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Wnt Signaling and Endosomal Trafficking as Regulators of Cellular Protein Degradation

Wnt 信号传导和内体运输作为细胞蛋白质降解的调节剂

基本信息

批准号：
9469785
负责人：
Lauren Veronica Albrecht
金额：
$ 5.67万
依托单位：
UNIVERSITY OF CALIFORNIA LOS ANGELES
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-12-01 至 2019-11-30
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9469785
关键词：
Address Area Arginine Biochemical Biomedical Research Biotin Catabolism Cell physiology Cells Congenital Abnormality Cultured Cells Cytoplasmic Protein Data Development Disease Embryonic Development Ensure Enzymes Event Genetic Glycogen Synthase Kinase 3 Goals Growth Factor Health Heart Diseases Homeostasis Human Human Development Image Label Left Link Malignant Neoplasms Mediating Membrane Methylation Mission Modification Molecular Morphogenesis Multivesicular Body Nerve Degeneration Pathologic Pathway interactions Phosphorylation Play Polyubiquitination Process Protein Methylation Protein translocation Protein-Arginine N-Methyltransferase Proteins Proteolysis Proteome Proteomics Public Health Regulation Research Role Signal Transduction Sum Testing Therapeutic Intervention Time Tissues Translating Translations Ubiquitin United States National Institutes of Health WNT Signaling Pathway Work Xenopus anticancer research base cell growth cell growth regulation cellular development chemical genetics cohort extracellular improved in vivo inhibitor/antagonist innovation late endosome multicatalytic endopeptidase complex neglect novel novel strategies protein aggregation protein degradation trafficking tumor progression

项目摘要

Project Summary/Abstract There is a fundamental gap in our understanding of the basic mechanisms underlying the regulation of cytosolic protein degradation. A portion of cytosolic proteins are engulfed by endolysosomes through a process known as microautophagy, however, the extent to which microautophagy can be regulated and which specific proteins are targeted through this mechanism are unknown. This gap represents an important problem because the misregulation of cytosolic protein turnover is a critical component of neurodegeneration and represents an emerging theme in cancer research. The long-term objective of this project is to determine the how protein catabolism is regulated by Wnt signaling, a pathway that is essential in development and is misregulated in disease. My preliminary data support the conceptually novel hypothesis that microautophagy is coordinated by canonical Wnt. Further, preliminary data suggests that cytosolic substrates targeted by microautophagy during Wnt signaling are modified by arginine methylation, a critical post-translation modification recently implicated in cytoplasmic signaling. Based on these findings, the central hypothesis of this proposal is that Wnt signaling stimulates arginine methylation to promote cytosolic protein degradation in endolysosomes through microautophagy (Fig. 1). I propose two specific aims: (1) elucidate the role of arginine methylation in Wnt signaling during cell growth and embryogenesis; and (2) determine how Wnt signaling and microautophagy regulate cytosolic protein degradation in endolysosomes. Aim 1 will examine the roles arginine methylation and Protein Arginine Methyl-Transferase 1 (PRMT1) in promoting Wnt signaling during cell growth and embryogenesis in human cells and Xenopus. Aim 1 is conceptually innovative as it examines a novel role for arginine methylation, a modification only recently discovered in cytoplasmic signaling, in the Wnt pathway and endolysosomes. Further, technical innovation through the use of chemical- genetic protein labeling strategies will offer the highest levels of sensitivity to examine the role of methylation in promoting GSK3 phosphorylation in live cells. Aim 2 will define the mechanism through which Wnt signaling regulates microautophagy to promote cytosolic proteolysis using genetic biochemical approaches to assess endolysosomal proteolysis in cultured human cells. I will apply a technically innovative in vivo biotin-protein labeling strategy to examine the novel concept that microautophagy targets specific cytosolic proteins during Wnt signaling. The proposed research is significant because elucidating the regulation of cytosolic proteolytic pathways could contribute to the development of innovative therapeutic interventions for targeting Wnt signaling in cancer and may reveal key details into the mechanisms of protein degradation in disease. In sum, this proposal offers a novel approach to investigate an integrated view of the pathologic mechanisms of protein degradation regulated by extracellular signaling factors during development and tissue morphogenesis.

项目总结/文摘