Regulation of Protein Kinase C Theta by Phosphorylation
通过磷酸化调节蛋白激酶 C Theta
基本信息
- 批准号:10679152
- 负责人:
- 金额:$ 4.01万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2026-03-31
- 项目状态:未结题
- 来源:
- 关键词:AffectAgonistAutoimmune DiseasesAutomobile DrivingBiochemicalBioinformaticsBiologicalBiological AssayBiological Response ModifiersBiologyBiosensorBlood PlateletsCD28 geneCellsCellular AssayClustered Regularly Interspaced Short Palindromic RepeatsCollaborationsDiglyceridesDiseaseEnzymesExhibitsExperimental DesignsGenesGoalsHematological DiseaseHematopoieticHematopoietic NeoplasmsHemostatic functionHydrolysisHydrophobicityImmune System DiseasesImmune signalingIn VitroInflammatoryInvestigationIsoenzymesJurkat CellsKnowledgeLaboratoriesLocationLuciferasesMass Spectrum AnalysisMolecularMutationPathologyPathway interactionsPhospholipidsPhosphorylationPhosphotransferasesPlatelet ActivationPlayPositioning AttributePropertyProtein Kinase CRegulationReporterResearchRoleSignal PathwaySignal TransductionSiteT-Cell ReceptorT-LymphocyteTailTechniquesThrombosisTrainingTranscription Factor AP-1Transcriptional ActivationVisionWorkexperienceexperimental studyinsightmimeticsnovelnuclear factors of activated T-cellsparalogous genepathogenpharmacologicphosphoproteomicsprotein kinase C-deltareceptorresponseselective expressiontooltranscription factor
项目摘要
PROJECT SUMMARY
The overall vision of the proposed research is to gain a comprehensive understanding of how phosphorylation
regulates the activity and function of a key regulator of immune signaling, the Ser/Thr protein kinase C (PKC)
Theta (). This kinase is selectively expressed in hematopoietic cells where it transduces signals resulting in T
cell and platelet activation.1,2 Its dysregulation is associated with a variety of pathophysiological conditions
including blood cancers,3,4 inflammatory diseases,5 thrombosis,6 and hemostasis.7 Despite this, the regulation
and function of PKC remains largely unknown and necessitates further investigation. Phosphorylation of PKC
plays an essential role in regulating its maturation, catalytic activity, and subcellular localization,8 all of which are
crucial for PKC function in T cells and platelets. This proposal aims to understand how phosphorylation at
known conserved priming sites (activation loop, turn motif, hydrophobic motif),9 a bioinformatically-identified new
potential priming site (Ser662), and an uncharacterized activation-induced site (Ser685), regulate the maturation,
activity, and/or localization of PKC. Unbiased phosphoproteomics approaches have revealed that
phosphorylation of Ser685 significantly increases in T cells10 and platelets11 in response to stimulation, however
its function has not yet been determined due, in part, to a lack of available research tools. This site, and Ser662
are positioned on a key regulatory segment, the C-tail, and are evolutionarily conserved. The central hypothesis
driving this proposal is that phosphorylation of S662 is involved in the maturation of PKC and that activation-
induced phosphorylation of S685 promotes the re-autoinhibition of activated PKC to facilitate signal termination.
To this end, I will investigate how nonphosphorylatable or phosphomimetic mutations at these residues impact
PKC biochemical properties, cellular activity, subcellular localization, and downstream signaling (Aim 1).
Additionally, I will examine the phosphoproteome of PKC in Jurkat cells and platelets and examine how
phosphorylation at the agonist-induced site, Ser685, affects downstream signaling. I will also aim to identify the
kinase(s) regulating PKC Ser685 phosphorylation using various phosphoproteomics approaches (Aim 2).
These key studies will elucidate the functional impact of PKC phosphorylation at critical residues and how this
influences downstream signaling. Moreover, this proposal will elucidate substrates and signaling networks
regulated by PKC. Uncovering the regulation and function of PKC, a key regulator of T cells and platelets, is
crucial to understanding T cell and platelet signaling in both normal and disease states.
项目摘要
拟议研究的总体愿景是全面了解磷酸化是如何
调节免疫信号传导的关键调节因子Ser/Thr蛋白激酶C(PKC)的活性和功能
Theta(θ)。这种激酶选择性地在造血细胞中表达,在造血细胞中它转导导致T细胞增殖的信号。
细胞和血小板活化。1,2其失调与多种病理生理条件有关
包括血癌、3、4炎性疾病、5血栓形成、6和止血。7尽管如此,
蛋白激酶C β的功能尚不清楚,需要进一步研究。PKC β的磷酸化
在调节其成熟、催化活性和亚细胞定位方面起着重要作用,8所有这些都是
对于T细胞和血小板中的PKC β功能至关重要。该提案旨在了解磷酸化在
已知的保守引发位点(激活环,转向基序,疏水基序),9一个生物信息学鉴定的新的
潜在的引发位点(Ser 662)和未表征的激活诱导位点(Ser 685)调节成熟,
活性和/或PKC β的定位。无偏见的磷酸蛋白质组学方法已经揭示,
然而,在T细胞10和血小板11中,Ser 685的磷酸化响应于刺激而显著增加,
其职能尚未确定,部分原因是缺乏可用的研究工具。这个网站和Ser 662
位于一个关键的调控片段,C-尾,并在进化上是保守的。核心假设
推动这一提议的是,S662的磷酸化参与了PKC β的成熟,而PKC β的激活-
诱导的S685磷酸化促进激活的PKC β的再自抑制,以促进信号终止。
为此,我将研究这些残基上的非磷酸化或磷酸化模拟突变如何影响
蛋白激酶C的生物化学特性、细胞活性、亚细胞定位和下游信号传导(Aim 1)。
此外,我将研究Jurkat细胞和血小板中PKC β的磷酸化蛋白质组,
激动剂诱导位点Ser 685的磷酸化影响下游信号传导。我亦会致力找出
使用各种磷酸化蛋白质组学方法研究调节PKC β Ser 685磷酸化的激酶(目的2)。
这些关键的研究将阐明PKC β磷酸化在关键残基的功能影响,以及这是如何影响蛋白质表达的。
影响下游信号。此外,该建议将阐明底物和信号网络
由PKC β调节。揭示PKC β的调节和功能,T细胞和血小板的关键调节因子,
对于理解正常和疾病状态下的T细胞和血小板信号传导至关重要。
项目成果
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