Functional analysis of carboxy-terminal peptide signaling of pro-amphiregulin and pro-epiregulin

双调蛋白原和上皮调节蛋白原羧基端肽信号传导的功能分析

• 批准号: 20390082
• 负责人: HIGASHIYAMA Shigeki
• 金额: $ 12.48万
• 依托单位: Ehime University
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (B)
• 财政年份: 2008
• 资助国家: 日本
• 起止时间: 2008 至 2010
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-20390082/
• 关键词: amphiregulin; epiregulin; ectodomain shedding; EGFファミリー; CTF; 膜型増殖因子; エンドサイトーシス; レトログレード小胞輸送; 核膜移行; shedding; repressor

Amphiregulin (AREG) and epiregulin (EREG), members of the EGF family, are synthesized as type I transmembrane protein precursors (proAREG and proEREG) and expressed on the cell surface. Shedding of proAREG and proEREG yield transmembrane-cytoplasmic fragments (AREGF-CTF and EREG-CTF), as well as soluble forms AREG and EREG. Here we demonstrated that the ectodomain shedding stimuli triggered endocytosis of both their CTFs and un-shed forms. They translocated from the plasma membrane to the nuclear membrane via retrograde membrane trafficking. Nuclear envelope localization of proAREG involves truncation of the C-terminus, which subsequently activates the ER-retrieval signal. The truncated form of proAREG interacts with A-type lamin and is retained at the inner nuclear membrane. Heterochromatin formation is then induced and global transcription is transiently suppressed. This study gives new insight into epigenetic chromatin organization in mammalian cells : a plasma-membrane-anchored growth factor is targeted to the inner nuclear membrane where it participates in dynamic chromatin organization and control of transcription.

双调蛋白（AREG）和表皮调节蛋白（EREG），EGF家族的成员，被合成为I型跨膜蛋白前体（proAREG和proEREG），并在细胞表面表达。proAREG和proEREG的脱落产生跨膜-胞质片段（AREGF-CTF和EREG-CTF），以及可溶形式AREG和EREG。在这里，我们证明了胞外域脱落刺激触发了它们的CTF和未脱落形式的内吞作用。它们通过逆行膜运输从质膜易位到核膜。proAREG的核膜定位涉及C-末端的截短，其随后激活ER-恢复信号。proAREG的截短形式与A型核纤层蛋白相互作用并保留在内核膜处。然后诱导异染色质形成，并短暂抑制整体转录。这项研究为哺乳动物细胞中的表观遗传染色质组织提供了新的见解：质膜锚定生长因子靶向于内核膜，在那里它参与动态染色质组织和转录控制。

项目成果

BCL6 degradation caused by the interaction with the C-terminus of pro-HB-EGF induces cyclin D2 expression in gastric cansers

与 pro-HB-EGF C 末端相互作用引起的 BCL6 降解诱导胃癌中细胞周期蛋白 D2 的表达

• 发表时间: 2009
• 期刊: BrJCancer 100
• 作者: Hirata Y;Ogasawara N;Sasaki M;Mizushima T;Shimura T;Mizoshita T;Mori Y;Kubota E;Wada T;Tanida S;Kataoka H;Kamiya T;Higashiyama S;Joh T
• 通讯作者: Joh T

Promyelocytic leukemia zinc finger protein regulates interferon-mediated innate immunity.

• DOI: 10.1016/j.immuni.2009.04.013
• 发表时间: 2009-06-19
• 期刊: Immunity
• 影响因子: 32.4
• 作者: Xu D;Holko M;Sadler AJ;Scott B;Higashiyama S;Berkofsky-Fessler W;McConnell MJ;Pandolfi PP;Licht JD;Williams BR
• 通讯作者: Williams BR

Region-specific proliferative response of neural progenitors to exogenous stimulation by growth factors following ischemia

• DOI: 10.1097/wnr.0b013e3282ff8641
• 发表时间: 2008-05-28
• 期刊: NEUROREPORT
• 影响因子: 1.7
• 作者: Oya, Soichi;Yoshikawa, Gakushi;Kawahara, Nobutaka
• 通讯作者: Kawahara, Nobutaka

Novel monoclonal antibodies recognizing the active conformation of epidermal growth factor receptor

• DOI: 10.1016/j.bbrc.2010.03.052
• 发表时间: 2010-04-09
• 期刊: BIOCHEMICAL AND BIOPHYSICAL RESEARCH COMMUNICATIONS
• 影响因子: 3.1
• 作者: Ise, Nobuyuki;Omi, Kazuya;Goishi, Katsutoshi
• 通讯作者: Goishi, Katsutoshi

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