Intracellular and intercellular signaling mediated by Eph tyrosine kinase receptor in vascular endothelial cells
血管内皮细胞中 Eph 酪氨酸激酶受体介导的细胞内和细胞间信号传导
基本信息
- 批准号:14380342
- 负责人:
- 金额:$ 9.6万
- 依托单位:
- 依托单位国家:日本
- 项目类别:Grant-in-Aid for Scientific Research (B)
- 财政年份:2002
- 资助国家:日本
- 起止时间:2002 至 2004
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
In this research project, we have identified a Rho guanine nucleotide exchange factor(GEF)espetially expressed in vascular smooth muscle cells. We named this exchange factor Vsm-RhoGEF(Vascular smooth muscle specific GEF) after its expression and characterized the exchange specificity and localization. Vsm-RhoGEF functions downstream of EphA4 receptor and is expressed exclusively in the arterial smooth muscle cells (VSMCs), where EphA4 receptor is localized/. Furtheremore, Vsm-RhoGEF exhibits GEF activity for Rac as well as Rho. Consistently, when VSMCs were stimulated with ephrin-A1,they showed remarkable membrane ruffling, which is a hallmark of Rac activation. Vsm-RhoGEF is localized on actin stress fiber in unstimulated VSMCs, whereas it is dissociated from stress fiber to peripheral ruffled membrane upon ephrin-A1 simulation. Thus, while the Vsm-RhoGEF on stress fiber may function as a RhoGEF for Rho-RhoKinase signaling to regulate acttin-myosin coupling, the dissocicated Vsm-RhoG … More EF activates Rac for membrane extension.We further investigated the Ras family GTPases, especially R-Ras family functioning downstream of Eph tyrosine kinase. R-Ras has been suggested to function for extracellular matrix-cell adhesion when simulated by ephrin. We hypothesized that actomyosin is regulated by R-Ras, because MysoinIX contains Ras binding domain in its ajnino-terminus of the myosin head. R-Ras family consists of R-Ras, M-Ras, and TC21. We found that among them R-Ras and TC21 preferentially bind to myosinIX. Other Ras family members, H-Ras, Rap1 and Ral do not bind to MysoinIX. Thus Eph-activated R-Ras and TC21 may promote myosinIX-based motor function such as vesicular frafficking or muscle contraction.Eph tyrosine kinase receptor is endocytosed similarly to other tyrosine kinase receptor family members. We first explored the endocytosis of carboxy-terminally EGFP-tagged EphB receptors upon ephrin-B1 stimulation. PECAM-1-EGFP was used as a negative control. The cells expressing either EphB1-EGFP or PECAM-1-EGFP stimulated with ephrin-B1 were time-lapse imaged. We found that EphB1-EGFP exhibited the oligomerization upon stimulation while PECAM-1 EGFP did not. In addition to oligomerization, we found that oligomerized EphB1-EGFP was endocytosed into the cell body f from the plasma membrane. These results suggest that Eph-ephrin-mediated intracellular signaling is triggerd upon cell-cell contact and modulated by endocytosis. We will prceed to examine the molecular mechanism how Vsm-RhoGEF functions as GEF switch for Rho and/or Rac. Less
在这个研究项目中,我们发现了一个在血管平滑肌细胞中表达的鸟嘌呤核苷酸交换因子(GEF)。我们将该交换因子命名为Vsm-RhoGEF(Vascular smooth muscle specific GEF),并描述了交换的特异性和定位。Vsm-RhoGEF在EphA4受体下游发挥作用,仅在EphA4受体定位的动脉平滑肌细胞(VSMCs)中表达。此外,Vsm-RhoGEF对Rac和Rho都表现出GEF活性。一致地,当VSMCs受到ephrin-A1刺激时,它们表现出显著的膜褶皱,这是Rac激活的标志。在未受刺激的VSMCs中,Vsm-RhoGEF定位于肌动蛋白应激纤维上,而在ephrin-A1模拟中,它从应激纤维解离到周围皱襞膜上。因此,虽然应力纤维上的Vsm-RhoGEF可能作为Rho-RhoKinase信号的RhoGEF来调节肌动蛋白-肌球蛋白偶联,但分离的Vsm-RhoGEF可以激活Rac进行膜延伸。我们进一步研究了Ras家族gtpase,特别是R-Ras家族在Eph酪氨酸激酶下游的功能。经ephrin模拟,R-Ras被认为对细胞外基质-细胞粘附起作用。我们假设肌动球蛋白受R-Ras调控,因为MysoinIX在其肌凝蛋白头的末端含有Ras结合域。R-Ras家族包括R-Ras、M-Ras和TC21。我们发现其中R-Ras和TC21优先结合myosinIX。其他Ras家族成员,H-Ras, Rap1和Ral不与MysoinIX结合。因此,epf激活的R-Ras和TC21可能促进基于myosinix的运动功能,如囊泡贩运或肌肉收缩。与其他酪氨酸激酶受体家族成员相似,Eph酪氨酸激酶受体被内吞。我们首先探索了羧基末端egfp标记的EphB受体在ephrin-B1刺激下的内吞作用。PECAM-1-EGFP作为阴性对照。在ephrin-B1刺激下表达EphB1-EGFP或PECAM-1-EGFP的细胞延时成像。我们发现EphB1-EGFP在刺激下表现出寡聚化,而PECAM-1 EGFP则没有。除了寡聚化外,我们还发现寡聚化的EphB1-EGFP从质膜被内吞进入细胞体。这些结果表明,肾上腺素介导的细胞内信号是在细胞与细胞接触时触发的,并由内吞作用调节。我们将进一步研究Vsm-RhoGEF作为Rho和/或Rac的GEF开关的分子机制。少
项目成果
期刊论文数量(48)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
A Selective inhibition of vascular endothelial growth factor receptor-2(VEGFR-2)indentifies a central role for VEGFR-2 in human aortic endothelial cell responses to VEGF.
