Phosphatase-dependent regulation of desmosome intercellular junctions
桥粒细胞间连接的磷酸酶依赖性调节
基本信息
- 批准号:10677182
- 负责人:
- 金额:$ 7.18万
- 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 2024-03-31
- 项目状态:已结题
- 来源:
- 关键词:AcantholysisAddressAdhesionsAdhesivesAffectAffinityApicalBindingC-terminalCadherinsCell AdhesionCell divisionCell-Cell AdhesionCellsCoupledCouplesCutaneousCytoskeletonDNA Sequence AlterationDataDefectDeficiency DiseasesDeletion MutationDesmosomesDevelopmentDevelopment PlansDiseaseDisease modelEctopic ExpressionEpidermisEpidermolysis BullosaEquilibriumEventExhibitsExperimental ModelsExposure toFamily DasypodidaeFamily memberFoundationsFundingFutureGeneticGoalsHumanImmuneIn VitroIntercellular JunctionsIntermediate FilamentsKeratinLabelMaintenanceMechanical StressMechanicsMediatingMembraneMicroscopyModelingPemphigusPhosphoric Monoester HydrolasesPhosphorylationPhosphotransferasesPoint MutationPost-Translational Protein ProcessingProcessPropertyProtein DephosphorylationProtein Phosphatase InhibitorProtein phosphataseProteinsProteomicsRegulationResearch PersonnelRoleSignal TransductionSkinStratificationStressStretchingSyndromeTailTechniquesTestingTissuesTrainingWorkarrhythmogenic cardiomyopathycareercareer developmentdesmoplakindesmoplakin IIendosulfinegenetic approachinsightkeratinocytemechanical forcemechanical propertiesmechanotransductionmolecular phenotypemouse modelmutantnovelpreservationprotective effectrecruitresearch and developmentresponseskin barriersuperresolution microscopytraffickingtraining opportunity
项目摘要
Project Summary
Intercellular junctions and their cytoskeletal connections are essential for maintaining tissue stability and function.
This is particularly true of the multi-layered epidermis as it is exposed to high levels of mechanical stress while
maintaining an essential physical and immune barrier. Critical contributors to the epidermis' ability to maintain
the epidermal barrier while simultaneously adjusting to stress are attachments between keratin intermediate
filaments (IF) and intercellular junctions called desmosomes. Within desmosomes, a cytoskeletal linker protein
called desmoplakin (DP) is responsible for anchoring the IF to the junctions. DP is ubiquitously expressed in all
desmosome-forming cells and is regulated by post-translational modification (PTM) of its C-terminal tail domain
to control DP-IF affinity. Consistent with the importance of this phospho-regulatory region of DP for desmosome
function, genetic deletions of the C-terminal region cause multiple diseases associated with severe cardio-
cutaneous and lethal epidermal barrier defects. Functionally, when the C-terminal motif is in its hypo-
phosphorylated state, DP exhibits its highest affinity towards IF. In experimental models, the increased DP-IF
association had protective effects in mature cell sheets by generating stronger, more stable desmosomes.
Conversely, during desmosome assembly hypo-phosphorylated DP accumulates on the IF network, disrupting
it's trafficking to desmosome junctions, and interfering with the formation and maturation of new cell-cell
desmosome junctions. Given the strong molecular phenotypes associated with DP's hypo-phosphorylated form
in vitro, a coordinated process must exist to regulate DP phosphorylation for proper desmosome function. We
previously identified GSK3 as the kinase responsible for phosphorylating DP; however, the protein phosphatase
responsible for negatively regulating DP phosphorylation was previously unknown. My preliminary data identified
PP2A-B55 as capable of binding to and dephosphorylating DP's C-terminus. This proposal will test the
hypothesis that PP2A-B55 regulates DP phosphorylation during the dynamic process of desmosome
assembly and in response to mechanical stress to allow cells to respond to the changing properties and
specialized functions of the stratified epidermis. Aim 1 will employ cutting-edge microscopy and proteomics-
based approaches to identify the mechanism by which PP2A regulates DP during desmosome assembly. Aim 2
will establish how PP2A phospho-regulation of DP impacts 1) desmosome-dependent cell adhesion and 2) the
desmosomal response to mechanical stress using novel mechano-biology techniques. The proposed work will
provide important insight into how phosphatase signaling controls desmosome assembly and function to
maintain the human epidermal barrier and, therefore, how dysregulated phosphatase signaling could contribute
to barrier-related diseases. Together, the proposed research and career development plan will provide a
springboard for my development as an independent investigator and planned K99/R00 application.
项目总结
项目成果
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