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Molecular Mechanisms of Semaphorin/Plexin-mediated Cytoskeletal Reorganization

信号蛋白/丛蛋白介导的细胞骨架重组的分子机制

基本信息

批准号：
10352310
负责人：
JONATHAN R TERMAN
金额：
$ 35.44万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2011
资助国家：
美国
起止时间：
2011-02-15 至 2024-01-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10352310
关键词：
Actins Addictive Behavior Adult Affect Amino Acids Animal Model Automobile Driving Axon Behavior Binding Biochemical Biological Biological Assay Biological Process Biophysics Brain Cell model Cues Cytoskeletal Modeling Cytoskeleton Dendrites Development Diagnosis Drosophila genus Emotions Enzymes Event F-Actin Family Filament Functional disorder Funding Genetic Genetic Models Goals Human Injury Instruction Learning Ligands Link Mammals Mediating Microfilaments Microtubules Molecular Morphology Motion Mouse Protein Mus Nervous System control Nervous system structure Neurons Neurosciences Research Oxidation-Reduction Oxides Oxidoreductase Polymers Prevention strategy Process Property Protein Family Proteins Recovery Regulation Semaphorins Shapes Signal Pathway Signal Transduction Spinal Cord Stimulus Structure Synaptic Transmission System Testing Therapeutic Time Tissues Traumatic injury Tubulin Vertebral column Walking Work adhesion process axon growth axon guidance cell behavior cell motility extracellular genetic approach genetic regulatory protein in vivo member migration nervous system disorder novel oxidation plexin polymerization prevent receptor response screening spatiotemporal

项目摘要

The goals of this project are to decipher the mechanisms that regulate the actin and microtubule cytoskeletons, the structures underlying neural cell behaviors including morphology, polarity, adhesion, process elongation, motility, navigation, connectivity, and plasticity. To change their size, shape, and connectivity, neurons require actin and tubulin proteins to assemble together into long polymers (F-actin and microtubules, respectively) – and numerous extracellular stimuli have now been identified that alter the assembly and organization of these cytoskeletal structures. Yet, we still know little of how these extracellular cues exert their precise effects on the cytoskeleton. To better understand these mechanisms, my lab has been focusing on one of the largest families of extracellular cues, the Semaphorins (Semas) – which alter neuronal behaviors by eliciting destabilizing effects on both F-actin and microtubules. Our strategy has been to use model organisms and screening approaches to search for proteins that work in the signal transduction cascade utilized by Semas and their Plexin receptors. Among the proteins that we have identified, is a new family of intracellular proteins called the MICALs that are required for Sema/Plexin signal transduction. Now, work in my lab during the previous funding cycle of this R01 has revealed that the MICALs employ a previously unknown Redox signaling system to control the actin cytoskeleton. Namely, we have found that Mical is a novel F-actin disassembly factor – and our results reveal that Sema/Plexin-mediated reorganizations of the actin cytoskeleton can be precisely achieved in space and time through activation of Mical. We have also found that the MICALs belong to a class of oxidoreductase (Redox) enzymes and that Mical employs its Redox enzymatic activity to alter the properties of F-actin. Our work has gone on to identify that Mical uses F-actin as a direct substrate and post- translationally oxidizes conserved amino acids on actin, simultaneously dismantling F-actin and decreasing polymerization. Moreover, we find that this Sema/Plex/Mical-mediated Redox regulation of actin is reversible (by a protein called SelR/MsrB) – and that this specific reversible Redox actin regulatory system directs multiple different biological processes in neuronal and non-neuronal tissues. Therefore, I hypothesize that Sema/Plexin guidance cues utilize a reversible Redox signaling mechanism composed of Mical and SelR to directly and spatiotemporally coordinate cytoskeletal remodeling to drive cellular form and function. I propose to test this hypothesis by following-up on several lines of preliminary observations that illuminate critical molecular mechanisms of Sema/Plexin/Mical-mediated cytoskeletal reorganization including 1) specific types of F-actin/networks of F-actin that are most responsive to Sema/Plex/Mical effects, 2) molecular interactions that allow Sema/Plexins to coordinate the disassembly of the actin and microtubule cytoskeletons, 3) ligand/receptor systems that allow Sema/Plex/Mical cytoskeletal effects to be magnified spatiotemporally, and 4) specific actin regulatory proteins that protect actin filaments from Sema/Plex/Mical effects.

这个项目的目标是破译调节肌动蛋白和微管细胞骨架的机制，