选择性抑制血管内皮生长因子受体 2 (VEGFR-2) 表明 VEGFR-2 在人主动脉内皮细胞对 VEGF 的反应中发挥核心作用。
- DOI:
- 发表时间:2003
- 期刊:
- 影响因子:0
- 作者:Fukuhara S.;et al.
- 通讯作者:et al.
Cyclic AMP potentiates VE-cadherin-mediated cell-cell contact to enhance endothelial barrier function through an Epac-Rap1 signaling pathway.
环 AMP 增强 VE-钙粘蛋白介导的细胞间接触,通过 Epac-Rap1 信号通路增强内皮屏障功能。
- DOI:
- 发表时间:2005
- 期刊:
- 影响因子:0
- 作者:Fukuhara S;Sakurai A;Sano H;Yamagishi A;Somekawa S;Takakura N;Saito Y;Kangawa K;Mochizuki N.
- 通讯作者:Mochizuki N.
Activity of Rho-family GTPases during cell division as visualized with FRET-based probes.
用基于FRET的探针可视化的细胞分裂过程中Rho-Family GTPase的活性。
- DOI:10.1083/jcb.200212049
- 发表时间:2003-07-21
- 期刊:
- 影响因子:7.8
- 作者:Yoshizaki, Hisayoshi;Ohba, Yusuke;Kurokawa, Kazuo;Itoh, Reina E;Nakamura, Takeshi;Mochizuki, Naoki;Nagashima, Kazuo;Matsuda, Michiyuki
- 通讯作者:Matsuda, Michiyuki
Regulatory roles for APJ, a seven-transmembrane receptor related to angiotensin-type 1 receptor in blood pressure in vivo
- DOI:10.1074/jbc.m404149200
- 发表时间:2004-06-18
- 期刊:
- 影响因子:4.8
- 作者:Ishida, J;Hashimoto, T;Fukamizu, A
- 通讯作者:Fukamizu, A
Shinohara M, et al.: "SWAP-70 is a guanine nucleotide-exchange factor that mediates signalling of membrane ruffling"Nature. 416. 759-763 (2002)
Shinohara M 等人:“SWAP-70 是一种鸟嘌呤核苷酸交换因子,可介导膜波动信号传导”Nature。
- DOI:
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- 期刊:
- 影响因子:0
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- 通讯作者:
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MOCHIZUKI Naoki其他文献
MOCHIZUKI Naoki的其他文献
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{{ truncateString('MOCHIZUKI Naoki', 18)}}的其他基金
Deciphering the function for S1P transporter, Spns2, in mammals
破译哺乳动物中 S1P 转运蛋白 Spns2 的功能
- 批准号:
24370084 - 财政年份:2012
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Molecular mechanism of adhesion and deadhesion of endothelial cells required for angiogenesis
血管生成所需内皮细胞粘附和死粘附的分子机制
- 批准号:
20370083 - 财政年份:2008
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
G protein-regulated trafficking analyzed by bio-imaging
通过生物成像分析 G 蛋白调节的运输
- 批准号:
17079009 - 财政年份:2005
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
Rap1-and R-Ras-regulated vascular endothelial cell-cell adhesion
Rap1 和 R-Ras 调节血管内皮细胞-细胞粘附
- 批准号:
17370075 - 财政年份:2005
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
相似海外基金
MODIFICATION OF RADIOSENSITIVITY BY ALTERATION OF ACTIVITY OF RECEPTOR TYROSINE KINASE AND ITS SIGNAL TRANSDUCTION PATHWAYS
通过改变受体酪氨酸激酶的活性及其信号转导途径来改变放射敏感性
- 批准号:
11670867 - 财政年份:1999
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Role of the signal transduction by c-kit receptor tyrosine kinase in the breast
c-kit受体酪氨酸激酶在乳腺信号转导中的作用
- 批准号:
11670230 - 财政年份:1999
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Signal transduction for cell proliferation, apoptosis and differentiation via receptor-type tyrosine kinase and Shc molecule.
通过受体型酪氨酸激酶和Shc分子进行细胞增殖、凋亡和分化的信号转导。
- 批准号:
10680662 - 财政年份:1998
- 资助金额:
$ 9.6万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
SIGNAL TRANSDUCTION BY THE ECK RECEPTOR TYROSINE KINASE
ECK 受体酪氨酸激酶的信号转导
- 批准号:
2430280 - 财政年份:1996
- 资助金额:
$ 9.6万 - 项目类别:
SIGNAL TRANSDUCTION BY THE ECK RECEPTOR TYROSINE KINASE
ECK 受体酪氨酸激酶的信号转导
- 批准号:
2152830 - 财政年份:1996
- 资助金额:
$ 9.6万 - 项目类别: