Histidine Phosphorylation in Mammals: Regulation, Protein Targets, and Biology
哺乳动物中的组氨酸磷酸化:调节、蛋白质靶点和生物学
基本信息
- 批准号:10152661
- 负责人:
- 金额:$ 39.83万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-08-01 至 2023-04-30
- 项目状态:已结题
- 来源:
- 关键词:AdenocarcinomaAutoimmune DiseasesB-LymphocytesBeta CellBindingBiochemicalBiologicalBiological ProcessBiologyCD4 Positive T LymphocytesCalcium-Activated Potassium ChannelCell membraneCell physiologyCellsCleaved cellDefectDiabetes MellitusDiseaseExhibitsFailureFamilyGeneticGlucoseHepaticHistidineHumanHypersensitivityHypoglycemiaImmuneImpairmentInternshipsLeptinLinkMammalian CellMammalsMediatingMetabolicMonoclonal AntibodiesMusMutationNeonatal HypoglycemiaNewborn InfantNon-Insulin-Dependent Diabetes MellitusPancreasPathway interactionsPatientsPeptide HydrolasesPersistent Hyperinsulinemia Hypoglycemia of InfancyPhenotypePhosphoglycerate MutasePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPhysiologicalPlayPotassiumProcessProtein DephosphorylationProtein IsoformsProteinsProtomerReagentReceptor ActivationReceptor SignalingRegulationRoleSecond Messenger SystemsSerineSignal PathwaySignal TransductionSignaling MoleculeStructure of beta Cell of isletT-Cell ActivationT-Cell ReceptorT-LymphocyteTRP channelThreonineTimeTumor ImmunityTumor Suppressor ProteinsTyrosinecomplement C2belectrical propertyhuman diseasein vivoinorganic phosphateinsightmast cellnucleoside diphosphatephosphohistidineprotein-histidine kinaseresponsetrafficking
项目摘要
Project Summary
Whereas phosphorylation of serine, threonine and tyrosine are exceedingly well characterized, relatively
little is known about phosphorylation of histidine (His), which may account for as much as ~6% of all incorporation
of phosphate into mammalian proteins. We have provided genetic and biochemical evidence that the histidine
kinase, NDPK-B, and the histidine phosphatases (PTases), PHPT1 and (PGAM5, regulate the activity of the
Ca2+-activated K+ channel KCa3.1 by reversible His phosphorylation, and thereby the activation of CD4 T and
mast cells. While NDPK-B His phosphorylates and activates KCa3.1, PGAM5 and PHPT1 inhibit KCa3.1 His
phosphorylation by specifically dephosphorylating and inhibiting NDPK-B and KCa3.1 respectively. Using
recently developed monoclonal antibodies to 1- and 3-phospho-Histidine (pHis), we demonstrate for the first time
the regulation of histidine phosphorylation in vivo in mammalian cells, which we in turn linked to TCR signaling.
SA1 we will build on these studies, we will assess changes in His phosphorylation of NDPK-B and KCa3.1 in the
context of TCR signaling, determine how it is regulated by various signaling molecules such as PI3KC2, whether
other pHis proteins are present in T cells and/or regulated by TCR signaling, and the specific role for PGAM5,
PHPT1 and NDPK-B to modulate changes in pHis proteins. We have found that the 24 cleaved PGAM5-L
isoform is most critical to dephosphorylate NDPK-B. We will determine whether the 24 cleaved PGAM5-L
isoform negatively regulates CD4 T cells in vivo, whether the amount of this isoform changes following TCR
stimulation, and the intramembranous proteases that mediates cleavage in CD4 T cells.
We also identified a critical role for histidine phosphorylation in pancreatic cell function. We found that
cells from PHPT1-/- mice have electrical properties similar to those of patients with mutations in KATP channel
subunits and KATP channel-/- mice. The defect in PHPT1-/- β cells can be explained by the failure of KATP channels
to relocalize from an intracellular compartment to the plasma membrane (PM) in response to low glucose and
leptin and we have now linked the defect in PHPT1-/- β cells to impaired activation of transient receptor potential
channel 4 (TRPC4). Our hypothesis is that reversible His phosphorylation of TRPC4 by PHPT1, NDPK-B,
PGAM5 regulates TRPC4 channel activity in a similar manner to KCa3.1, albeit in opposite directions; whereas
His phosphorylation of KCa3.1 activates, His phosphorylation of TRPC4 inhibits. In SA 2, we will determine if
PHPT1, NDPK-B, and PGAM5 regulate His phosphorylation of TRPC4 in a manner similar to KCa3.1, their role
in KATP channel trafficking and TRPC4 activation, and whether decreased KATP trafficking to the PM in TRPC4-/-
and PGAM5-/- mice leads congenital hyperinsulinemia hypoglycemia that is similar to PHPT-/- mice and patients
with CHI. We will then extend these studies to human cells and assess the potential relevance of these
molecules to human disease that include CHI and type 2 diabetes mellitus.
