Spatial regulation of Protein Kinase A in cell migration
Spatial regulation of Protein Kinase A in cell migration
批准号:
8000162
负责人:
Alan K Howe
金额:
$6.97万
依托单位国家:
美国
项目类别:
财政年份:
2010
资助国家:
美国
项目状态:
已结题
起止时间:
2010-01-14 至 2010-12-31
关键词:
ActinsAddressAdenylate CyclaseAdhesionsBackBehaviorBiochemicalBiological AssayCellsChemotaxisCyclic AMPCyclic AMP-Dependent Protein KinasesCytoskeletal ModelingDataDevelopmentEnzymesEventExtracellular MatrixFluorescence Resonance Energy TransferGuanosine Triphosphate PhosphohydrolasesHeartHomeostasisImageIndividualInfluentialsIntegrin-mediated Cell Adhesion PathwayLifeMalignant NeoplasmsMass Spectrum AnalysisMicroscopyMolecularOrganismPTPN12 genePathologic ProcessesPhosphorylationPhosphotransferasesProtein KinaseProtein Kinase InteractionProtein Tyrosine PhosphataseProteinsPseudopodiaRegulationResearch PersonnelRoleSignal TransductionSpatial DistributionStructureTechniquesTestingTwo-Dimensional Gel ElectrophoresisUrsidae FamilyWorkcell motilityfeedingmigrationnovelphosphoric diester hydrolaseprogramsprotein kinase modulatorvasodilator-stimulated phosphoprotein
中文摘要
描述(由申请人提供):由肌动蛋白细胞骨架动力学驱动的细胞迁移是一种基本重要的细胞行为。正常的细胞迁移程序有助于生物体的发育和体内平衡,而异常的细胞迁移是病理过程的核心,如恶性肿瘤的转移扩散。camp依赖性蛋白激酶(PKA)长期以来一直被证明对细胞迁移和细胞骨架组织有积极和消极的影响。然而,很少有研究能够调和这些不同的观察结果,并阐明这种古老而有影响力的激酶对细胞迁移调节的贡献。初步研究表明,PKA的活性及其亚细胞分布是趋化细胞迁移的重要因素。具体来说,PKA调控亚基、PKA活性以及PKA关键细胞骨架底物的磷酸化在迁移细胞前沿形成的突起结构中显著富集。此外,PKA活性的抑制和PKA定位的破坏都会抑制前沿结构的形成和趋化细胞的迁移。这支持了一种假设,即PKA在迁移细胞的前沿被特异性激活,这种局部活性调节肌动蛋白细胞骨架动力学和细胞迁移的关键调节因子。拟议的工作将通过提出两个广泛的问题来验证这一假设:这种定位是如何发生的,以及它的分子后果是什么。显微术(3-、4-和5-D成像;FRET)和生化技术(免疫分析、激酶测定、二维凝胶电泳;质谱法)将用于确定PKA定位到前沿的细胞动力学,并确定负责它的锚定蛋白(Specific Aim 1),以及确定PKA信号定位对已知PKA细胞骨架靶点的影响,并确定PKA可能通过其调节细胞运动的新靶点(Specific Aim 2)。
英文摘要
DESCRIPTION (provided by applicant): Cell migration, driven by actin cytoskeletal dynamics, is a fundamentally important cellular behavior. Normal programs of cell migration contribute to organism development and homeostasis, while abnormal migration lays at very heart of pathological processes such as the metastatic spread of malignant tumors. The cAMP-dependent protein kinase (PKA) has oft and long been shown to exert both negative and positive effects on cell migration and cytoskeletal organization. However, little work has been done to reconcile these disparate observations and elucidate the contribution of this venerable and influential kinase to the regulation of cell migration. Preliminary studies show that it is not only the activity of PKA, but also the subcellular distribution of that activity, that is important for chemotactic cell migration. Specifically, PKA regulatory subunits, PKA activity, and the phosphorylation of key cytoskeletal substrates for PKA are significantly enriched in protrusive structures formed at the leading edge of migrating cells. Moreover, both inhibition of PKA activity and disruption of PKA localization inhibit formation of leading edge structures and chemotactic cell migration. This supports an hypothesis in which PKA is activated specifically in the leading edge of migrating cells and this localized activity modulates key regulators of actin cytoskeletal dynamics and cell migration. The proposed work will test this hypothesis by asking two broad questions: How does this localization occur and what are its molecular consequences. A combination of microscopy (3-, 4-, and 5-D imaging; FRET) and biochemical techniques (immunoanalyses, kinase assays, 2-D gel electrophoresis; mass spectrometry) will be used to determine the cellular dynamics of PKA localization to the leading edge and identify the anchoring proteins responsible for it (Specific Aim 1), as well as determine the effects of localized PKA signaling on known cytoskeletal targets for PKA and identify new targets through which PKA might regulate cell motility (Specific Aim 2).
期刊论文(3)
专著(0)
科研奖励(0)
会议论文
Protein kinase A activity and anchoring are required for ovarian cancer cell migration and invasion.
