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http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23806完整後設資料紀錄
| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 陳瑞華 | |
| dc.contributor.author | Mei-Yao Lin | en |
| dc.contributor.author | 林美瑤 | zh_TW |
| dc.date.accessioned | 2021-06-08T05:10:22Z | - |
| dc.date.copyright | 2011-10-05 | |
| dc.date.issued | 2011 | |
| dc.date.submitted | 2011-07-14 | |
| dc.identifier.citation | Adams, J., Kelso, R., and Cooley, L. (2000). The kelch repeat superfamily of proteins: propellers of cell function. Trends Cell Biol 10, 17-24.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/23806 | - |
| dc.description.abstract | 神經細胞軸突分枝及生長在神經發育及再生過程中扮演重要的角色。在本篇論文中，我們發現在神經細胞中, BTB-kelch蛋白KLHL20藉由與Cul3結合形成泛素接合酉毎複合體而具有促進神經細胞軸突分枝及生長功能。Cul3-KLHL20 接合酉毎複合體會促使一個在腦部高度表現的蛋白PDZ-RhoGEF的泛素化，並造成其降解。我們更進一步發現，神經滋養因子(Neurotrophins)可以藉由影響PDZ-RhoGEF的泛素化進而促使神經元的生長。神經細胞接收到神經滋養因子的刺激後，會活化下游的p38 MAPK，進一步促使PDZ-RhoGEF磷酸化。磷酸化的PDZ-RhoGEF會被KLHL20所辨識，並將其送至Cul3-KLHL20 接合酉毎複合體，促進PDZ-RhoGEF的泛素化，並引發PDZ-RhoGEF蛋白的降解。此一過程會進導致RhoA活性降低，而促使神經元的生長。由於神經滋養因子在神經發育過程中扮演著重要的角色，不僅可以促進神經細胞的存活更具有促進神經元生長的功能。因此，我們的研究提出了神經滋養因子藉由促進PDZ-RhoGEF降解而達到其調控神經分化的功能。 | zh_TW |
| dc.description.abstract | The induction of neurite outgrowth and arborization is critical for developmental and regenerative processes. Here we report that the BTB-kelch protein KLHL20 promoted neurite outgrowth and arborization in hippocampal and cortical neurons through its interaction with Cullin3 to form a ubiquitin ligase complex. This complex targeted PDZ-RhoGEF, a protein abundantly expressed in brain, for ubiquitin-dependent proteolysis, thereby restricting RhoA activity and facilitating growth cone spreading and neurite outgrowth. Importantly, targeting PDZ-RhoGEF to KLHL20 required PDZ-RhoGEF phosphorylation by p38 MAPK. In response to p38-activating neurotrophins, such as brain-derived neurotrophic factor and neurotrophin-3, KLHL20-mediated PDZ-RhoGEF destruction was potentiated, leading to neurotrophin-induced neurite outgrowth. Our study identified a ubiquitin-dependent pathway that targets PDZ-RhoGEF destruction to facilitate neurite outgrowth, and indicates a key role of this pathway in neurotrophin-induced neuronal morphogenesis. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-08T05:10:22Z (GMT). No. of bitstreams: 1 ntu-100-D94448005-1.pdf: 8386079 bytes, checksum: 535dd647f1433355ff84e08c5590a910 (MD5) Previous issue date: 2011 | en |
| dc.description.tableofcontents | Table Contents 1
Abbreviations 7 中文摘要 9 Abstract 10 Chapter I. Literature Review 11 1. Neuronal Differentiation 11 1.1 Overview of neuronal differentiation 11 1.2 Development of neuronal polarity 12 1.3 Axonal growth, branching and pruning 13 1.3.1 Axonal growth 13 1.3.2 Axonal branching 14 1.3.3 Axonal pruning 15 1.4 Factors regulating neurite outgrowth 16 1.4.1 Attractive factors 16 1.4.1.1 Adhesive molecules 16 1.4.1.2 Trophic factors 17 1.4.2 Inhibitory factors 17 1.4.3 Guidance cues 18 2. Neurotrophins 19 2.1 Neurotrophic proteins 19 2.2 Neurotrophic receptors 21 2.3 Neurotrophin signaling pathway 22 2.3.1 Neurotrophin signaling mediated by Trk receptors 22 2.3.1.1Ras-MAP kinase pathway 22 2.3.1.2 PI3K-Akt pathway 23 2.3.1.3 PLC-γ............................... 24 2.3.2 Neurotrophin signaling mediated by p75NTR receptors .............................. 24 3. Rho GTPases .............. 25 3.1 Rho family ............ 25 3.2 The regulation of GTPases activity .................... 26 3.2.1 RhoGEFs and RhoGAPs ......... 26 3.2.2 Temporal modularity of Rho GTPase signaling ................... 28 3.2.3 Transcriptional regulation and differential degradation .......... 28 3.3 Effectors and functions of Rho GTPases ............. 29 3.3.1 Rac and Cdc42 effectors ......... 29 3.3.1.1 PAK ............ 29 3.3.1.2 Wiskott-Aldrich syndrome family ............. 