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GPCR - Linked RhoGEFs in Tumor Growth and Metastasis

GPCR - 连接 RhoGEF 在肿瘤生长和转移中的作用

基本信息

批准号：
10338123
负责人：
John Tesmer
金额：
$ 34.86万
依托单位：
PURDUE UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2018
资助国家：
美国
起止时间：
2018-03-01 至 2024-02-29
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10338123
关键词：
Binding Sites Biological Biological Assay CRISPR/Cas technology Cancer Cell Growth Cancer Patient Catalytic Domain Cell Proliferation Cell model Cell physiology Cells Cellular biology Chemotaxis Collaborations Complex Cryoelectron Microscopy Crystallization Deuterium Development Enzymes Family G Protein-Coupled Receptor Signaling G-Protein-Coupled Receptors GTP-Binding Proteins Goals Growth Guanine Nucleotide Exchange Factors Heterotrimeric GTP-Binding Proteins Homeostasis Hormones Human Hydrogen In Vitro Lead Light Link Lipids Malignant Neoplasms Mammary Neoplasms Mass Spectrum Analysis Metastatic breast cancer Molecular Mutation NMR Spectroscopy Neoplasm Metastasis Ocular Melanoma PH Domain Pathologic Pathway interactions Peptide aptamers Peptides Physiological Play Prostatic Neoplasms Regulation Role Signal Pathway Signal Transduction Stimulus Structure System Testing Therapeutic Variant X-Ray Crystallography biophysical techniques cancer cell cancer genome cell growth combat design extracellular genome editing innovation insight leukemia link protein malignant breast neoplasm member migration novel strategies novel therapeutic intervention overexpression prevent response rho rho GTP-Binding Proteins small molecule inhibitor stem synergism tumor growth

项目摘要

PROJECT SUMMARY G protein-coupled receptors (GPCRs) are well known for their ability to convert extracellular information encoded in hormones, odorants, and peptides into rapid changes in cellular homeostasis by modulating the function of effector enzymes and channels in the cell. However, analysis of human cancer genomes indicates that some GPCR signaling pathways lead to sustained signals that in pathological settings are linked to tumor growth and metastasis. A common feature of such pathways is the activation of Rho GTPases by Dbl family Rho guanine nucleotide exchange factors (RhoGEFs). The TrioC subfamily (composed of Trio, Kalirin, and p63RhoGEF) is directly activated by heterotrimeric Gαq subunits and is strongly implicated in ocular melanoma and leukemia. The P-Rex subfamily (composed of P-Rex1 and 2) is activated synergistically by direct interactions with GBetagamma and the lipid PIP3, and is overexpressed in many breast and prostate tumors where it plays a metastatic role. Trio and P-Rex1/2 have thus emerged as important chemotherapeutic targets. The fact that the molecular and cellular mechanisms underlying regulation of these enzymes are as of yet poorly understood prevents a rational approach to the design of novel therapeutic approaches. By determining crystallographic and cryo-EM structures of members from these RhoGEF subfamilies, this proposal seeks to define molecular mechanisms of activation and to test these hypotheses through a battery of functional assays. In parallel, we extend our functional analysis into model cell systems to understand how constitutively active heterotrimeric G proteins and GPCRs promote cancer cell growth (as in ocular melanoma) and metastasis (as in breast cancer) via TrioC and P-Rex subfamily RhoGEFs. By understanding the basis for regulation of RhoGEF activity by heterotrimeric G proteins both in vitro and in relevant cellular contexts, we will accelerate discovery of new biological insights and novel therapeutic strategies that can be used to combat cancer.

项目摘要 G蛋白偶联受体（GPCRs）以其转换细胞外信息的能力而闻名在激素、气味物质和肽中编码的蛋白质，通过调节细胞中效应酶和通道的功能。然而，对人类癌症基因组的分析表明，一些GPCR信号通路导致持续的信号，这些信号在病理环境中与肿瘤相关，生长和转移。这些途径的共同特征是通过Dbl家族激活Rho GTP酶 Rho鸟嘌呤核苷酸交换因子（RhoGEFs）。TrioC亚家族（由Trio、Kalirin和 p63 RhoGEF）被异源三聚体G α q亚基直接激活，并与眼黑色素瘤密切相关和白血病P-Rex亚家族（由P-Rex 1和2组成）被直接协同激活。与GBetagamma和脂质PIP3的相互作用，并在许多乳腺和前列腺肿瘤中过表达，具有转移作用。因此，Trio和P-Rex 1/2成为重要的化疗靶点。的事实这些酶调节的分子和细胞机制迄今为止还不清楚，这种理解阻碍了设计新的治疗方法的合理方法。通过确定晶体学和cryo-EM结构的成员从这些RhoGEF亚家族，该提案旨在定义激活的分子机制，并通过一系列功能测定来测试这些假设。与此同时，我们将功能分析扩展到模型细胞系统中，以了解组成性活性如何异源三聚体G蛋白和GPCR促进癌细胞生长（如眼黑色素瘤）和转移（如眼黑色素瘤）。在乳腺癌中）通过TrioC和P-Rex亚家族RhoGEF。通过了解监管的基础， RhoGEF活性的异源三聚体G蛋白在体外和相关的细胞环境中，我们将加速发现新的生物学见解和新的治疗策略，可用于对抗癌症。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

High-Throughput Cryo-EM Enabled by User-Free Preprocessing Routines

DOI：
10.1016/j.str.2020.03.008
发表时间：
2020-07-07
期刊：
STRUCTURE
影响因子：
5.7
作者：
Li, Yilai;Cash, Jennifer N.;Cianfrocco, Michael A.
通讯作者：
Cianfrocco, Michael A.

Characterization of a hyperphosphorylated variant of G protein-coupled receptor kinase 5 expressed in E. coli.

大肠杆菌中表达的 G 蛋白偶联受体激酶 5 过度磷酸化变体的表征。

DOI：
10.1016/j.pep.2019.105547
发表时间：
2020
期刊：
Protein expression and purification
影响因子：
1.6
作者：
Beyett,TylerS;Chen,Qiuyan;Labudde,EmilyJ;Krampen,Joseph;Sharma,PrateekV;Tesmer,JohnJG
通讯作者：
Tesmer,JohnJG