项目概要
尽管丝氨酸、苏氨酸和酪氨酸的磷酸化已得到非常充分的表征,但相对而言
关于组氨酸 (His) 的磷酸化知之甚少,组氨酸 (His) 的磷酸化可能占所有掺入量的约 6%
将磷酸盐转化为哺乳动物蛋白质。我们提供了遗传和生化证据表明组氨酸
激酶、NDPK-B 和组氨酸磷酸酶 (PTase)、PHPT1 和 (PGAM5) 调节
Ca2+ 通过可逆的 His 磷酸化激活 K+ 通道 KCa3.1,从而激活 CD4 T 和
肥大细胞。 NDPK-B His 磷酸化并激活 KCa3.1,而 PGAM5 和 PHPT1 抑制 KCa3.1 His
分别通过特异性去磷酸化和抑制 NDPK-B 和 KCa3.1 来实现磷酸化。使用
我们首次展示了最近开发的针对 1- 和 3-磷酸-组氨酸 (pHis) 的单克隆抗体
哺乳动物细胞体内组氨酸磷酸化的调节,我们进而将其与 TCR 信号传导联系起来。
SA1,我们将在这些研究的基础上,我们将评估 NDPK-B 和 KCa3.1 磷酸化的变化
TCR 信号传导的背景,确定它如何受到各种信号分子(例如 PI3KC2)的调节,是否
其他 pHis 蛋白存在于 T 细胞中和/或受 TCR 信号传导调节,以及 PGAM5 的具体作用,
PHPT1 和 NDPK-B 调节 pHis 蛋白的变化。我们发现 24 裂解的 PGAM5-L
同种型对于 NDPK-B 去磷酸化最为关键。我们将确定 24 是否裂解 PGAM5-L
同工型在体内负调节 CD4 T 细胞,TCR 后该同工型的数量是否发生变化
刺激和介导 CD4 T 细胞裂解的膜内蛋白酶。
我们还确定了组氨酸磷酸化在胰腺 细胞功能中的关键作用。我们发现
PHPT1-/- 小鼠的 细胞具有与 KATP 通道突变患者相似的电特性
亚基和 KATP 通道-/- 小鼠。 PHPT1-/- β 细胞的缺陷可以通过 KATP 通道的故障来解释
响应低葡萄糖和从细胞内区室重新定位到质膜(PM)
瘦素,我们现在已经将 PHPT1-/- β 细胞的缺陷与瞬时受体电位激活受损联系起来
通道 4 (TRPC4)。我们的假设是 PHPT1、NDPK-B 对 TRPC4 的 His 磷酸化是可逆的,
PGAM5 以与 KCa3.1 类似的方式调节 TRPC4 通道活性,尽管方向相反;然而
His 磷酸化 KCa3.1 激活,His 磷酸化 TRPC4 抑制。在 SA 2 中,我们将确定是否
PHPT1、NDPK-B 和 PGAM5 以与 KCa3.1 类似的方式调节 TRPC4 的 His 磷酸化,它们的作用
KATP 通道运输和 TRPC4 激活的影响,以及 TRPC4-/- 中 KATP 向 PM 的运输是否减少
和 PGAM5-/- 小鼠导致先天性高胰岛素血症低血糖,与 PHPT-/- 小鼠和患者相似
与气。然后,我们将把这些研究扩展到人类 细胞,并评估这些研究的潜在相关性。
人类疾病的分子,包括 CHI 和 2 型糖尿病。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
EDWARD Y SKOLNIK其他文献
EDWARD Y SKOLNIK的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ truncateString('EDWARD Y SKOLNIK', 18)}}的其他基金
Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
- 批准号:
10462701 - 财政年份:2021
- 资助金额:
$ 39.83万 - 项目类别:
Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
- 批准号:
10629396 - 财政年份:2021
- 资助金额:
$ 39.83万 - 项目类别:
Identification of new therapeutic targets for ADPKD
ADPKD 新治疗靶点的确定
- 批准号:
10298937 - 财政年份:2021
- 资助金额:
$ 39.83万 - 项目类别:
Histidine Phosphorylation in Mammals: Regulation, Protein Targets, and Biology
哺乳动物中的组氨酸磷酸化:调节、蛋白质靶点和生物学
- 批准号:
10395477 - 财政年份:2019
- 资助金额:
$ 39.83万 - 项目类别:
Identification and characterization of a novel mammalian histidine phosphatase that negatively regulates CD4 T cells
负调节 CD4 T 细胞的新型哺乳动物组氨酸磷酸酶的鉴定和表征
- 批准号:
9330534 - 财政年份:2016
- 资助金额:
$ 39.83万 - 项目类别:
TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
- 批准号:
8667953 - 财政年份:2013
- 资助金额:
$ 39.83万 - 项目类别:
New Signaling pathways that positively and negatively regulate CD4 T cells via th
通过 th 正向和负向调节 CD4 T 细胞的新信号通路
- 批准号:
8742789 - 财政年份:2013
- 资助金额:
$ 39.83万 - 项目类别:
TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
