Molecular Mechanism of Regulation of Effector Activities by Small GTP-binding Proteins
小 GTP 结合蛋白调节效应子活性的分子机制
基本信息
- 批准号:11470034
- 负责人:
- 金额:$ 9.47万
- 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:1999
- 资助国家:日本
- 起止时间:1999 至 2000
- 项目状态:已结题
- 来源:
- 关键词:
项目摘要
1. We showed that the strength of interaction at the Raf cysteine-rich domain (CRD) determines the response of Raf-1 and B-Raf to Ras and Rap1, and that the interaction of Ras/Rap1 with CRD is regulated through phosphorylation of Raf-1 CR2 domain. These results strongly support our hypothesis that the strength of interaction between Ras/Rap1 and Raf-CRD must be in an adequate level to cause Raf activation2. We discovered a novel interaction between famesylated Ras and a complex between adenylyl cyclase-associated protein CAP and the C-terminus of adenylyl cyclase, and showed that this second interaction is responsible for the stimulatory effect of farnesylation on Ras-dependent adenylyl cyclase activation. This result taken together with the data on Raf suggests that the farnesylation-dependent second interaction may be generally required for activation of effector molecules by Ras/Rap1.3. We discovered a novel form of human phosphoinositide-specific phospholipase C, PLCε.PLCε exhibits GTP-dependent binding to both Ras and Rap1. PLCε is translocated from the cytoplasm to the Plasma membrane and the Golgi apparatus when coexpressed with Ras and Rap1, respectively, and its phospholipase C activity is stimulated by Ras. Further, PLCε possesses a stimulatory activity on guanine nucleotide exchange of Rap1 at its CDC25-like domain. These results indicate that PLCε defines a novel category of Ras/Rap1 effector with the ability to amplify its signaling through Rap1 activation.4. We discovered a novel form of guanine nucleotide exchange factor (GEF) for Rap1, RA-GEF.Human RA-GEF-1 binds Rap1-GTP at its RA domain and exhibits GEF activity toward Rap1/2 at its GEF domain. Further, we showd that RA-GEF-1 is translocated to the Golgi apparatus by association with Rap1-GTP and catalyzes activation of Rap1-GDP, thereby causing an amplification of cellular responses induced by Rap1. Similarly, human RA-GEF-2 binds M-Ras-GTP at its RA domain.
1.我们发现Raf富含半胱氨酸结构域(CRD)的相互作用强度决定了Raf-1和B-Raf对Ras和Rap 1的反应,并且Ras/Rap 1与CRD的相互作用通过Raf-1 CR2结构域的磷酸化来调节。这些结果强烈支持我们的假设,Ras/Rap 1和Raf-CRD之间的相互作用的强度必须在一个足够的水平,导致Raf激活2。我们发现了一种新的相互作用之间的法呢基化的Ras和腺苷酸环化酶相关蛋白CAP和腺苷酸环化酶的C-末端之间的复合物,并表明,这第二个相互作用是负责的刺激作用的Ras依赖的腺苷酸环化酶的激活。这一结果与Raf的数据一起表明,法尼基化依赖的第二次相互作用可能是Ras/Rap1.3激活效应分子所必需的。我们发现了一种新的人磷脂酰肌醇特异性磷脂酶C(PLCε),PLCε与Ras和Rap 1均具有GTP依赖性结合。当PLCε分别与Ras和Rap 1共表达时,PLCε从细胞质转移到质膜和高尔基体,并且其磷脂酶C活性被Ras激活。此外,PLCε对Rap 1在其CDC 25样结构域的鸟嘌呤核苷酸交换具有刺激活性。这些结果表明PLCε定义了一类新的Ras/Rap 1效应子,具有通过Rap 1激活放大其信号传导的能力.我们发现了Rap 1的一种新的鸟嘌呤核苷酸交换因子(GEF),RA-GEF-1在其RA结构域与Rap 1-GTP结合,在其GEF结构域对Rap 1/2具有GEF活性。此外,我们发现RA-GEF-1通过与Rap 1-GTP结合而易位到高尔基体,并催化Rap 1-GDP的活化,从而引起Rap 1诱导的细胞反应的放大。类似地,人RA-GEF-2在其RA结构域结合M-Ras-GTP。
项目成果
期刊论文数量(43)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
H.Sendoh et al:,: "Role of Raf-1 conserved region 2 in regulation of Ras-dependent Raf-1 activation."Biochemical and Biophysical Research Commmunications. 271巻3号. 596-602 (2000)
H.Sendoh 等人:“Raf-1 保守区 2 在 Ras 依赖性 Raf-1 激活调节中的作用”。生物化学和生物物理研究通讯,第 271 卷,第 3 期。596-602 (2000)
- DOI:
- 发表时间:
- 期刊:
- 影响因子:0
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- 通讯作者:
H.Sendoh et al.: "Role of Raf-1 conserved region 2 in regulation of Rasdependent Raf-1 activation."Biochem.Biophys.Res.Comm.. 271(3). 596-602 (2000)
H.Sendoh 等人:“Raf-1 保守区 2 在 Ras 依赖性 Raf-1 激活调节中的作用。”Biochem.Biophys.Res.Comm.. 271(3)。
