Understanding and Targeting Tiam1 in Cancer
了解 Tiam1 并针对癌症进行靶向治疗
基本信息
- 批准号:10093529
- 负责人:
- 金额:$ 22.58万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2021
- 资助国家:美国
- 起止时间:2021-01-01 至 2022-12-31
- 项目状态:已结题
- 来源:
- 关键词:AffectAmino Acid SequenceAnimal ModelAnimalsApplications GrantsAutomobile DrivingB-Cell LymphomasBiologicalBiological ProcessCell Cycle ProgressionCell ProliferationCellsColonColon CarcinomaColorectal CancerConsensus SequenceConserved SequenceCritical PathwaysCytoskeletonDataDevelopmentDiagnosisDiffuseDiseaseEventFamilyFutureGene ExpressionGenesGuanine Nucleotide Exchange FactorsGuanosine Triphosphate PhosphohydrolasesHomologous GeneHumanIn VitroInterventionMalignant - descriptorMalignant NeoplasmsMeasuresMediatingMetabolismModificationMolecularMonomeric GTP-Binding ProteinsMutateMutationNeoplasm MetastasisNormal CellNucleotidesOncogenicOutcomePathway interactionsPharmaceutical ChemistryPhosphorylationPhosphorylation SitePhysiologicalPost-Translational Protein ProcessingProtein BiosynthesisProto-OncogenesReagentResearchRoleSignal PathwaySignal TransductionSignal Transduction PathwaySite-Directed MutagenesisSpecificityStructureStructure-Activity RelationshipSurfaceTestingTissuesTyrosineTyrosine PhosphorylationWorkXenograft procedurebasecancer cellcancer therapycell motilitycell transformationcolon cancer treatmentcolon tumorigenesisefficacious interventionexperimental studyfunctional outcomesgain of function mutationimprovedin silicoin vivoinnovationmigrationmouse modelnew therapeutic targetnovelpromoterprotein functionprotein metabolismrhorho GTP-Binding Proteinssmall molecule inhibitortooltumortumorigenesis
项目摘要
Project Summary:
Understanding the detailed mechanisms that underlie proliferative signal transduction pathways is of critical
importance for developing strategies for diagnosis and treatment of human cancer. Because most proliferative
pathways are critical for the functioning of all normal cells, the development of cancer-cell-selective interventions
without off-target effects is tremendously important yet highly challenging. The research proposed in this grant
application focuses on unique ‘players’ in proliferative signaling, the guanine nucleotide exchange factors (GEFs)
from the Dbl (diffuse B cell lymphoma) family.
GEFs control proliferative signaling by stimulating nucleotide exchange on the small GTPases, Rho, Rac, and
Cdc42. In doing so, GEFs regulate numerous cellular activities such as gene expression, cytoskeletal
rearrangements, protein synthesis, and metabolism. Gain-of-function mutations in GEFs are associated with
multiple human cancers, and GEFs from the Dbl family constitute one of the largest families of proto-oncogenes.
Although different Dbl-family GEFs share similar mechanisms of action, their expression is extremely tissue- and
cell-specific, and their respective mutated forms are associated with distinct and different cancers. Thus,
intervention with GEF signaling may be extremely useful in multiple, seemingly unrelated malignant diseases.
The proposed work relies on our recent discovery of a novel tyrosine phosphorylation sequence motif
(TEXXYVXXL) that regulates the activity of some Dbl-like GEFs implicated in human cancers. We hypothesize
that selective interreference with this phosphorylation comprises a unique, novel and effective selective
intervention approach in relevant cancers. This proof-of-principle proposal focuses on Tiam1, a GEF whose
dysregulation drives colorectal tumorigenesis and metastasis. We propose to decipher the molecular
mechanisms and functional outcomes of TEXXYVXXL phosphorylation in Tiam1, and to test novel reagents that
target Tiam1’s tyrosine phosphorylation as selective intervention tools. In Specific Aim 1 we will decipher the role
of TEXXYVXXL phosphorylation in regulating Tiam1’s key activities, i.e. GTPase activation, cell invasion and
proliferation in vitro, and tumorigenesis and metastasis in vivo. In Specific Aim 2, we will evaluate the utility of
novel reagents that target Tiam1’s TEXXYVXXL phosphorylation site for intervention in a mouse model of colon
cancer. These proof-of-concept experiments in cells and animals will open the door for future development and
translational work in GEF-associated malignancies.
项目总结:
项目成果
期刊论文数量(0)
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{{ truncateString('DANNY MANOR', 18)}}的其他基金
Understanding and Targeting Tiam1 in Cancer
了解 Tiam1 并针对癌症进行靶向治疗
- 批准号:
10322680 - 财政年份:2021
- 资助金额:
$ 22.58万 - 项目类别:
Functions of vitamin E and the tocopherol transfer protein
维生素 E 和生育酚转移蛋白的功能
- 批准号:
10541855 - 财政年份:2021
- 资助金额:
$ 22.58万 - 项目类别:
Functions of vitamin E and the tocopherol transfer protein
维生素 E 和生育酚转移蛋白的功能
- 批准号:
10394948 - 财政年份:2021
- 资助金额:
$ 22.58万 - 项目类别:
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