GRB2 在人类胶质瘤中的新效应子-猫眼课题宝

GRB2 在人类胶质瘤中的新效应子

批准号：

7577554

负责人：

ALBERT J. WONG

金额：

$31.61万

依托单位：

STANFORD UNIVERSITY

依托单位国家：

美国

项目类别：

财政年份：

1996

资助国家：

美国

项目状态：

已结题

起止时间：

1996-04-15 至 2010-02-28

来源：

https://reporter.nih.gov/project-details/7577554

关键词：

2-tyrosine Affect Arts Astrocytoma Binding Binding Sites Biological Cell Death Cell Fractionation Cell Line Cell Proliferation Cells Chemicals Complex Data Diffuse Docking Drug Delivery Systems EGF gene Epidermal Growth Factor Receptor FDA approved Family Fluorescence Resonance Energy Transfer Frequencies G Protein-Coupled Receptor Genes GRB2 gene Gene Silencing Glioblastoma Glioma Gliomagenesis Goals Growth Growth Factor Human Hydrogen Peroxide Immunoprecipitation Ligands MAPK14 gene MAPK8 gene Monomeric GTP-Binding Proteins Nature Neuroglia Non-Receptor Type 11 Protein Tyrosine Phosphatase Oxidative Stress PTPN11 gene Pathogenesis Pathway interactions Pattern Peripheral Pharmaceutical Preparations Phenotype Phosphorylation Phosphorylation Site Play Process Property Protein Tyrosine Kinase Protein Tyrosine Phosphatase Proteins Reactive Oxygen Species Receptor Protein-Tyrosine Kinases Research Role Signal Transduction Signaling Molecule Site Spectrometry, Mass, Matrix-Assisted Laser Desorption-Ionization Staining method Stains Stimulus Structure System TP53 gene Time Tumorigenicity Tyrosine Ultraviolet Rays Vesicle Western Blotting Work angiogenesis cancer cell cell growth cytokine interest knock-down next generation novel overexpression receptor research study response tool tumor

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DESCRIPTION (provided by applicant): Gab1 is a docking protein that is downstream of multiple receptor tyrosine kinases (RTKs). Our goals are to further understand the role of Gab1 in EGF receptor and reactive oxygen species (ROS) signaling and how it participates in the process of gliomagenesis. We have shown that Gab1 can be a substrate for the SHP-2 tyrosine phosphatase and this interaction is essential for cell growth and transformation in NIH3T3 cells. In contrast, under oxidative stress we find that the Gab1/SHP-2 complex promotes cell death and is correlated with JNK activation. For the first time, we have observed that Gab1 is overexpressed in high grade astrocytoma tumors in comparison with normal glia, suggesting a role for Gab1 in gliomagenesis. It also presents two different patterns of localization, one diffuse and the other an unusual vesicular staining at the periphery which increases in frequency with tumor grade. In Specific Aim #1, we will study the role of Gab1 in cell growth and transformation by: 1) analyzing the sites in Gab1 dephosphorylated by SHP-2; 2) using this information to identify the pathways downstream of the Gab1/SHP2 interaction responsible for cell growth and/or transformation. Specific Aim #2 will focus on its role in ROS stimulation by :1) studying the localization of Gab1/SHP2 interaction after oxidative stress via FRET and cell fractionation; 2) the phosphorylation sites of Gab1 after H2O2 addition as revealed by MS-MALDI; and 3) how JNK is specifically activated by the Gab1/SHP-2 interaction. In Specific Aim #3, we will examine the role of Gab1 in astrocytomas by studying: 1) if knock down of Gab1 expression in grade III and grade IV cell lines impairs tumorigenicity; 2) if the presence of Gab1 correlates with grade IV tumors arising from the secondary pathway; and 3) what is the nature of the vesicle-like structure where Gab1 is localized. This work will apply state of the art tools that have not been extensively used in cancer cells and may reveal new aspects of how cellular localization correlates with signaling and unique properties of signaling molecules in tumors.

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