Molecular mechanisms of Tie2/Angiopoietin signaling initiation
Molecular mechanisms of Tie2/Angiopoietin signaling initiation
批准号:
9321086
负责人:
DIMITAR B NIKOLOV
金额:
$44.81万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-08-01 至 2020-07-31
关键词:
AgonistAngiopoietin-2AngiopoietinsBindingBiochemicalBiologicalBiological AssayBiophysicsCell LineCell surfaceCellsCharacteristicsChemicalsComplementComplexCrystallizationDataEngineeringEventFluorescence Resonance Energy TransferGlycoproteinsGoalsIndividualInsectaIntegrinsKineticsLengthLigandsLigationLymphatic SystemMaintenanceMediatingMediator of activation proteinMethodsMolecularMonitorPhosphotransferasesPlayProductionPropertyProtein Tyrosine KinaseProteinsReceptor Protein-Tyrosine KinasesRoleSignal TransductionSpectrum AnalysisStructureSurfaceSystemTIE-2 ReceptorTechniquesThermodynamicsTransmembrane DomainVascular SystemWorkX-Ray Crystallographyanalytical ultracentrifugationangiogenesisbasebiological systemsbiophysical analysisexperimental studyextracellularin vivomicrocalorimetrymilligramoverexpressionreceptor
中文摘要
摘要
英文摘要
Abstract
The angiopoietins are a small class of secreted glycoproteins that play key roles in the maturation
and maintenance of the mammalian vascular and lymphatic systems. They exert their effects through the
Tie receptor tyrosine kinases. All four angiopoietins (Ang1-4) directly bind Tie2, while none of them binds
the related Tie1, although the latter has been shown to modulate the Ang/Tie2 signaling. Integrins, and in
particular a5b1, are involved in regulating Ang1-dependent angiogenesis and were shown to directly
interact with Tie2. The Ang/Tie signaling is unique among receptor kinase-ligand systems in that distinct
angiopoietin ligands, although all highly homologous, may function as agonist or antagonist in a context
dependent manner. A detailed understanding of the mechanisms of Angiopoietin/Tie signaling and their
precise function during angiogenesis requires a comprehensive structural and biophysical analysis of the
angiopoietins, of the Tie receptors and their co-receptors, as well as of their interactions. We will use X-ray
crystallography, combined with other biophysical, biochemical and cell-biological techniques, to study these
molecules. We have previously determined the structures of Tie2, Ang1, Ang2, as well as of the Tie2/Ang1
and Tie2/Ang2 complexes, revealing important and unique characteristics of Tie2 signaling initiation. We
also performed FRET-based studies on live cells to monitor the Tie1/Tie2 interactions on the cell surface.
An important conclusion of our experiments is that the distinct signaling properties of the individual
angiopoietins are likely the result of Tie2 co-receptors that respond differently to the different ligands.
Therefore, we now propose to study the molecular mechanisms by which co-receptors modulate, in a
regulated and cell/context-dependent manner, the Ang/Tie2 signaling events. We specifically propose to
investigate the roles of Tie1 and intergrin a5b1. Finally, our ultimate goal is to determine crystal structures of
the complete Tie2 receptor, including its transmembrane region, alone and in complex with ligands and co-
receptors, and we will work on the production and structural characterization of functional full-length Tie
proteins.
+ PHS 398/2590 (Rev. 05/01)
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