MAL2 regulation of hepatic protein trafficking: mechanisms and binding partners
MAL2 对肝蛋白运输的调节:机制和结合伙伴
基本信息
- 批准号:8281689
- 负责人:
- 金额:$ 17.56万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2009
- 资助国家:美国
- 起止时间:2009-07-01 至 2015-05-31
- 项目状态:已结题
- 来源:
- 关键词:AccountingAdenovirusesApicalB-LymphocytesBile fluidBindingBinding ProteinsBiological ModelsBloodBlood CirculationC-terminalCancerousCell LineCell PolarityCell membraneCell physiologyCellsChemicalsChimera organismChimeric ProteinsCholesterolCollaborationsComplexCytoplasmic TailDietary FatsEndocytosisEnvironmentEpithelialEpithelial CellsExcisionFaceFamily memberFoodGlycosphingolipidsGoalsHepaticHepatocyteHumanImmunoglobulin AInvestigationLifeLipidsLiverLocationLymphocyteMalignant NeoplasmsMediatingMembrane Protein TrafficMembrane ProteinsMetabolicModelingMolecularMyelinOrganPathway interactionsPhosphorylationProtein FamilyProteinsReagentRecombinantsRecruitment ActivityRegulationScienceSoapsSorting - Cell MovementSpecificitySurfaceSystemTPD52 geneTestingTight JunctionsTissuesUbiquitinVesicleWaste ProductsXenobioticsYeastsabsorptionbasebasolateral membraneexperienceliver functionmemberprotein protein interactionprotein transportreceptorresearch studytooltranscytosistumorwastingyeast two hybrid system
项目摘要
Project Summary
The liver is the body's metabolic center that converts food into chemicals required for life and synthesizes
countless compounds that are released into the circulation for use by other organs. The liver is also the major
detoxifying center, ridding the body of xenobiotics and endogenous waster products. Most of these functions
are carried out in hepatocytes, the major epithelial cell of the liver. These cells form a barrier between the
internal and external environments by cementing themselves together by the formation of tight junctions that
restrict distinct activities to specific plasma membrane (PM) domains: the basolateral and apical. The
basolateral surface faces the blood (the internal environment) whereas the apical surface faces the bile (the
external environment), the complex molecular "soap" that helps in absorption of dietary fats and waste
removal. The functional asymmetry (or polarity) is mirrored by the asymmetrical distribution of PM proteins;
each domain is characterized by distinct subsets of proteins. Because proper liver function depends on
hepatocyte polarity, this proposal asks how is polarity established and maintained? The answer, in part,
comes from understanding polarized membrane trafficking. Our focus is to identify regulators of hepatic apical
protein delivery. Unlike simple epithelial cells that directly target newly synthesized proteins from the TGN to
the apical PM, hepatocytes mainly use an indirect pathway where apical proteins are first delivered to the
basolateral PM, retrieved by endocytosis and then transcytosed to the apical surface. We determined that
hepatic transcytotic sorting requires cholesterol and glycosphingolipids. Because MAL2 (myelin and
lymphocyte protein 2) was identified as a regulator of transcytosis and because its activity requires cholesterol
and glycosphingolipids, we have been examining how MAL2 functions in apical delivery. For these studies,
WIF-B cells will be used. This cell line is an excellent polarized, hepatic model system. Aim 1 is aimed at
identifying what steps in the indirect pathway are under the regulation of MAL2. Aim 2 examines what
structural features of MAL2 are important and asks whether the cytoplasmic N- and C-termini are required for
function. Aim 3 seeks to identify new and characterize known MAL2 binding proteins that collaborate in
regulating apical protein trafficking. In Aims 3A and B, studies are proposed to characterize interactions
between MAL2 and a known interactor, tumor protein D52. In Aim 3C, experiments are described that will
identify new binding partners using the split-ubiquitin yeast two-hybrid system. Because our WIF-B cells are a
great polarized, hepatic model system and because we have many important tools and reagents, we are well-
poised to perform these experiments and hope to provide fundamental advances in our understanding of apical
protein targeting.
