A Novel RNA-Binding Protein, Ossa/C9orf10, Regulates Activity of Src Kinases To Protect Cells from Oxidative Stress-Induced Apoptosis

Abstract

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 stressassociated Src activator) is a novel RNA-binding protein that guards cancer cells from oxidative stressinduced 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 dualfunctional protein and might be a novel therapeutic target which modulates the sensitivity of tumors to oxidative stress.

IL13 Receptor α2 Signaling Requires a Scaffold Protein, FAM120A, to Activate the FAK and PI3K Pathways in Colon Cancer Metastasis

“…In this report, we describe a key role for FAM120A, also known as OSSA or C9orf10 (16), in the signal transduction of IL13 through IL13Ra2 for the migration and invasion of colon cancer cells. FAM120A was identified as a scaffold protein that interacts with IL13Ra2 using mass spectrometry and coimmunoprecipitation experiments.…”

“…FAM120A recruits PI3K and works as a scaffold protein for PI3K and the Src family kinases (SFK), enabling phosphorylation and activation of PI3K (16). Silencing of FAM120A impaired the activation of PI3K, AKT, and mTOR in the metastatic cells.…”

“…In addition, we identified other 22 proteins involved in vesicle trafficking from Golgi and endoplasmatic reticulum to cell membrane (Supplementary Table S4). One of the five proteins, FAM120A (Family with sequence similarity 120A), a scaffold protein, was related to the Src family kinases (16), which were already known to be involved in IL13Ra2 signaling (2). Amongst the other four identified proteins were EPHB4, a receptor tyrosine kinase that mediates ephrin signaling; CMTM6, an unknown transmembrane protein; and PDZD8 and ACTB proteins, which are involved in cytoskeletal organization (Fig.…”

ARAP3 inhibits peritoneal dissemination of scirrhous gastric carcinoma cells by regulating cell adhesion and invasion

“…Both the 58As9 and NKPS cell lines are highly metastatic (Yanagihara et al, 2005;Tanaka et al, 2009). After establishing 58As9 and NKPS cells that stably expressed wild-type ARAP3, we injected the cells into the peritoneal cavities of BALB/c nude mice (Figure 3 and Supplemental Figure 1).…”

“…Recently, we reported that Src substrates such as CUB domain-containing protein 1 (CDCP1) (Uekita et al, 2008) and Homo sapiens chromosome 9 open reading frame 10/oxidative stress-associated Src activator (C9orf10/Ossa) (Tanaka et al, 2009) are hyperphosphorylated in the peritoneal nodules formed after inoculating the scirrhous gastric carcinoma cell line 44As3 into BALB/c nude mice. In our studies, we also detected another substrate of Src, Arf-GAP with Rho-GTPase-activated protein (GAP) domain, ankyrin repeat and PH domain 3 (ARAP3), in these nodules.…”