The regulation and targeting of cell survival pathways in cancer

癌症细胞存活途径的调控和靶向

• 批准号: 9813068
• 负责人: Joshua Lyon Andersen
• 金额: $ 43.2万
• 依托单位: BRIGHAM YOUNG UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-12-22 至 2022-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9813068
• 关键词: AMP-activated protein kinase kinase; Address; Autoimmunity; Automobile Driving; Autophagocytosis; Autophagosome; B-Cell Lymphomas; CRISPR/Cas technology; Cancer Biology; Cancer Patient; Cell Survival; Cells; Cessation of life; Clinical; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Data; Degenerative Disorder; Disease; Early Endosome; Fill-It; Functional disorder; Genetic Transcription; Goals; Golgi Apparatus; Growth; Homeostasis; Human; Hypoxia; Immune; Immunologic Deficiency Syndromes; Impairment; Integral Membrane Protein; Ischemia; Knock-in; Link; Lymphoma; Lysosomes; Malignant Neoplasms; Mediating; Modeling; Molecular; Mutation; Nutrient; Pathway interactions; Patients; Pharmacology; Phosphoric Monoester Hydrolases; Phosphorylation; Phosphotransferases; Physiological; Play; Process; Protein Dephosphorylation; Proteins; Proteomics; Public Health; Recycling; Regulation; Research; Risk; Role; Signal Pathway; Signal Transduction; Site; Stress; Structure; Techniques; Tertiary Protein Structure; Testing; Vesicle; Work; base; cancer cell; chemotherapy; confocal imaging; design; disease-causing mutation; experimental study; genetic regulatory protein; human disease; improved outcome; innovation; neoplastic cell; novel; protein protein interaction; response; scaffold; targeted treatment; trafficking; tumor; tumor growth; tumorigenesis

PROJECT SUMMARY/ABSTRACT The cellular recycling process of autophagy is essential for tumor cells to survive and adapt to a variety of stresses, including ischemia and chemotherapies, which ultimately leads to more aggressive tumor growth and chemoresistance. ATG9A is known to play a governing role in driving tumor cell autophagy, yet fundamental gaps exist in our understanding of 1) how ATG9A is regulated post-transcriptionally; 2) how protein-protein interactions mediate the mobilization of ATG9A to promote autophagy; and 3) mechanisms that link defective ATG9A function to human diseases, including cancer. These gaps hinder the rational design of targeted therapies to block tumor cell autophagy. The long-term goal is to discover mechanisms of tumor cell survival and develop targeted strategies, based on these mechanisms, to exploit cancer cell vulnerabilities The overall objective of this proposal is to elucidate a detailed mechanism of ATG9A-mediated regulation of autophagy. The central hypothesis is that ATG9A phosphorylation is positively regulated by AMPK within the ULK1 complex and negatively regulated by a nutrient sensitive phosphatase, which control its mobilization and trafficking toward the autophagosome. In addition, our data revealed novel ATG9A interactions with LRBA and an ULK1-independent ATG13 subcomplex that we propose regulate ATG9A trafficking in autophagy. In particular, we posit that the interaction between ATG9A and LRBA is defective in patients carrying LRBA mutations, which may explain how these mutations cause immunodeficiency and B cell lymphoma. Guided by preliminary data, this hypothesis will be tested in the following specific aims: Aim 1: Determine the mechanism of ATG9A phosphorylation and its impact on ATG9A trafficking. Aim 2: Determine the mechanism by which an ULK1-independent ATG13 subcomplex regulates ATG9A. Aim 3: Determine if LRBA regulates ATG9A and whether disease-causing mutations in LRBA disrupt ATG9A function in autophagy. The proposal is innovative because it elucidates novel concepts/models of ATG9A regulation and applies emerging techniques (14-3-3 phospho-probing, BioID) to overcome the inherent challenges of studying ATG9A. The proposed research is significant because it fills fundamental gaps in our understanding of one of the least- understood autophagy regulators, ATG9A, and elucidates a potential role for defective ATG9A regulation in human disease.