项目摘要
肝脏是人体的代谢中心,将食物转化为生命所需的化学物质并合成
释放到循环中的无数化合物供其他器官使用。肝脏也是主要的
排毒中心,摆脱异种生物和内源性浪潮产物的身体。这些功能大多
是在肝细胞中进行的,肝细胞是肝脏的主要上皮细胞。这些单元在
内部和外部环境通过形成紧密连接的形成来巩固自己
将不同的活性限制在特定的质膜(PM)域:基底外侧和顶端。这
基底外侧表面面对血液(内部环境),而顶部表面面对胆汁(
外部环境),复杂的分子“肥皂”,有助于吸收饮食脂肪和废物
移动。 PM蛋白的不对称分布反映了功能不对称性(或极性)。
每个结构域的特征是蛋白质的不同子集。因为适当的肝功能取决于
肝细胞极性,该提议问如何建立和维护极性?答案部分是
来自了解两极分化的膜贩运。我们的重点是确定肝根尖的调节剂
蛋白质递送。与简单的上皮细胞不同,该细胞直接靶向新合成的蛋白质从TGN到
顶端PM,肝细胞主要使用间接途径,首先将根尖蛋白传递到该途径
基底外侧PM,通过内吞作用检索,然后转到顶端表面。我们确定了这一点
肝胞单胞菌分选需要胆固醇和糖磷脂。因为mal2(髓鞘和
淋巴细胞蛋白2)被鉴定为跨胞菌病的调节剂,因为其活性需要胆固醇
和糖磷脂,我们一直在研究MAL2在顶端递送中的功能。对于这些研究,
将使用Wif-B细胞。该细胞系是一种极好的极化肝模型系统。目标1针对
在MAL2的调节下,确定间接途径中的哪些步骤。 AIM 2检查什么
MAL2的结构特征很重要,并询问是否需要细胞质N和C末端
功能。 AIM 3试图确定合作的新的和特征已知的MAL2结合蛋白
调节根尖蛋白运输。在AIMS 3A和B中,提出了研究以表征相互作用
MAL2和已知相互作用的肿瘤蛋白D52之间。在AIM 3C中,描述了将会
使用分裂泛素酵母两杂交系统确定新的结合伴侣。因为我们的Wif-B细胞是一个
伟大的两极化,肝模型系统,因为我们有许多重要的工具和试剂,所以我们很擅长
准备进行这些实验,并希望在我们对顶的理解中提供基本进步
蛋白质靶向。
项目成果
期刊论文数量(3)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
Rab17 regulates apical delivery of hepatic transcytotic vesicles.
- DOI:10.1091/mbc.e18-07-0433
- 发表时间:2018-11-15
- 期刊:
- 影响因子:3.3
- 作者:Striz AC;Stephan AP;López-Coral A;Tuma PL
- 通讯作者:Tuma PL
A Serine/Threonine Kinase 16-Based Phospho-Proteomics Screen Identifies WD Repeat Protein-1 As A Regulator Of Constitutive Secretion.
- DOI:10.1038/s41598-018-31426-1
- 发表时间:2018-08-29
- 期刊:
- 影响因子:4.6
- 作者:López-Coral A;Striz AC;Tuma PL
- 通讯作者:Tuma PL
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{{ truncateString('PAMELA L. TUMA', 18)}}的其他基金
Mechanisms that promote hepatocellular carcinoma due to chronic ethanol exposure
长期接触乙醇促进肝细胞癌的机制
- 批准号:
10666121 - 财政年份:2023
- 资助金额:
$ 17.56万 - 项目类别:
Alcohol-induced changes in hepatic microtubules: mechanisms and consequences
酒精引起的肝微管变化:机制和后果
- 批准号:
7784386 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
Alcohol-induced changes in hepatic microtubules: mechanisms and consequences
酒精引起的肝微管变化:机制和后果
- 批准号:
8197678 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
Alcohol-induced changes in hepatic microtubules: mechanisms and consequences
酒精引起的肝微管变化:机制和后果
- 批准号:
7994222 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
Alcohol-induced changes in protein acetylation: mechanisms and consequences
酒精引起的蛋白质乙酰化变化:机制和后果
- 批准号:
10705588 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
MAL2 regulation of hepatic protein trafficking: mechanisms and binding partners
MAL2 对肝蛋白运输的调节:机制和结合伙伴
- 批准号:
7866597 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
MAL2 regulation of hepatic protein trafficking: mechanisms and binding partners
MAL2 对肝蛋白运输的调节:机制和结合伙伴
- 批准号:
7736454 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
Alcohol-induced alterations in protein acetylation: mechanisms and consequences
酒精引起的蛋白质乙酰化改变:机制和后果
- 批准号:
9107324 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
MAL2 regulation of hepatic protein trafficking: mechanisms and binding partners
MAL2 对肝蛋白运输的调节:机制和结合伙伴
- 批准号:
8096703 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
Alcohol-induced changes in protein acetylation: mechanisms and consequences
酒精引起的蛋白质乙酰化变化:机制和后果
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10440163 - 财政年份:2009
- 资助金额:
$ 17.56万 - 项目类别:
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