Mechanistic studies of core Hippo pathway kinases

核心 Hippo 通路激酶的机制研究

基本信息

批准号：
9974545
负责人：
Jennifer Marie Kavran
金额：
$ 34.39万
依托单位：
JOHNS HOPKINS UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2019
资助国家：
美国
起止时间：
2019-07-08 至 2024-05-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9974545
关键词：
Address Affect Affinity Belief Binding Biochemical Biological Assay Cell Maintenance Cell Nucleus Cell Proliferation Cells Circular Dichroism Color Complex Data Development Disease Drosophila genus Ensure Enzymes Event Future Goals Homodimerization In Vitro Investigation Kinetics Label Laboratories Link Mass Spectrum Analysis Mediating Methods Molecular Names Natural regeneration Organ Organ Size Outcome Pathway interactions Phosphorylation Phosphorylation Site Phosphotransferases Property Proteins Proteolysis Reagent Regulation Research Series Signal Pathway Signal Transduction Tertiary Protein Structure Therapeutic Tissues Trefoil Motif Work X-Ray Crystallography analytical ultracentrifugation anti-cancer base experimental study insight novel programs repaired stem cell niche stem cells stoichiometry therapeutic target tumorigenesis

项目摘要

PROJECT SUMMARY The long-term goal of our research is to understand the molecular mechanisms that control eukaryotic signaling pathways. The objective of this application is to elucidate the principles that regulate the core kinases in the Hippo pathway. The Hippo pathway controls organ size during development, tumorigenesis, and maintains the stem-cell niche through the coordinated activity of a kinase cassette that includes two kinases, Mst1/2 and Lats1/2, and two accessory proteins, Mob1 and hSalvador. In Aim 1, we will establish a molecular basis for understanding complex formation between SARAH domain proteins (hSalvador, Mst1/2, and RassF5) to inform on how these proteins regulate pathway activity. In Aim 2, our investigations will further understanding of Mst1/2 activation and provide a mechanistic link between upstream pathway components and kinase activation. In Aim 3 we will elucidate the molecular mechanisms governing the activity of Lats1 and Mst2 activity. Outcomes from the proposed work will fundamentally alter our picture of Hippo signaling in normal and disease states and stimulate new directions of cellular and therapeutic investigation.

项目摘要我们研究的长期目标是了解控制真核信号传导的分子机制途径。该应用的目的是阐明调节核心激酶的原理河马途径。河马途径在发育，肿瘤发生过程中控制器官大小，并保持干细胞小众通过激酶盒的协调活性，其中包括两个激酶，MST1/2和 LATS1/2，以及两个附件蛋白MOB1和HSALVADOR。在AIM 1中，我们将建立一个分子基础了解Sarah域蛋白质（HSALVADOR，MST1/2和RASSF5）之间的复杂形成以告知这些蛋白如何调节途径活性。在AIM 2中，我们的投资将进一步了解MST1/2 激活并提供上游途径成分与激酶激活之间的机械联系。目标 3我们将阐明管理LATS1和MST2活性活性的分子机制。结果拟议的工作从根本上会改变我们在正常和疾病状态下以及刺激细胞和治疗投资的新方向。