30 3.3.2 Rho effectors ........................... 30 3.4 Rho GTPases in axonal outgrowth, branching, and guidance ............................ 31 3.4.1 Neurite extension and outgrowth .................. 31 3.4.1.1 Rac and Cdc42 signaling pathways promoting neurite outgrowth .......... 32 3.4.1.2 The role of Rho signaling in neurite retraction ................ 33 3.4.2 Axonal growth and branching ....................... 34 3.4.3 Axon guidance ........................ 35 4. Ubiquitination ............ 36 4.1 The ubiquitin-proteasome system ...................... 36 4.2 The diversity of E3 ubiquitin ligases.................. 37 4.3 The functions of ubiquitination in nervous system .................... 39 4.3.1 Protein turnover during neuronal development .................... 39 4.3.1.1 Axonal formation ............... 39 4.3.1.2 Axonal growth and branching .................. 40 4.3.1.3 Dendritic pruning ............... 41 4.3.1.4 Regulation of synaptic number and size .......................... 42 4.3.2 Regulation of synaptic plasticity by ubiquitination .............. 42 4.4 BTB-kelch protein and KLHL20 ....................... 43 4.4.1 BTB proteins ........................... 43 4.4.2 BTB-kelch proteins ................. 44 4.4.3 KLHL20 .......... 45 5. PDZ-RhoGEF ............ 46 5.1 RGS family ........... 46 5.1.1 RGS-RhoGEFs ........................ 46 5.1.1.1 Deactivation of Gα12/13 by RGS proteins ...................... 47 5.1.1.2 Regulation of RGS-RhoGEFs by Gα12/13 ..................... 48 5.2 PDZ-RhoGEF function ................ 49 5.2.1 The role of PDZ-RhoGEF in neuronal progression .............. 49 5.2.2 Regulation of cell polarity and migration ............................. 50 5.3 The regulation of PDZ-RhoGEF ........................ 51 5.3.1 Oligomerization ...................... 51 5.3.2 Phosphorylation ...................... 51 5.3.2 Protein-protein interaction ............................ 51 Chapter II. PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite growth ..................... 53 Introduction .................... 54 Results ............................ 55 KLHL20 promotes neurite outgrowth/arborization. ........................ 55 KLHL20 interacts with PDZ-RhoGEF. ................... 55 KLHL20 promotes PDZ-RhoGEF ubiquitination and destruction to inactivate RhoA.......................... 56 KLHL20 promotes neurite outgrowth and growth cone spreading through PDZ-RhoGEF degradation................. 57 KLHL20-mediated PDZ-RhoGEF destruction is potentiated by p38 MAPK and participates in neurotrophin-induced morphogenesis...................... 58 Discussion ...................... 59 Materials and Methods ........................... 63 Cell culture and transfection .............. 63 Plasmids ..................... 63 RNA interference ............................. 64 Yeast two-hybrid screen ..................... 64 Antibodies and reagents ..................... 64 Immunofluorescence .......................... 65 Analyses of neurite outgrowth, neuronal morphology and growth cone morphology ................................... 65 Production of baculovirus .................. 66 In vitro phosphorylation ..................... 66 Immunoprecipitation and GST pull down .................. 66 In vitro ubiquitination......................... 67 RhoA activity assay ............................ 67 Table .............................. 68 Table 1: Genes identified by yeast two-hybrid using kelch-repeats domain of KLHL20 as bait .......... 68 Figures........................... 69 Fig.1 The expression of KLHL20 in primary hippocampal neurons. ...................... 69 Fig. 2 Specificity of the KLHL20 antibody. .............. 70 Fig. 3 KLHL20 promotes neurite outgrowth/arborization in hippocampal neurons. ................................... 