Regulation of Ras through the Ras GRF exchange factor
通过 Ras GRF 交换因子调节 Ras
基本信息
- 批准号:6878501
- 负责人:
- 金额:$ 19.87万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2001
- 资助国家:美国
- 起止时间:2001-04-01 至 2007-03-31
- 项目状态:已结题
- 来源:
- 关键词:G proteinbiological signal transductioncalcium ioncalmodulincerebral cortexenzyme activityguanine nucleotide binding proteinguanine nucleotide exchange factorsguanosine triphosphatehippocampusintermolecular interactionlaboratory rabbitlaboratory ratmass spectrometrymitogen activated protein kinasephosphorylationreceptor couplingserinesite directed mutagenesis
项目摘要
APPLICANT'S DESCRIPTION: Aberrant activation of Ras is a major contributor to
human cancer. The Ras-GRF1 exchange factor, which activates Ras in response to
G protein-coupled receptors, is highly expressed in central neurons and plays
an essential role in the establishment of memory. Over-expression of Ras-GRF1
in human tumors implicates this exchange factor in carcinogenesis. The activity
of Ras-GRF1 is controlled, at least in part, by alterations in its
phosphorylation state, but a detailed picture of its regulation has not been
achieved. The long-range goal of this project is to obtain a detailed
understanding of the physiological and pharmacological significance of the
Ras-GRF exchange factors. The objective of this proposal is to determine how
the Ras-GRF1 exchange factor is controlled by phosphorylation. The central
hypothesis is that Ras-GRF1 serves as a key integrator of signal transduction
by regulation of its activity through both phosphorylation and interaction with
calcium/calmodulin. The rationale for this proposal is that, through definition
of the mechanisms that control Ras-GRF1, we will produce greater insight into a
new and physiologically important pathway for Ras activation. This project will
be performed in an environment that is very favorable for its successful
completion through excellent collegial interactions and substantial
institutional commitment. The objective of this proposal will be attained
through testing the central hypothesis in three specific aims: 1).Determine the
sites of regulated phosphorylation in Ras-GRFI. The hypothesis to be tested is
that a combination of phosphorylation events is required for G
protein-dependent activation of Ras-GRF1. 2).Define the integration of control
of Ras-GRF1 by phosphorylation and calcium signaling. The ability of Ras-GRF1
to integrate multiple signals into the activation of Ras will be tested.
3).Elucidate a dual role for phosphorylation of Ras-GRFI at Serine-916. The
working hypothesis is that Serine-916 is a physiologically significant site of
regulated phosphorylation that contributes to both activation and
down-regulation of the exchange factor.
The proposed studies are innovative in that they address an important mechanism
for Ras activation in the CNS that has been subject to less investigation. The
results will be significant as they will provide key understanding of the
control of Ras by G protein-coupled receptors, and thus may potentially lead to
the identification of new therapeutic targets for intervention in cancer. The
results are likely to be of fundamental importance to our comprehension of the
role of the Ras/MAP kinase system in learning and memory.
申请人描述:Ras的异常激活是导致
项目成果
期刊论文数量(7)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Mitogen-activated protein kinase signaling in drug-resistant neuroblastoma cells.
耐药神经母细胞瘤细胞中丝裂原激活的蛋白激酶信号传导。
- DOI:10.1385/1-59259-356-9:71
- 发表时间:2003
- 期刊:
- 影响因子:0
- 作者:Mattingly,RaymondR
- 通讯作者:Mattingly,RaymondR
Activated Ras as a Therapeutic Target: Constraints on Directly Targeting Ras Isoforms and Wild-Type versus Mutated Proteins.
- DOI:10.1155/2013/536529
- 发表时间:2013
- 期刊:
- 影响因子:0
- 作者:Mattingly RR
- 通讯作者:Mattingly RR
Angiotensin II directly stimulates activity and alters the phosphorylation of Na-K-ATPase in rat proximal tubule with a rapid time course.
- DOI:10.1152/ajprenal.00065.2004
- 发表时间:2004-05
- 期刊:
- 影响因子:0
- 作者:D. Yingst;Katherine J. Massey;N. Rossi;M. Mohanty;R. Mattingly
- 通讯作者:D. Yingst;Katherine J. Massey;N. Rossi;M. Mohanty;R. Mattingly
Phosphorylation of rat kidney Na-K pump at Ser938 is required for rapid angiotensin II-dependent stimulation of activity and trafficking in proximal tubule cells.
- DOI:10.1152/ajpcell.00113.2015
- 发表时间:2016-02
- 期刊:
- 影响因子:0
- 作者:Katherine J. Massey;Quanwen Li;N. Rossi;Susan M. Keezer;R. Mattingly;D. Yingst
- 通讯作者:Katherine J. Massey;Quanwen Li;N. Rossi;Susan M. Keezer;R. Mattingly;D. Yingst
Angiotensin II-dependent phosphorylation at Ser11/Ser18 and Ser938 shifts the E2 conformations of rat kidney Na+/K+-ATPase.
- DOI:10.1042/bj20111398
- 发表时间:2012-04-01
- 期刊:
- 影响因子:0
- 作者:Massey KJ;Li Q;Rossi NF;Mattingly RR;Yingst DR
- 通讯作者:Yingst DR
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RAYMOND R MATTINGLY其他文献
RAYMOND R MATTINGLY的其他文献
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{{ truncateString('RAYMOND R MATTINGLY', 18)}}的其他基金
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
8665529 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
7666266 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
7531616 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
8073003 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
8396645 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
7849609 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
8244681 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
7931069 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
8072463 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
Proteolytic Pathways in Progression of Pre-Malignant Breast Disease
乳腺癌前病变进展中的蛋白水解途径
- 批准号:
8267714 - 财政年份:2008
- 资助金额:
$ 19.87万 - 项目类别:
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