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Probing a novel signaling complex that sustains AKT activation to support stress survival in cancer

探索维持 AKT 激活以支持癌症应激生存的新型信号复合物

基本信息

批准号：
10689065
负责人：
Matthew R Zanotelli
金额：
$ 6.95万
依托单位：
CORNELL UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-09-01 至 2025-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10689065
关键词：
Aggressive behavior Anchorage-Independent Growth Anoikis Binding Biochemical C2 Domain Cancer cell line Cell Survival Cells Cellular Stress Characteristics Complex Cytokinesis Dimerization Docking Exhibits Exposure to FRAP1 gene Family member GTP Binding Genetic Growth Growth Factor Guanine Nucleotide Exchange Factors Human Individual Intervention Laboratories Lipid Binding Location Lysosomes Maintenance Malignant - descriptor Malignant Neoplasms Mediating Membrane Metabolism Nutrient Oncogenic Outcome PIK3CG gene Phenotype Phospholipids Phosphorylation Play Proteins Proto-Oncogene Proteins c-akt Ribosomal Protein S6 Kinase Role Serum Signal Pathway Signal Transduction Site Starvation Stress Surface Therapeutic Intervention Work biological adaptation to stress cancer cell cancer survival cancer therapy cell transformation insight new therapeutic target novel nutrient deprivation scaffold targeted treatment therapeutic target tumor metabolism tumor progression tumorigenesis

项目摘要

PROJECT SUMMARY Abnormal metabolism is a hallmark of cancer that helps cancer cells to grow, undergo malignant transformation, and survive under stressful conditions such as nutrient deprivation. Cancer cells are exposed to many cellular stresses during tumorigenesis, which must be overcome for the propagation of malignancy. In cancer, the abnormal activation of many signaling networks serves to disconnect the control of growth, metabolism, and survival, and recent efforts have sought to therapeutically target cancer metabolism. The phosphatidylinositol 3- kinase (PI3K)-AKT (protein kinase B) signaling pathway is the most activated in human cancer and has a wide range of effects on cellular metabolism. We have recently identified the Cdc42/Rac guanine nucleotide exchange factor (GEF) dedicator of cytokinesis 7 (Dock7) as a novel signaling node that supports sustained basal AKT activation and mechanistic target of rapamycin (mTOR) activity as determined by its downstream target S6 kinase (S6K) during stressful conditions to maintain signaling activity required for cell survival and transformation. We find that Dock7 is required for multiple cancer cell lines to resist anoikis and exhibit anchorage-independent growth. While we observe relatively low levels of AKT phosphorylation compared to stimulation by growth factors, Dock7-dependent signaling is critical for the survival of cancer cells during nutrient deprivation. I hypothesize that under cellular stress Dock7 serves as a scaffold for AKT, sustaining its phosphorylation and organizing signaling partners for mTOR signaling required for stress survival. This project will investigate the role of this novel Dock7/AKT/mTOR signaling activity in providing a survival benefit to cancer cells under cellular stress. I propose to study the impact of Dock7-dependent signaling activity on AKT/mTOR signaling, cell survival under stress, and critical characteristics of malignant progression and aggression. In Aim 1, I will investigate the functional activities of the Dock-homology region 2 (DHR2) domain of Dock7, which is responsible for GEF activity, in basal AKT phosphorylation for cancer cell stress survival and malignant transformation. In Aim 2, I will next identify the novel role of the DHR1 domain in Dock7-dependent AKT phosphorylation, cancer cell stress survival, and malignant transformation. Then, in Aim 3, I will identify the subcellular location of this Dock7 signaling complex under stress conditions and determine the individual roles of DHR1, DHR2, and activated Cdc42 in Dock7 localization. The work in this proposal will provide biochemical characterization of Dock7 signaling activity that will lead to a mechanistic understanding of Dock7-dependent AKT/mTOR activation in cancer cell stress survival. These findings will not only contribute to the understanding of cancer aggression and metabolism but may also identify new therapeutic targets for cancer treatment.

项目总结