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- 影响因子:0
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T.Okada et al.: "The strength of interaction at the Raf cysteine-rich domain is a critical determinant of response of Raf to Ras family, small GTPases"Mol.Cell.Biol.. 19(9). 6057-6064 (1999)
T.Okada 等人:“Raf 富含半胱氨酸结构域的相互作用强度是 Raf 对 Ras 家族、小 GTP 酶反应的关键决定因素”Mol.Cell.Biol.. 19(9)。
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- 发表时间:
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- 影响因子:0
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- 通讯作者:
Okada,T.,et al.: "The strength of interaction at the Raf cysteine-rich domain is a critical determinant of response of Raf to Ras family small GTPases"Mol.Cell.Biol.. 19. 6057-6064 (1999)
Okada,T.,et al.:“Raf 富含半胱氨酸结构域的相互作用强度是 Raf 对 Ras 家族小 GTPase 反应的关键决定因素”Mol.Cell.Biol.. 19. 6057-6064 (1999)
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- 影响因子:0
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Y.Liao et al.,: "RA-GEF, a novel Rap1A guanine nucleotide exchange factor containing a Ras/Rap1A-associating domain, is conserved between nematode and humans."Journal of Biological Chemistry. 274巻53号. 37815-37820 (1999)
Y.Liao 等人:“RA-GEF 是一种新型 Rap1A 鸟嘌呤核苷酸交换因子,包含 Ras/Rap1A 相关结构域,在线虫和人类之间是保守的。”《生物化学杂志》,第 274 卷,第 53 期。 37815-37820 (1999)
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KATAOKA Tohru其他文献
KATAOKA Tohru的其他文献
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{{ truncateString('KATAOKA Tohru', 18)}}的其他基金
Analysis of the function of Rap1-activating factors which mediate the cross-talks between different species of small G proteins
Rap1激活因子介导不同物种小G蛋白间串扰的功能分析
- 批准号:
20390080 - 财政年份:2008
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Mechanism of cell growth regulation by small G proteins
小G蛋白调节细胞生长的机制
- 批准号:
17014061 - 财政年份:2005
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
Elucidation of the in vivo function of the Ras/Rap effector phospholipase Cε
阐明 Ras/Rap 效应磷脂酶 Cε 的体内功能
- 批准号:
17390078 - 财政年份:2005
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Analysis of the Regulatory Mechanism and Function of a Novel Class of Phospholipase C, PLCε
一类新型磷脂酶 C PLCε 的调控机制和功能分析
- 批准号:
15390093 - 财政年份:2003
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Analysis of the Function of a Novel Class of Mammalian Phospholipase C, PLCε
一类新型哺乳动物磷脂酶 C (PLCε) 的功能分析
- 批准号:
13470022 - 财政年份:2001
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Elucidation of the Molecular Mechanism Underlying the Stimulatory Effect of Posttranslational Lipid Modification of Ras Protein on Activation of Its Effectors
阐明 Ras 蛋白翻译后脂质修饰对其效应子激活的刺激作用的分子机制
- 批准号:
09470031 - 财政年份:1997
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
The Significance of Posttranslational Modification (Farnesylation) of Ras Protein in Activation of Its Effectors
Ras 蛋白翻译后修饰(法呢基化)对其效应子激活的意义
- 批准号:
08457038 - 财政年份:1996
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Development of a Strategy for Selective Inhibition of a Particular Ras Function by Interfering Ras-Effector Interaction
通过干扰 Ras-效应器相互作用来选择性抑制特定 Ras 功能的策略的开发
- 批准号:
07557333 - 财政年份:1995
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research (A)
Mechanism of Intracellular Signaling via Ras Protein
Ras 蛋白的细胞内信号传导机制
- 批准号:
06280218 - 财政年份:1994
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for Scientific Research on Priority Areas
The Function of Yeast Adenylyl Cyclase-Associated Proteins in Regulation of Cell Growth and Cytoskeletal Structure
酵母腺苷酸环化酶相关蛋白在调节细胞生长和细胞骨架结构中的功能
- 批准号:
06454167 - 财政年份:1994
- 资助金额:
$ 9.47万 - 项目类别:
Grant-in-Aid for General Scientific Research (B)