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PI3 kinase PIK3CB (p110beta) in membrane trafficking and metabolism

膜运输和代谢中的 PI3 激酶 PIK3CB (p110beta)

基本信息

批准号：
10249278
负责人：
Wei-Xing Zong
金额：
$ 35.46万
依托单位：
RUTGERS, THE STATE UNIV OF N.J.
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：
2018-09-01 至 2022-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10249278
关键词：
1-Phosphatidylinositol 3-Kinase Ablation Abnormal Cell Address Alleles Autophagocytosis Binding Biochemical Bioenergetics Biological Cancer Model Cell Line Cell Lineage Cell surface Cells Cellular Metabolic Process Clinical Data Cultured Cells Data Defect Development Embryo Endocytosis Event FRAP1 gene Failure G-Protein-Coupled Receptors GTP Binding GTPase-Activating Proteins Genetic Glucose Growth Growth Factor Guanosine Triphosphate Hematologic Neoplasms Hematopoietic Homeostasis Human Hydrolysis Intracellular Membranes Lead Lymphocyte MCF10A cells Malignant Neoplasms Mammary gland Mediating Membrane Metabolic Metabolic Diseases Metabolism Molecular Monomeric GTP-Binding Proteins Mus Mutation Nutrient Oncogenes Oncogenic PIK3CA gene PIK3CB gene Pathologic Pathway interactions Phosphotransferases Physiological Process Protein Isoforms Protein Tyrosine Kinase Proteome Receptor Signaling Reporting Role SLC2A1 gene Signal Pathway Signal Transduction Signaling Molecule Surface Testing Tumor Suppressor Proteins animal data cell growth deprivation design glucose uptake human disease in vivo in vivo Model mutant novel phosphatidylinositol 3,4,5-triphosphate phosphatidylinositol phosphate, PtdIns(4,5)P2 phosphoinositide-3,4,5-triphosphate prevent public health relevance receptor response scaffold small hairpin RNA trafficking tumorigenesis

项目摘要

PROJECT SUMMARY: The Class IA phosphatidylinositol 3-kinases (PI3Ks) p110a and p110b isoforms are ubiquitously expressed and respond to membrane receptor signals. They PI(3,4,5)P3, which acts as a signaling molecule to activate downstream signaling pathways including the Akt/mTOR pathway. Despite their similarities, two isoforms have distinct biochemical and biological features, one of which is that p110b has a kinase-independent function. We have reported that p110b positively regulates the small GTPase Rab5 in a manner that is independent of its catalytic activity. p110b, through a direct binding and as a molecular scaffold, keeps Rab5 in its “active” GTP- bound form by preventing Rab5 from interacting with its GTPase-activating protein (GAP), which inactivates Rab5 by hydrolyzing its GTP to GDP. Rab5 is well known for regulating endocytosis. Our preliminary data strongly indicate that p110b can regulate endocytic turnover of cell surface nutrient transporters such as glucose transporter 1 (GLUT1) in response to growth factor deprivation. We found that genetic ablation or shRNA silencing of p110b decreased the level of Rab5-GTP. This resulted in increased cell surface GLUT1 that led to increased glucose utilization of cell lines and promoted their oncogenic transformation. These findings lead us to propose the hypothesis that p110b, as a molecular scaffold, activates Rab5 and endocytic turnover of nutrient transporters. We further propose that this novel function of p110b regulates membrane trafficking and cell metabolism and homeostasis. We have designed two Specific Aims to test this hypothesis and establish its biological relevance. Aim 1: Test the hypothesis that p110b facilitates Rab5-mediated endocytic turnover of nutrient transporters. We will use FL5.12, MEFs, HK-2, and MCF10A cells to determine that p110b deficiency can lead to the stabilization of nutrient transporters, and to determine if the failure of endocytic turnover is the result of Rab5 inactivation. Aim 2. Determine the molecular and cell biological consequence of the stabilized nutrient transporters in p110b-deficient cells (with a focus on GLUT1). We will characterize the metabolic features associated with the nutrient transporter stabilization, and characterize the growth/proliferation signaling in p110b-deficient cells. We will also determine the physiological effects of the p110b-Rab5 interaction in vivo. !

项目总结: