A novel RNA-binding protein, Ossa/C9orf10, regulates activity of Src kinases to protect cells from oxidative stress-induced apoptosis.
During the process of tumor progression and clinical treatments, tumor cells are exposed to oxidative stress. Tumor cells are frequently resistant to such stress by producing antiapoptotic signaling, including activation of Src family kinases (SFKs), although the molecular mechanism is not clear. In an attempt to identify the SFK-binding proteins selectively phosphorylated in gastric scirrhous carcinoma, we identified an uncharacterized protein, C9orf10. Here we report that C9orf10 (designated Ossa for oxidative stress-associated Src activator) is a novel RNA-binding protein that guards cancer cells from oxidative stress-induced apoptosis by activation of SFKs. Exposure to oxidative stress such as UV irradiation induces the association of Ossa/C9orf10 with regulatory domains of SFKs, which activates these kinases and causes marked tyrosine phosphorylation of C9orf10 in turn. Tyrosine-phosphorylated Ossa recruits p85 subunits of phosphatidylinositol 3-kinase (PI3-kinase) and behaves as a scaffolding protein for PI3-kinase and SFKs, which activates the Akt-mediated antiapoptotic pathway. On the other hand, the carboxyl terminus of Ossa has a distinct function that directly binds RNAs such as insulin-like growth factor II (IGF-II) mRNA and promotes the extracellular secretion of IGF-II. Our findings indicate that Ossa is a dual-functional protein and might be a novel therapeutic target which modulates the sensitivity of tumors to oxidative stress.
Tanaka
Masamitsu
M
Department of Growth Factor Division, National Cancer Center Research Institute, 5-1-1 Tsukiji, Chuo-ku, Tokyo 104-0045, Japan.
Sasaki
Kazuki
K
Kamata
Reiko
R
Hoshino
Yukari
Y
Yanagihara
Kazuyoshi
K
Sakai
Ryuichi
R
D002293:Adenocarcinoma, Scirrhous / Q000378:metabolism / Q000473:pathology; D000818:Animals; D017209:Apoptosis / Q000235:genetics; D020134:Catalytic Domain / Q000502:physiology; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D006801:Humans; D007335:Insulin-Like Growth Factor II / Q000378:metabolism; D051379:Mice; D008807:Mice, Inbred BALB C; D009368:Neoplasm Transplantation; D018384:Oxidative Stress; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D016601:RNA-Binding Proteins / Q000737:chemistry / Q000235:genetics / Q000378:metabolism*; D013274:Stomach Neoplasms / Q000378:metabolism / Q000473:pathology; D018909:src Homology Domains / Q000502:physiology; D019061:src-Family Kinases / Q000378:metabolism*
C534604:FAM120A protein, human; D016601:RNA-Binding Proteins; D007335:Insulin-Like Growth Factor II; D019869:Phosphatidylinositol 3-Kinases; D019061:src-Family Kinases