.forename: Christina A
authors.initials: CA
authors.lastname: Mitchell
mesh_terms: D000199:Actins / Q000235:genetics / Q000378:metabolism*; D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism*; D000818:Animals; D002465:Cell Movement / Q000502:physiology; D004622:Embryo, Mammalian / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D022001:Focal Adhesions / Q000235:genetics / Q000378:metabolism; D000072181:Inositol Polyphosphate 5-Phosphatases; D051379:Mice; D018345:Mice, Knockout; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism*; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases; D010744:Phosphoric Monoester Hydrolases / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism*; D011554:Pseudopodia / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology*; D022502:Stress Fibers / Q000235:genetics / Q000378:metabolism*
chemical_list: D000199:Actins; D048868:Adaptor Proteins, Signal Transducing; C487979:Bag4 protein, mouse; D019869:Phosphatidylinositol 3-Kinases; D051057:Proto-Oncogene Proteins c-akt; C531212:Pps protein, mouse; D010744:Phosphoric Monoester Hydrolases; D000072181:Inositol Polyphosphate 5-Phosphatases; C000606433:Inpp5d protein, mouse; C000606435:Inppl1 protein, mouse; D000072183:Phosphatidylinositol-3,4,5-Trisphosphate 5-Phosphatases