- 批准号:
8541082 - 财政年份:2012
- 资助金额:
$ 39.83万 - 项目类别:
TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
- 批准号:
8218480 - 财政年份:2012
- 资助金额:
$ 39.83万 - 项目类别:
TRIM27 is a new negative regulator of CD4 T cells and Mast cells.
TRIM27 是 CD4 T 细胞和肥大细胞的新型负调节因子。
- 批准号:
8875012 - 财政年份:2012
- 资助金额:
$ 39.83万 - 项目类别:
相似国自然基金
Autoimmune diseases therapies: variations on the microbiome in rheumatoid arthritis
- 批准号:31171277
- 批准年份:2011
- 资助金额:60.0 万元
- 项目类别:面上项目
相似海外基金
Effects of maternal immune activation on autoimmune diseases in offsprings
母体免疫激活对后代自身免疫性疾病的影响
- 批准号:
23H02155 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Grant-in-Aid for Scientific Research (B)
Autoantibodies and antibody-secreting cells in neurological autoimmune diseases: from biology to therapy
神经性自身免疫性疾病中的自身抗体和抗体分泌细胞:从生物学到治疗
- 批准号:
479128 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Operating Grants
IPP: AUTOIMMUNE DISEASES STATISTICAL AND CLINICAL COORDINATING CENTER (ADSCCC)
IPP:自身免疫性疾病统计和临床协调中心 (ADSCCC)
- 批准号:
10788032 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Biomarkers of vascular endothelial dysfunction in systemic autoimmune diseases: analysis of circulating microRNAs
系统性自身免疫性疾病中血管内皮功能障碍的生物标志物:循环 microRNA 分析
- 批准号:
23K14742 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Grant-in-Aid for Early-Career Scientists
NOVEL HUMORAL AND CELLULAR BIOMARKERS OF AUTOIMMUNE DISEASES CAUSED BY IMMUNOTHERAPY
免疫治疗引起的自身免疫性疾病的新型体液和细胞生物标志物
- 批准号:
10593224 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Structural mechanisms of autoimmune diseases targeting cys-loop receptors
针对半胱氨酸环受体的自身免疫性疾病的结构机制
- 批准号:
10864719 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Developing non-immunosuppressive immune-based therapeutics for targeted treatment of autoimmune diseases
开发非免疫抑制性免疫疗法来靶向治疗自身免疫性疾病
- 批准号:
10586562 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Regulation of autoimmune diseases by PTPN22 phosphatase
PTPN22磷酸酶对自身免疫性疾病的调节
- 批准号:
23K06589 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Decipher and target GABA metabolism and GABA receptor-mediated signaling in autoimmune diseases
破译并靶向自身免疫性疾病中的 GABA 代谢和 GABA 受体介导的信号传导
- 批准号:
10623380 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别:
Targeting the long isoform of the prolactin receptor to treat autoimmune diseases and B-cell malignancies
靶向催乳素受体的长亚型来治疗自身免疫性疾病和 B 细胞恶性肿瘤
- 批准号:
10735148 - 财政年份:2023
- 资助金额:
$ 39.83万 - 项目类别: