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PMID:21712384

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Citation

Rahman, P, Huysmans, RD, Wiradjaja, F, Gurung, R, Ooms, LM, Sheffield, DA, Dyson, JM, Layton, MJ, Sriratana, A, Takada, H, Tiganis, T and 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. J. Biol. Chem. 286:29758-70

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.

Links

PubMed PMC3191017 Online version:10.1074/jbc.M111.263103

Keywords

Actins/genetics; Actins/metabolism; Adaptor Proteins, Signal Transducing/genetics; Adaptor Proteins, Signal Transducing/metabolism; Animals; Cell Movement/physiology; Embryo, Mammalian/metabolism; Fibroblasts/metabolism; Focal Adhesions/genetics; Focal Adhesions/metabolism; Mice; Mice, Knockout; Phosphatidylinositol 3-Kinases/genetics; Phosphatidylinositol 3-Kinases/metabolism; Phosphoric Monoester Hydrolases/antagonists & inhibitors; Phosphoric Monoester Hydrolases/genetics; Phosphoric Monoester Hydrolases/metabolism; Proto-Oncogene Proteins c-akt/genetics; Proto-Oncogene Proteins c-akt/metabolism; Pseudopodia/genetics; Pseudopodia/metabolism; Signal Transduction/physiology; Stress Fibers/genetics; Stress Fibers/metabolism

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:SHIP2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8CI61

F

Seeded From UniProt

complete

HUMAN:BAG4

located_in

GO:0005634: nucleus

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BAG4

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BAG4

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:BAG4

involved_in

GO:0071356: cellular response to tumor necrosis factor

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAG4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:O15357

F

Seeded From UniProt

complete

MOUSE:BAG4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q92835

F

Seeded From UniProt

complete

MOUSE:BAG4

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q9BT40

F

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0033138: positive regulation of peptidyl-serine phosphorylation

ECO:0000315: mutant phenotype evidence used in manual assertion

P

  • has_input:(UniProtKB:P31750)
  • has_input:(UniProtKB:Q9R1E0)

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0030838: positive regulation of actin filament polymerization

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0010763: positive regulation of fibroblast migration

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:2001145: negative regulation of phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:Q9BT40)

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0051897: positive regulation of protein kinase B signaling

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0051496: positive regulation of stress fiber assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0072659: protein localization to plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

P

  • has_input:(UniProtKB:P63034)

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0071364: cellular response to epidermal growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0045785: positive regulation of cell adhesion

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:BAG4

involved_in

GO:0097178: ruffle assembly

ECO:0000315: mutant phenotype evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:SHIP1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8CI61

F

Seeded From UniProt

complete

HUMAN:INP5K

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:Q8CI61

F

Seeded From UniProt

complete

HUMAN:INP5K

enables

GO:0034485: phosphatidylinositol-3,4,5-trisphosphate 5-phosphatase activity

ECO:0000314: direct assay evidence used in manual assertion

F

Seeded From UniProt

complete

HUMAN:INP5K

involved_in

GO:0016311: dephosphorylation

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:INP5K

located_in

GO:0048471: perinuclear region of cytoplasm

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:INP5K

located_in

GO:0005829: cytosol

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:INP5K

located_in

GO:0005886: plasma membrane

ECO:0000314: direct assay evidence used in manual assertion

C

Seeded From UniProt

complete

HUMAN:INP5K

involved_in

GO:0071364: cellular response to epidermal growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

HUMAN:INP5K

involved_in

GO:0071356: cellular response to tumor necrosis factor

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete

MOUSE:AKT1

involved_in

GO:0071364: cellular response to epidermal growth factor stimulus

ECO:0000314: direct assay evidence used in manual assertion

P

Seeded From UniProt

complete


See also

References

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