71 Fig. 4 KLHL20 promotes neurite outgrowth in cortical neurons. ............................ 72 Fig. 5 KLHL20 does not affect neuronal polarity. ........................... 73 Fig. 6 Cul3 depletion blocks KLHL20-induced neurite outgrowth. ........................ 74 Fig. 7 KLHL20 interacts specifically with PDZ-RhoGEF. .............. 75 Fig. 8 KLHL20 interacts with PDZ-RhoGEF via kelch-repeats domain. ................ 76 Fig. 9 The C-terminus of PDZ-RhoGEF is required for KLHL20 binding ............. 77 Fig. 10 Interaction of endogenous PDZ-RhoGEF amd KLHL20 in mouse brain. .. 78 Fig. 11 KLHL20 forms a complex with Cul3 and PDZ-RhoGEF ........................... 79 Fig. 12 KLHL20-based Cul3 complex promotes PDZ-RhoGEF ubiquitination in vivo. ............................ 80 Fig. 13 Endogenous KLHL20 promotes PDZ-RhoGEF ubiquitination. .................. 81 Fig. 14 KLHL20-based Cul3 complex promotes PDZ-RhoGEF ubiquitination in vitro. ........................... 82 Fig. 15 Purification of the KLHL20-based Cul3 complex by GST pull down assay. ................................... 83 Fig. 16 KLHL20 promotes proteasomal degradation of PDZ-RhoGEF. ................. 84 Fig. 17 KLHL20 promotes PDZ-RhoGEF turnover. ....................... 85 Fig. 18 Knockdown of KLHL20 increases PDZ-RhoGEF steady-state level.......... 86 Fig. 19 KLHL20 promotes PDZ-RhoGEF degradation to inactivate RhoA. ........... 87 Fig. 20 Depletion of KLHL20 in hippocampal neurons potentiates RhoA activity without affecting RhoA expression.......................... 88 Fig. 21 Overexpression of PDZ-RhoGEF abolishes the effect of KLHL20 on neurite outgrowth in hippocampal neurons................ 89 Fig. 22 KLHL20 promotes neurite outgrowth through down-regulating PDZ-RhoGEF. ........... 90 Fig. 23 Blockage of ROCK or myosin II abrogates the effect of KLHL20 on neurite outgrowth. ................. 91 Fig. 24 Overexpression of KLHL20 abolishes the effect of PDZ-RhoGEF on growth cones collpase in hippocampal neurons. ............................. 92 Fig. 25 KLHL20-mediated PDZ-RhoGEF degradation is important to maintain growth cones spreading. ..................... 93 Fig. 26 p38 enhances the PDZ-RhoGEF interaction with KLHL20. ....................... 94 Fig. 27 Phosphorylation is required for PDZ-RhoGEF ubiquitination by KLHL20/Cul3/Roc1. .......................... 95 Fig. 28 p38, but not ERK, potentiates the ubiquitination of PDZ-RhoGEF catalyzed by KLHL20/Cul3/Roc1. ..................... 96 Fig. 29 p38 directly phosphorylates PDZ-RhoGEF. ........................ 97 Fig. 30 Pharmacological inhibition of p38 MAPK increases PDZ-RhoGEF level. . 98 Fig. 31 Pharmacological inhibition of p38 MAPK increases RhoA activity. .......... 99 Fig. 32 p38-activating neurotrophins up-regulate the KLHL20-dependent PDZ-RhoGEF degradation pathway. ..................... 100 Fig. 33 p38- and KLHL20-mediated PDZ-RhoGEF destruction participates in BDNF- and NT-3-induced differentiation................ 101 Fig. 34 Model for p38-activating neurotrophin induces PDZ-RhoGEF degradation by KLHL20-Cul3-Roc1 E3 ligase complex ............ 102 Reference ..................... 103 | |
| dc.language.iso | en | |
| dc.title | Cullin3-KLHL20對PDZ-RhoGEF泛素化在神經滋養因子引起神經突生長之探討 | zh_TW |
| dc.title | PDZ-RhoGEF ubiquitination by Cullin3-KLHL20 controls neurotrophin-induced neurite outgrowth | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 99-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 李芳仁,陳鴻震,張智芬,戴晶瑩 | |
| dc.subject.keyword | PDZ-RhoGEF,Rho,Cullin3泛素接合酶,神經分化,神經滋養因子, | zh_TW |
| dc.subject.keyword | PDZ-RhoGEF,Rho,Cullin3 ubiquitin ligase,neuronal differentiatio,neurotrophin, | en |
| dc.relation.page | 121 | |
| dc.rights.note | 未授權 | |
| dc.date.accepted | 2011-07-14 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| 顯示於系所單位： | 分子醫學研究所 | |
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