DOI:
10.1371/journal.pone.0026552
发表时间:
2011
期刊:
PloS one
影响因子:
3.7
作者:
[McKenzie AJ, Campbell SL, Howe AK]
通讯作者:
Howe AK
DOI:
10.1016/j.ceb.2011.05.006
发表时间:
2011-10
期刊:
CURRENT OPINION IN CELL BIOLOGY
影响因子:
7.5
作者:
[Howe, Alan K.]
通讯作者:
Howe, Alan K.
Protein Kinase A in Focal Adhesions - Mechanisms and Consequences
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批准号:10156931
-
项目类别:
-
资助金额:$37.54万
-
财政年份:2021
-
负责人:Alan K Howe
-
依托单位:
Mechano-Chemical Regulation of GPCR/PKA Signaling During Cell Migration
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批准号:9019564
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项目类别:
-
资助金额:$35.96万
-
财政年份:2016
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负责人:Alan K Howe
-
依托单位:
Cross-talk between PKA, cellular tension, and Ca2+ channels during cell migration
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批准号:8503067
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项目类别:
-
资助金额:$0.39万
-
财政年份:2011
-
负责人:Alan K Howe
-
依托单位:
Cross-talk between PKA, cellular tension, and Ca2+ channels during cell migration
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批准号:8086140
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项目类别:
-
资助金额:$28.29万
-
财政年份:2011
-
负责人:Alan K Howe
-
依托单位:
Cross-talk between PKA, cellular tension, and Ca2+ channels during cell migration
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批准号:8727054
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项目类别:
-
资助金额:$28.98万
-
财政年份:2011
-
负责人:Alan K Howe
-
依托单位:
Cross-talk between PKA, cellular tension, and Ca2+ channels during cell migration
-
批准号:8536860
-
项目类别:
-
资助金额:$27.96万
-
财政年份:2011
-
负责人:Alan K Howe
-
依托单位:
Cross-talk between PKA, cellular tension, and Ca2+ channels during cell migration
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批准号:8321958
-
项目类别:
-
资助金额:$33.21万
-
财政年份:2011
-
负责人:Alan K Howe
-
依托单位:
P1-SPATIAL REGULATION OF PROTEIN KINASE A SIGNALING DURING GROWTH CONE GUIDANCE
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批准号:8168059
-
项目类别:
-
资助金额:$23.96万
-
财政年份:2010
-
负责人:Alan K Howe
-
依托单位:
P1-SPATIAL REGULATION OF PROTEIN KINASE A SIGNALING DURING GROWTH CONE GUIDANCE
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批准号:7959686
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项目类别:
-
资助金额:$23.34万
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财政年份:2009
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负责人:Alan K Howe
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依托单位:
P1-SPATIAL REGULATION OF PROTEIN KINASE A SIGNALING DURING GROWTH CONE GUIDANCE
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批准号:7725300
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项目类别:
-
资助金额:$23.44万
-
财政年份:2008
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负责人:Alan K Howe
-
依托单位:
P1-SPATIAL REGULATION OF PROTEIN KINASE A SIGNALING DURING GROWTH CONE GUIDANCE
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批准号:7609870
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项目类别:
-
资助金额:$22.48万
-
财政年份:2007
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负责人:Alan K Howe
-
依托单位:
PP1-SPATIAL REGULATION OF PROTEIN KINASE A SIGNALING DURING GROWTH CONE GUIDANCE
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批准号:7381254
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项目类别:
-
资助金额:$9.14万
-
财政年份:2006
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负责人:Alan K Howe
-
依托单位:
Spatial regulation of Protein Kinase A in cell migration
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批准号:7094552
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项目类别:
-
资助金额:$3.71万
-
财政年份:2005
-
负责人:Alan K Howe
-
依托单位:
PP1-SPATIAL REGULATION OF PROTEIN KINASE A SIGNALING DURING GROWTH CONE GUIDANCE
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批准号:7170484
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项目类别:
-
资助金额:$9.09万
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财政年份:2005
-
负责人:Alan K Howe
-
依托单位:
Spatial regulation of Protein Kinase A in cell migration
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批准号:6908695
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项目类别:
-
资助金额:$21.28万
-
财政年份:2005
-
负责人:Alan K Howe
-
依托单位:
Spatial regulation of Protein Kinase A in cell migration
-
批准号:7437267
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项目类别:
-
资助金额:$25.94万
-
财政年份:2005
-
负责人:Alan K Howe
-
依托单位:
Spatial regulation of Protein Kinase A in cell migration
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批准号:7060015
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项目类别:
-
资助金额:$27.02万
-
财政年份:2005
-
负责人:Alan K Howe
-
依托单位:
Spatial regulation of Protein Kinase A in cell migration
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批准号:7231730
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项目类别:
-
资助金额:$25.94万
-
财政年份:2005
-
负责人:Alan K Howe
-
依托单位:
Spatial regulation of Protein Kinase A in cell migration
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批准号:7618741
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项目类别:
-
资助金额:$25.94万
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财政年份:2005
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负责人:Alan K Howe
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依托单位:
PKA and PAK in Adhesion Dependent Signal Transduction
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批准号:6522717
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项目类别:
-
资助金额:$10.11万
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财政年份:2001
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负责人:Alan K Howe
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依托单位:
海外基金