Carboxy-ternminal fragment signaling of membrane-anchored growth factors the EGF family

EGF家族膜锚定生长因子的羧基末端片段信号传导

• 批准号: 17390081
• 负责人: HIGASHIYAMA Shigeki
• 金额: $ 9.41万
• 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: 2005
• 资助国家: 日本
• 起止时间: 2005 至 2006
• 项目状态: 已结题
• 来源: https://kaken.nii.ac.jp/grant/KAKENHI-PROJECT-17390081/
• 关键词: HB-EGF; CTF; PLZF; c-myc; EGF; bFGF; PDGF; cell cycle progression; EGF-ファミリー; Shedding; TGF-α; ampbiregulin; epiregulin; メタロプロテアーゼ; γ-セクレターゼ

A key step for signaling through the epidermal growth factor receptor (EGFR) is the release of mature ligands such as heparin-binding EGF-like growth factor (HB-EGF) from their membrane-anchored precursor forms, a process termed "ectodomain shedding". The HB-EGF precursor (proHB-EGF) is cleaved by members of the "a disintegrin and metalloprotease" (ADAM) protease family, yielding the carboxyl terminal fragment of proHB-EGF (HB-EGF-CTF) in parallel with the production of HB-EGF. We have previously characterized HB-EGF-CTF as a novel intracellular signaling molecule acquired posttranslationally which is translocated into the nucleus, binding and inactivating the promyelocytic leukemia zinc finger protein (PLZF). PLZF is a transcriptional repressor that suppresses the transcription of genes such as c-MYC, Cyclin A2, and HoxD11. Activation of growth factor receptors by ligand binding leads to increased expression of c-Myc, a transcriptional regulator for cell proliferation. The activation … More of transcriptional factors through the activated receptors has been thought to be a main role in the c-Myc gene expression. We demonstrate here that EGFR-,FGFR-, and PDGFR-mediated c-Myc induction and cell cycle progression in the primary cultured mouse embryonic fibroblasts (MEFs) are abrogated by knockout of the heparin-binding EGF-like growth factor (Hb-egf) gene, or by a metalloproteinase inhibitor, although the downstream of the receptors is activated. The induction of c-Myc expression by EGF or bFGF recovers in the Hb-egf-knockouted MEFs by overexpression of wildtype proHB-EGF, though no recovery with an uncleavable mutant of proHB-EGF. It is also observed that the uncleavable mutant inhibits the EGF-induced acetylation of histone H3 at the mouse c-Myc first intron region which negatively affects the transcriptional activation. We conclude that the signal transduction initiated by generation of the carboxyl terminal fragment of proHB-EGF (HB-EGF-CTF) in the shedding event can play an essential intermediary role between growth factor receptor activation and c-Myc gene induction. Less

通过表皮生长因子受体 (EGFR) 发出信号的关键步骤是从其膜锚定前体形式中释放成熟配体，例如肝素结合 EGF 样生长因子 (HB-EGF)，这一过程称为“胞外域脱落”。 HB-EGF 前体 (proHB-EGF) 被“解整合素和金属蛋白酶”(ADAM) 蛋白酶家族的成员裂解，在产生 HB-EGF 的同时产生 proHB-EGF 的羧基末端片段 (HB-EGF-CTF)。我们之前已将 HB-EGF-CTF 描述为一种通过翻译后获得的新型细胞内信号分子，其易位到细胞核中，结合并灭活早幼粒细胞白血病锌指蛋白 (PLZF)。 PLZF 是一种转录阻遏蛋白，可抑制 c-MYC、Cyclin A2 和 HoxD11 等基因的转录。通过配体结合激活生长因子受体会导致细胞增殖转录调节因子 c-Myc 的表达增加。通过激活的受体激活转录因子被认为是 c-Myc 基因表达的主要作用。我们在这里证明，在原代培养的小鼠胚胎成纤维细胞（MEF）中，EGFR、FGFR 和 PDGFR 介导的 c-Myc 诱导和细胞周期进程可以通过敲除肝素结合 EGF 样生长因子（Hb-egf）基因或通过金属蛋白酶抑制剂来消除，尽管受体的下游被激活。 EGF 或 bFGF 对 c-Myc 表达的诱导在 Hb-egf 敲除的 MEF 中通过野生型 proHB-EGF 的过表达而恢复，但不可切割的 proHB-EGF 突变体则没有恢复。还观察到不可切割突变体抑制 EGF 诱导的小鼠 c-Myc 第一个内含子区域组蛋白 H3 的乙酰化，从而对转录激活产生负面影响。我们得出的结论是，在脱落事件中由 proHB-EGF 的羧基末端片段 (HB-EGF-CTF) 的产生启动的信号转导可以在生长因子受体激活和 c-Myc 基因诱导之间发挥重要的中介作用。较少的

项目成果

The HNF-1 target Collectrin controls insulin exocytosis by SNARE complex formation

• DOI: 10.1016/j.cmet.2005.11.003
• 发表时间: 2005-12-01
• 期刊: CELL METABOLISM
• 影响因子: 29
• 作者: Fukui, K;Yang, Q;Yamagata, K
• 通讯作者: Yamagata, K

Loss of HB-EGF in smooth muscle or endothelial cell lineages causes heart valve malformation and cardiac hypertrophy.

平滑肌或内皮细胞谱系中 HB-EGF 的缺失会导致心脏瓣膜畸形和心脏肥大。

• 发表时间: 2006
• 期刊: Biochem Biophys Res Commun. 350
• 作者: Nanba;D.;Kinugasa;Y.;Morimoto;C.;Koizumi;M.;Yamamutra;H.;Takahashi;K.;Takakura;N.;Mekada;E.;Hashimoto;K.;Higashiyama;S.
• 通讯作者: S.

Regenerative and therapeutic effects of heparin-binding epidermal growth factor-like growth factor on diabetes by gene transduction through retrograde pancreatic duct injection of adenovirus vector

• DOI: 10.1097/01.mpa.0000163177.59920.f8
• 发表时间: 2005-07-01
• 期刊: PANCREAS
• 影响因子: 2.9
• 作者: Kozawa, J;Tokui, Y;Miyagawa, J
• 通讯作者: Miyagawa, J

Pbxl is a major target of PLZF-mediated melanoma cell growth suppression

Pbxl 是 PLZF 介导的黑色素瘤细胞生长抑制的主要靶点

• 发表时间: 2006
• 作者: K;Shiraishi;Y;Shirakata;K;Yamasaki;Y;Hanakawa;S;Higashiyama;K;Hashimoto
• 通讯作者: Hashimoto

Induction of keratinocyte migration via transactivation of the epidermal growth factor receptor by the antimicrobial peptide LL-37

• DOI: 10.4049/jimmunol.175.7.4662
• 发表时间: 2005-10-01
• 期刊: JOURNAL OF IMMUNOLOGY
• 影响因子: 4.4
• 作者: Tokumaru, S;Sayama, K;Hashimoto, K
• 通讯作者: Hashimoto, K