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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：
DANNY MANOR
金额：
$ 22.58万
依托单位：
CASE WESTERN RESERVE UNIVERSITY
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：
https://reporter.nih.gov/project-details/10093529
关键词：
Affect Amino Acid Sequence Animal Model Animals Applications Grants Automobile Driving B-Cell Lymphomas Biological Biological Process Cell Cycle Progression Cell Proliferation Cells Colon Colon Carcinoma Colorectal Cancer Consensus Sequence Conserved Sequence Critical Pathways Cytoskeleton Data Development Diagnosis Diffuse Disease Event Family Future Gene Expression Genes Guanine Nucleotide Exchange Factors Guanosine Triphosphate Phosphohydrolases Homologous Gene Human In Vitro Intervention Malignant - descriptor Malignant Neoplasms Measures Mediating Metabolism Modification Molecular Monomeric GTP-Binding Proteins Mutate Mutation Neoplasm Metastasis Normal Cell Nucleotides Oncogenic Outcome Pathway interactions Pharmaceutical Chemistry Phosphorylation Phosphorylation Site Physiological Post-Translational Protein Processing Protein Biosynthesis Proto-Oncogenes Reagent Research Role Signal Pathway Signal Transduction Signal Transduction Pathway Site-Directed Mutagenesis Specificity Structure Structure-Activity Relationship Surface Testing Tissues Tyrosine Tyrosine Phosphorylation Work Xenograft procedure base cancer cell cancer therapy cell motility cell transformation colon cancer treatment colon tumorigenesis efficacious intervention experimental study functional outcomes gain of function mutation improved in silico in vivo innovation migration mouse model new therapeutic target novel promoter protein function protein metabolism rho rho GTP-Binding Proteins small molecule inhibitor tool tumor tumorigenesis

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: