The effects of extracellular cleavage of ephrin-B1 on cancer and nerve cells

ephrin-B1 细胞外裂解对癌症和神经细胞的影响

• 批准号: 17590282
• 负责人: TANAKA Masamitsu
• 金额: $ 2.11万
• 依托单位: National Cancer Center Research Institute and Research Center for Innovative Oncology, National Cancer Center Hospital East
• 依托单位国家: 日本
• 项目类别: Grant-in-Aid for Scientific Research (C)
• 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/en/grant/KAKENHI-PROJECT-17590282/
• 关键词: Cancer; Cell, tissue; signal transduction; ephrin

Ephrins function as ligands for Eph receptor protein tyrosine kinases in many physiological processes such as the development of the nervous system. Because ephrins are tethered to cell membrane, ephrins also have receptor-like activity and cause reverse signaling in response to the interaction with the cognate Eph receptors. However, we found that extracellular region of ephrin-B1 is secreted in the culture medium of some pancreas cancer cell lines, which is significantly stimulated by interaction with Eph receptor B2 (EphB2). While we investigated the mechanism of the cleavage of ephrin-B1 ectodomain, we observed that reverse signalling by ephrin-B1 promotes the invasive properties of cancer cells by regulating the secretion of matrix metalloproteinase-8 (MMP-8), which was the key enzyme of ephrin-B1 cleavage Ephrin-B1, a transmembrane protein, is often overexpressed in highly invasive tumours. We found that binding of EphB2 to ephrin-B1 expressed by pancreatic cancer cells promotes their secretion of MMP-8. This reverse signalling activity of ephrin-B1 requires its intracellular C terminus and involves the activation of Arf1 GTPase, a regulator of membrane trafficking. Furthermore, the promotion of pancreatic tumour cell invasion in vivo by ephrin-B1 also requires it to have an intact C terminus. Thus, we propose, the C terminus of ephrin-B1 regulates the invasive potential of cancer cells by stimulating the secretion of MMP-8. This then promotes extracellular matrix degradation, which is needed for invasion. Our results suggest that ephrin-B1 is a potential therapeutic target of cancers.

在许多生理过程中，例如神经系统的发展，ephrins充当EPH受体蛋白酪氨酸激酶的配体。由于以弗林的束缚在细胞膜上，所以埃弗林也具有类似受体的活性，并导致与同源EPH受体相互作用的反应。然而，我们发现在某些胰腺癌细胞系的培养基中分泌埃弗林-B1的细胞外区域，这是通过与EPH受体B2相互作用显着刺激的（EPHB2）。虽然我们研究了ephrin-b1外生域裂解的机制，但我们观察到，ephrin-b1的反向信号通过调节基质金属蛋白酶8（MMP-8）的分泌来促进癌细胞的侵入性特性，这是关键的酶蛋白酶。 ephrin-b1裂解ephrin-b1（一种跨膜蛋白）通常在高度浸润性的肿瘤中过表达。我们发现，胰腺癌细胞表达的Ephb2与Ephrin-B1的结合促进了其分泌MMP-8。 ephrin-b1的这种反向信号传导活性需要其细胞内C末端，并涉及膜运输调节剂ARF1 GTPase的激活。此外，以弗林-B1在体内促进胰腺肿瘤细胞侵袭还需要完整的C末端。因此，我们提出，ephrin-B1的C末端通过刺激MMP-8的分泌来调节癌细胞的侵入性潜力。然后，这促进了细胞外基质降解，这是入侵所需的。我们的结果表明，ephrin-b1是癌症的潜在治疗靶点。

项目成果

Phosphorylation of ephrin-B1 regulates dissemination of gastric scirrhous carcinoma.

肝配蛋白 B1 的磷酸化调节胃硬癌的扩散。

• 发表时间: 2007
• 期刊: Am. J. Pathol. 171
• 作者: Tanaka;M.;Kamata;R.;Takigahira;M.;Yanagihara;K.;Sakai;R.
• 通讯作者: R.

The carboxyl terminus of ephrin-B1 regulates metalloproteinase secretion and invasion ot cancer cells.

ephrin-B1 的羧基末端调节金属蛋白酶的分泌和癌细胞的侵袭。

• 发表时间: 2007
• 期刊: Journal of Cell Science 120(in press)
• 作者: Masamitsu Tanaka;Reiko Kamata;Misato Takigahira;Kazuyoshi Yanagihara and Ryuichi Sakai
• 通讯作者: Kazuyoshi Yanagihara and Ryuichi Sakai

The carboxyl terminus of ephrin-B1 regulates metalloproteinase secretion and invasion of cancer cells

ephrin-B1的羧基末端调节金属蛋白酶分泌和癌细胞的侵袭

• 发表时间: 2007
• 期刊: Journal of Cell Science 120(in press)
• 作者: Adachi M;Zhao X;Imai K.;Masamitsu Tanaka
• 通讯作者: Masamitsu Tanaka

Phosphorylation of ephrin-B1 via the interaction with claudin following cell-cell contact formation

• DOI: 10.1038/sj.emboj.7600831
• 发表时间: 2005-11-02
• 期刊: EMBO JOURNAL
• 影响因子: 11.4
• 作者: Tanaka, M;Kamata, R;Sakai, R
• 通讯作者: Sakai, R

Phosphorylation of ephrin-B1 regulates dissemination of gastric scirrhous carcinoma

ephrin-B1 磷酸化调节胃硬癌的扩散

• 发表时间: 2007
• 期刊: Am.J.Pathol 171
• 作者: Tanaka;M.
• 通讯作者: M.