Protein Phosphatase Control of AMPK Function
AMPK 功能的蛋白磷酸酶控制
基本信息
- 批准号:9899273
- 负责人:
- 金额:$ 30.17万
- 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:2019-04-01 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:AMP-activated protein kinase kinaseAddressBindingBiological ProcessBody WeightCancer ModelCatalytic DomainCellsChemicalsComplexDataDesire for foodDiabetes MellitusFamilyFatty LiverFatty acid glycerol estersGenesGlucoseGoalsHepaticHigh Fat DietHoloenzymesHomeostasisIn VitroInvestigationKnock-outKnockout MiceLipidsLiverMalignant NeoplasmsMalignant neoplasm of liverMass Spectrum AnalysisMediatingMediator of activation proteinMetabolicMetabolic stressMetabolic syndromeMetabolismModelingMolecularMusPathway interactionsPhenotypePhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPlayPrimary carcinoma of the liver cellsProtein DephosphorylationProtein FamilyProtein Phosphatase 2A Regulatory Subunit PR53Protein Serine/Threonine PhosphataseProtein phosphataseProteinsRecoveryRegulationReportingResearchRoleSeriesSignal TransductionSolidSpecificitySystemTissuesWeightWhole OrganismXenograft Modeladenoviral-mediatedbasecancer typeconditional knockoutenergy balanceexperimental studyfatty acid oxidationglucose toleranceglucose uptakeimprovedin vivoknock-downliver functionmouse modelnovelnovel therapeutic interventionnovel therapeuticspreventprotein phosphatase 6recruitrestorationsmall hairpin RNAtumortumor growthtumorigenesis
项目摘要
PROJECT SUMMARY
The goal of this proposed research is to reveal the negative regulator of AMPK and eventually target this pathway
to generate an efficient AMPK activator for treatment of metabolic syndromes. AMPK senses metabolic stress
and is a central mediator in maintaining metabolic homeostasis and energy balance. Thus, AMPK activation has
become an attractive target for treating metabolic syndromes, including diabetes and cancer. While it has been
demonstrated that AMPK activity is tightly regulated by reversible protein phosphorylation, and despite many
efforts to identify AMPK kinases, it is still unclear how AMPK is dephosphorylated or inactivated upon recovery
from metabolic stress. One of the main reasons for the limited progress in identifying an AMPK phosphatase is
because of the promiscuous activity of serine-threonine phosphatases and its specificity is governed by
associated proteins. We and others previously identified that PP2A family protein phosphatases are involved in
AMPK dephosphorylation. However, the PP2A phosphatase family contains hundreds of possible different
complexes. To identify a specific complex that directly dephosphorylates AMPK, using protein mass-
spectrometry analysis, we found that protein phosphatase 6 (PP6, a PP2A family phosphatase) regulatory
subunit SAPS3 is associated with AMPK. Furthermore, our preliminary data demonstrated that SAPS3/AMPK
binding is glucose responsive and required for AMPK dephosphorylation. To evaluate the role of SAPS3 in vivo,
we have generated a novel mouse model by flanking the gene encoding SAPS3, ppp6r3, with a loxP sequence
that allow us to develop tissue specific knock out of SAPS3. Using recently developed SAPS3 liver-specific
knockout mice, we found that deletion of SAPS3 increases AMPK phosphorylation in liver and displays
phenotypes similar to AMPK activation in regulation of metabolism and tumorigenesis. Therefore, we propose a
series of experiments in this application to address our central hypothesis that SAPS3-containing PP6
phosphatase complex dephosphorylates and inhibits AMPK activity, thereby regulating AMPK-mediated
functions. Three specific aims are proposed as follows: 1) elucidating molecular mechanisms underlying AMPK
inhibition by SAPS3-containing PP6 complex, 2) determining the biological function of SAPS3 in
metabolic/energy homeostasis in vivo via regulation of AMPK using SAPS3 liver specific knockout mice, 3)
examining the role of SAPS3 in tumorigenesis via regulation of AMPK in two mouse tumor models. These studies
will provide a solid mechanistic basis for AMPK signaling regulated by protein phosphatase and in vivo evidence
that AMPK-mediated biological functions are tightly controlled by protein phosphatase. Results from the
proposed research will also advance new therapeutic directions by targeting the SAPS3/AMPK interaction, which
could be an effective approach to activate AMPK for treating metabolic syndromes.
