Molecular mechanism of auto-translocation of membrane anchored EGFR ligand into the nuclear membrane and its diagnostic application of cancer

膜锚定EGFR配体自转入核膜的分子机制及其在癌症诊断中的应用

• 批准号: 22650228
• 负责人: HIGASHIYAMA Shigeki
• 金额: $ 2.13万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Challenging Exploratory Research
• 财政年份: 2010
• 资助国家: 日本
• 起止时间: 2010 至 2011
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-22650228/
• 关键词: がん細胞の特性; 膜型増殖因子; HB-EGF; amphiregulin; ER/核膜移行; レトログレード小胞輸送; 膜型プロテアーゼ; 抗がん剤抵抗性; 胃がん; epiregulin; エンドサイトーシス; 核膜移行; shedding

HB-EGF and AREG are synthesized as a membrane-anchored growth factor and expressed at the plasma membrane as pro-forms in normal cells. In some malignant tumor cells in culture, however, proHB-EGF and proAREG trans-locate at the ER/nuclear membrane, which endows resistance for anti-cancer drugs. In this study, we established mouse models bearing tumor expressing proAREG auto-translocation mutant, and showed that the tumor acquired resistance for chemotherapy in vivo. We also tried to identify C-terminal processing proteases of proHB-EGF and proAREG.

HB-EGF和AREG是以膜锚定生长因子的形式合成的，在正常细胞中以前体形式在质膜上表达。然而，在一些培养的恶性肿瘤细胞中，proHB-EGF和proAREG转位到ER/核膜上，这使得抗癌药物具有耐药性。在本研究中，我们建立了表达ProAREG自体易位突变体的荷瘤小鼠模型，并表明该肿瘤在体内获得了对化疗的耐药性。我们还试图鉴定ProHB-EGF和ProAREG的C-末端加工酶。

项目成果

Cell surface annexins regulate ADAM-mediated ectodomain shedding of proamphiregulin.

• DOI: 10.1091/mbc.e11-08-0683
• 发表时间: 2012-05
• 期刊: Molecular biology of the cell
• 影响因子: 3.3
• 作者: Nakayama H;Fukuda S;Inoue H;Nishida-Fukuda H;Shirakata Y;Hashimoto K;Higashiyama S
• 通讯作者: Higashiyama S

Lysophosphatidic acid stimulates epidermal growth factor-family ectodomain shedding and paracrine signaling from human lung fibroblasts.

• DOI: 10.1111/j.1524-475x.2010.00655.x
• 发表时间: 2011-03
• 期刊: Wound repair and regeneration : official publication of the Wound Healing Society [and] the European Tissue Repair Society
• 作者: Shiomi T;Boudreault F;Padem N;Higashiyama S;Drazen JM;Tschumperlin DJ
• 通讯作者: Tschumperlin DJ

Amphiregulin nuclear translocation might cause poor prognosis due to chemotherapeutic resistance in gastric cancer

双调蛋白核易位可能因胃癌化疗耐药而导致预后不良

• 发表时间: 2011
• 作者: Yoshida M;Shimura T;Fukuda S;Higashiyama S;Mizoshita T;Kataoka H;Joh T
• 通讯作者: Joh T

Identification of novel molecules that regulate ectodomain shedding of EGF ligands

调节 EGF 配体胞外域脱落的新分子的鉴定

• 发表时间: 2010
• 作者: 福田信治;中山寛尚;東山繁樹
• 通讯作者: 東山繁樹

Nuclear envelope-localized EGF family protein amphiregulin activates breast cancer cell migration in an EGF growth factor domain independent manner

核膜定位的 EGF 家族蛋白双调蛋白以不依赖于 EGF 生长因子结构域的方式激活乳腺癌细胞迁移

• 发表时间: 2012
• 期刊: Biochem. Biophys. Res. Commun
• 作者: Tanaka H;Nishioka Y;Yokoyama Y;Higashiyama S;Matsuura N;Matsuura S;Hieda M.
• 通讯作者: Hieda M.