title: Src Acts as an Effector for Ku70-dependent Suppression of Apoptosis through Phosphorylation of Ku70 at Tyr-530.
abstract: Src-family tyrosine kinases are widely expressed in many cell types and participate in a variety of signal transduction pathways. Despite the significance of Src in suppression of apoptosis, its mechanism remains poorly understood. Here we show that Src acts as an effector for Ku70-dependent suppression of apoptosis. Inhibition of endogenous Src activity promotes UV-induced apoptosis, which is impaired by Ku70 knockdown. Src phosphorylates Ku70 at Tyr-530, being close to the possible acetylation sites involved in promotion of apoptosis. Src-mediated phosphorylation of Ku70 at Tyr-530 decreases acetylation of Ku70, whereas Src inhibition augments acetylation of Ku70. Importantly, knockdown-rescue experiments with stable Ku70 knockdown cells show that the nonphosphorylatable Y530F mutant of Ku70 reduces the ability of Ku70 to suppress apoptosis accompanied by augmentation of Ku70 acetylation. Our results reveal that Src plays a protective role against hyperactive apoptotic cell death by reducing apoptotic susceptibility through phosphorylation of Ku70 at Tyr-530.
authors.affiliation: From the Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Mariko
authors.initials: M
authors.lastname: Morii
authors.affiliation: From the Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Sho
authors.initials: S
authors.lastname: Kubota
authors.affiliation: From the Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Takuya
authors.initials: T
authors.lastname: Honda
authors.affiliation: From the Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Ryuzaburo
authors.initials: R
authors.lastname: Yuki
authors.affiliation: From the Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Morinaga
authors.affiliation: the Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Takahisa
authors.initials: T
authors.lastname: Kuga
authors.affiliation: the Laboratory of Proteome Research, National Institutes of Biomedical Innovation, Health and Nutrition, Ibaraki, Osaka 567-0085, Japan.
authors.forename: Takeshi
authors.initials: T
authors.lastname: Tomonaga
authors.affiliation: From the Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan.
authors.forename: Noritaka
authors.initials: N
authors.lastname: Yamaguchi
authors.affiliation: From the Laboratory of Molecular Cell Biology, Graduate School of Pharmaceutical Sciences, Chiba University, Chiba 260-8675, Japan. Electronic address: nyama@faculty.chiba-u.jp.
authors.forename: Naoto
authors.initials: N
authors.lastname: Yamaguchi
mesh_terms: D019943:Amino Acid Substitution; D000818:Animals; D017209:Apoptosis; D019556:COS Cells; D002522:Chlorocebus aethiops; D006367:HeLa Cells; D006801:Humans; D000072200:Ku Autoantigen / Q000235:genetics / Q000378:metabolism*; D020125:Mutation, Missense; D010766:Phosphorylation / Q000235:genetics; D019061:src-Family Kinases / Q000235:genetics / Q000378:metabolism*
chemical_list: D019061:src-Family Kinases; D000072200:Ku Autoantigen
keywords: Ku70; Src; acetylation; apoptosis; phosphotyrosine signaling; tyrosine-protein kinase (tyrosine kinase)