项目总结/摘要 自噬的细胞再循环过程对于肿瘤细胞的生存和适应是必不可少的。 各种压力，包括缺血和化疗，最终导致更多 侵袭性肿瘤生长和化疗耐药性。ATG 9A在驾驶中发挥着重要作用 肿瘤细胞自噬，但我们对1）ATG 9A如何调节的理解存在根本性的差距 2）蛋白质-蛋白质相互作用如何介导ATG 9A的动员， 促进自噬;和3）将缺陷型ATG 9A功能与人类疾病联系起来的机制， 包括癌症这些缺陷阻碍了靶向治疗的合理设计， 自噬长期的目标是发现肿瘤细胞存活的机制，并开发靶向治疗。 基于这些机制的策略，以利用癌细胞的脆弱性。 该建议旨在阐明ATG 9A介导的自噬调节的详细机制。的 中心假设是ATG 9A磷酸化受到ULK 1内AMPK的正调控 复杂的和负调控的营养敏感磷酸酶，控制其动员 并向自噬体运输。此外，我们的数据揭示了新的ATG 9A相互作用， 与LRBA和ULK 1独立的ATG 13亚复合物，我们建议调节ATG 9A运输 在自噬中。特别是，我们认为ATG 9A和LRBA之间的相互作用是有缺陷的， 携带LRBA突变的患者，这可能解释了这些突变如何导致免疫缺陷 和B细胞淋巴瘤。在初步数据的指导下，这一假设将在以下几个方面得到检验： 目的1：确定ATG 9A磷酸化的机制及其对ATG 9A的影响 贩卖人口目的2：确定ULK 1非依赖性ATG 13亚复合物 调节ATG 9A。目的3：确定LRBA是否调节ATG 9A，以及致病基因是否与ATG 9A相关。 LRBA的突变破坏了ATG 9A在自噬中的功能。该提案具有创新性，因为它 阐明ATG 9A调节的新概念/模型，并应用新兴技术（14-3-3 磷酸探针，BioID），以克服研究ATG 9A的固有挑战。拟议 研究是重要的，因为它填补了我们对一个最小的理解的根本空白- 了解自噬调节剂，ATG 9A，并阐明了缺陷ATG 9A的潜在作用， 人类疾病的调控。

项目成果

A mechanism of ACK1 activation in cancer via C-terminal UBA domain truncation.

通过 C 端 UBA 结构域截断在癌症中激活 ACK1 的机制。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Balasooriya,Eranga;Eastmond,Reilly;Madusanka,Deshan;Owen,Jacob;Gashler,Jack;Lopez-Palacios,Tania;Andersen,Joshua
• 通讯作者: Andersen,Joshua

Cu/Zn Superoxide Dismutase (Sod1) regulates the canonical Wnt signaling pathway.

• DOI: 10.1016/j.bbrc.2020.11.011
• 发表时间: 2021-01-01
• 期刊: Biochemical and biophysical research communications
• 影响因子: 3.1
• 作者: Chandrasekharan B;Montllor-Albalate C;Colin AE;Andersen JL;Jang YC;Reddi AR
• 通讯作者: Reddi AR

ATG9A-mediated turnover of p62 condensates requires ubiquitin and occurs independently of the LC3-lipidation machinery.

ATG9A 介导的 p62 缩合物的周转需要泛素，并且独立于 LC3 脂化机制而发生。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: McEwan,ColtenM;Broadbent,DavidG;Poole,DanielM;Naylor,BradC;Price,JohnC;Schmidt,JensC;Andersen,JoshL
• 通讯作者: Andersen,JoshL

The dynamic and stress-adaptive signaling hub of 14-3-3: emerging mechanisms of regulation and context-dependent protein-protein interactions.

• DOI: 10.1038/s41388-018-0348-3
• 发表时间: 2018-10
• 期刊: Oncogene
• 影响因子: 8
• 作者: Pennington KL;Chan TY;Torres MP;Andersen JL
• 通讯作者: Andersen JL

A mechanism of regulation for the ubiquitin-sensing kinase TNK1.

泛素感应激酶 TNK1 的调节机制。

• 发表时间: 2022
• 期刊: FASEB journal : official publication of the Federation of American Societies for Experimental Biology
• 作者: Vaughan,AlecJ;Egbert,Christina;Chan,Yin;Lopez,Tania;Ashworth,Spencer;McCormack,Katherine;Andersen,Joshua
• 通讯作者: Andersen,Joshua