Understanding and Targeting Tiam1 in Cancer

了解 Tiam1 并针对癌症进行靶向治疗

• 批准号: 10322680
• 负责人: DANNY MANOR
• 金额: $ 18.44万
• 依托单位: CASE WESTERN RESERVE UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2021
• 资助国家: 美国
• 起止时间: 2021-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10322680
• 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-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

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.

项目摘要： 了解基于增殖信号转导途径的详细机制至关重要 对于制定诊断和治疗人类癌症的策略的重要性。因为最激增 途径对于所有正常细胞的功能至关重要，即癌细胞选择性干预措施的发展 没有脱离目标效果是极为重要但又高度挑战的。这项赠款提出的研究 应用侧重于鸟嘌呤核替象交换因子（GEFS）在增殖信号传导中的独特“播放器”。 来自DBL（弥漫性B细胞淋巴瘤）家族。 GEFS通过刺激小GTPases（RHO，RAC）和 CDC42。为此，GEF调节了许多细胞活性，例如基因表达，细胞骨架 重排，蛋白质合成和代谢。 GEF中的功能性突变与 多种人类癌症和来自DBL家族的GEF构成了原始癌基因的最大家族之一。 尽管不同的DBL家庭GEF具有相似的作用机制，但它们的表达是非常组织 - 细胞特异性及其各自的突变形式与不同的和不同的取消相关。那， 在多种，看似无关的恶性疾病中，使用GEF信号的干预可能非常有用。 拟议的工作依赖于我们最近发现的新型酪氨酸磷酸化序列基序 （Texxyvxxl）调节在人类癌症中实施的某些类似DBL的GEF的活性。我们假设 选择性与这种磷酸化的相互报复包括独特，新颖和有效的选择性 相关癌症的干预方法。此原理证明的提议重点是Tiam1，GEF的GEF 失调驱动结直肠肿瘤发生和转移。我们提议破译分子 TIAM1中Texxyvxxl磷酸化的机制和功能结果，并测试新试剂 靶标TIAM1的酪氨酸磷酸化作为选择性干预工具。在特定目标1中，我们将破译角色 在调节TIAM1的关键活动中，即GTPase激活，细胞侵袭和 体外增殖，肿瘤发生和体内转移。在特定目标2中，我们将评估 靶向Tiam1的Texxyvxxl磷酸化位点的新型试剂用于干预鼠标颜色模型 癌症。这些在细胞和动物中的概念验证实验将为将来的发展打开大门， 与GEF相关的恶性肿瘤中的翻译工作。