项目概要
这项研究的目标是揭示 AMPK 的负调节因子并最终针对该通路
产生用于治疗代谢综合征的有效 AMPK 激活剂。 AMPK 感知代谢压力
是维持代谢稳态和能量平衡的核心介质。因此,AMPK 激活
成为治疗代谢综合征(包括糖尿病和癌症)的一个有吸引力的目标。虽然已经
证明 AMPK 活性受到可逆蛋白质磷酸化的严格调节,尽管许多
尽管努力鉴定 AMPK 激酶,但仍不清楚 AMPK 在恢复后如何去磷酸化或失活
来自代谢压力。 AMPK 磷酸酶鉴定进展有限的主要原因之一是
由于丝氨酸-苏氨酸磷酸酶的混杂活性及其特异性受
相关蛋白质。我们和其他人之前发现 PP2A 家族蛋白磷酸酶参与
AMPK 去磷酸化。然而,PP2A 磷酸酶家族包含数百种可能的不同
复合物。使用蛋白质质量鉴定直接去磷酸化 AMPK 的特定复合物
光谱分析,我们发现蛋白磷酸酶6(PP6,PP2A家族磷酸酶)的调节
亚基 SAPS3 与 AMPK 相关。此外,我们的初步数据表明 SAPS3/AMPK
结合具有葡萄糖反应性并且是 AMPK 去磷酸化所必需的。为了评估 SAPS3 在体内的作用,
我们通过在编码 SAPS3、ppp6r3 的基因侧翼添加 loxP 序列,生成了一种新型小鼠模型
这使我们能够开发 SAPS3 的组织特异性敲除。使用最近开发的 SAPS3 肝脏专用
敲除小鼠中,我们发现 SAPS3 的缺失会增加肝脏中的 AMPK 磷酸化并显示
代谢和肿瘤发生调节中与 AMPK 激活相似的表型。因此,我们提出一个
本申请中的一系列实验旨在解决我们的中心假设,即含有 SAPS3 的 PP6
磷酸酶复合物去磷酸化并抑制 AMPK 活性,从而调节 AMPK 介导的
功能。提出三个具体目标如下:1)阐明AMPK的分子机制
含 SAPS3 的 PP6 复合物的抑制,2) 确定 SAPS3 在
使用 SAPS3 肝脏特异性敲除小鼠通过调节 AMPK 实现体内代谢/能量稳态,3)
通过在两种小鼠肿瘤模型中调节 AMPK 来检查 SAPS3 在肿瘤发生中的作用。这些研究
将为蛋白磷酸酶调节的AMPK信号传导提供坚实的机制基础和体内证据
AMPK 介导的生物功能受到蛋白磷酸酶的严格控制。结果来自
拟议的研究还将通过针对 SAPS3/AMPK 相互作用来推进新的治疗方向,这
可能是激活 AMPK 治疗代谢综合征的有效方法。
项目成果
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{{ truncateString('MEI KONG', 18)}}的其他基金
Using dietary glutamine supplementation for melanoma prevention and targeted therapy
使用膳食谷氨酰胺补充剂预防黑色素瘤和靶向治疗
- 批准号:
10372220 - 财政年份:2021
- 资助金额:
$ 30.17万 - 项目类别:
Using dietary glutamine supplementation for melanoma prevention and targeted therapy
使用膳食谷氨酰胺补充剂预防黑色素瘤和靶向治疗
- 批准号:
10657330 - 财政年份:2021
- 资助金额:
$ 30.17万 - 项目类别:
Using dietary glutamine supplementation for melanoma prevention and targeted therapy
使用膳食谷氨酰胺补充剂预防黑色素瘤和靶向治疗
- 批准号:
10211274 - 财政年份:2021
- 资助金额:
$ 30.17万 - 项目类别:
Protein Phosphatase Control of AMPK Function
AMPK 功能的蛋白磷酸酶控制
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10547739 - 财政年份:2019
- 资助金额:
$ 30.17万 - 项目类别:
Cancer cell adaptation to glutamine deprivation
癌细胞对谷氨酰胺剥夺的适应
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8811793 - 财政年份:2014
- 资助金额:
$ 30.17万 - 项目类别:
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