TY - JOUR
T1 - 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
AU - Rahman, Parvin
AU - Huysmans, Richard
AU - Wiradjaja, Fenny
AU - Gurung, Rajendra
AU - Ooms, Lisa
AU - Sheffield, David
AU - Dyson, Jennifer
AU - Layton, Meredith
AU - Sriratana, Absorn
AU - Takada, Hidetoshi
AU - Tiganis, Tony
AU - Mitchell, Christina Anne
PY - 2011
Y1 - 2011
N2 - Phosphoinositide 3-kinase (PI3K) regulates cell polarity and migration by generating 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 remodelling and thereby directed cell migration. The inositol polyphosphate 5-phosphatases (5-ptase) 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 reorganisation by opposing PI3K/Akt signalling. 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 (MEFs) 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 MEFs exhibit decreased EGF-stimulated F-actin stress fibers, lamellipodia and focal adhesion complexity, a phenotype that is rescued by 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 signalling to the actin cytoskeleton.
AB - Phosphoinositide 3-kinase (PI3K) regulates cell polarity and migration by generating 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 remodelling and thereby directed cell migration. The inositol polyphosphate 5-phosphatases (5-ptase) 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 reorganisation by opposing PI3K/Akt signalling. 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 (MEFs) 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 MEFs exhibit decreased EGF-stimulated F-actin stress fibers, lamellipodia and focal adhesion complexity, a phenotype that is rescued by 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 signalling to the actin cytoskeleton.
UR - http://www.jbc.org/content/286/34/29758.full.pdf+html
U2 - 10.1074/jbc.M111.263103
DO - 10.1074/jbc.M111.263103
M3 - Article
SN - 0021-9258
VL - 286
SP - 29758
EP - 29770
JO - Journal of Biological Chemistry
JF - Journal of Biological Chemistry
IS - 34
ER -