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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 賈景山 | zh_TW |
| dc.contributor.advisor | Jean-San Chia | en |
| dc.contributor.author | 林軒兆 | zh_TW |
| dc.contributor.author | Hsuan-Chao Lin | en |
| dc.date.accessioned | 2024-08-16T17:44:15Z | - |
| dc.date.available | 2024-08-17 | - |
| dc.date.copyright | 2024-08-16 | - |
| dc.date.issued | 2024 | - |
| dc.date.submitted | 2024-08-05 | - |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/94721 | - |
| dc.description.abstract | 在我們的綜合研究中，我們調查了影響細胞骨架重塑和細胞遷移的兩種不同機制。我們最初的工作集中在serine-threonine kinase 40 (STK40)和mitogen-activated protein kinase (MAPK)之間的協同作用，突顯出合成阻動的概念。通過shRNA-藥物的雙重篩選，我們觀察到STK40和MAPK的同時抑制顯著減少了細胞遷移。這種效應主要來自於STK40基因敲除強化了點狀粘附 (focal adhesion, FA)複合體，這種基因敲除降低了yes-associated protein (YAP) 蛋白的穩定性並減少了其核質比。MAPK的抑制進一步損害了YAP的活性，且破壞FA的動態平衡。這些對於STK40-YAP-MAPK路徑的協調調控, 為我們所稱的“合成阻動”提供了基礎，這是一種調節細胞運動性的新策略。接著我們進一步探討從合成阻動篩選中指出的另一對蛋白的交互作用——Ste20-like kinase (SLK)-Rho-associated protein kinase (ROCK)，我們將焦點放在SLK如何以非磷酸化的方式與Ezrin互動並重塑肌動蛋白結構。具體來說，我們證明了在SLK或Ezrin基因敲除下，HaCaT細胞中的收縮性肌動蛋白束會顯著增加，而抑制Ezrin的磷酸化並未增加這些收縮性肌動蛋白束。此外，Ezrin基因敲除引起的收縮性肌動蛋白束的增加可以通過過表達未磷酸化的Ezrin突變體所逆轉，支持SLK-Ezrin的串聯在細胞遷移期間獨立於磷酸化調控去調節收縮性肌動蛋白束。綜上所述，這些研究揭示了兩條獨立的路徑，通過這些路徑可以調節細胞骨架的重塑，每條路徑都具有其自身的重要性，並提供了管理細胞遷移和細胞骨架組織的創新方法。這些發現不僅加深了我們對細胞運動的理解，也為以異常細胞遷移為特徵的疾病引入了潛在的治療目標。 | zh_TW |
| dc.description.abstract | In our comprehensive study, we investigated two distinct mechanisms that influence cytoskeletal remodeling and cell migration. Our initial work focused on the synergistic interaction between serine-threonine kinase 40 (STK40) and mitogen-activated protein kinase (MAPK), highlighting the concept of synthetic dysmobility. Through an shRNA-drug two-hit screen, we observed a significant reduction in cell migration by concurrent inhibition of STK40 and MAPK. This effect primarily stemmed from strengthening of focal adhesion (FA) complexes by STK40 knockdown, which destabilized yes-associated protein (YAP) and reduced its nuclear translocation. MAPK inhibition further impaired YAP activities, leading to disruptions in FA dynamics. These insights into the coordinated STK40-YAP-MAPK pathway provide a basis for what we term “synthetic dysmobility”, a novel strategy to modulate cell motility. We further explored another interaction pair identified from our screen, the Ste20-like kinase (SLK)-Rho-associated protein kinase (ROCK) interaction, focusing on how SLK interacts with Ezrin to remodel actin structures in a particularly phosphorylation-independent manner. Specifically, we demonstrated a significant increase in contractile actin bundles in migrating HaCaT cells under knockdown of SLK or Ezrin, while suppression of Ezrin phosphorylation did not increase those bundles. Moreover, the increase in contractile actin bundles caused by Ezrin knockdown could be reversed by overexpression an unphosphorylated Ezrin mutant, supporting the phosphorylation-independent facet of SLK-Ezrin cascade in regulating of contractile actin bundles during cell migration. Collectively, these studies unveil two separate pathways by which cytoskeletal remodeling can be modulated, each significant in its own right, and provide innovative approaches for managing cell migration and cytoskeletal organization. These findings not only deepen our understanding of cell motility but also introduce potential therapeutic targets for diseases characterized by abnormal cell migration. | en |
| dc.description.provenance | Submitted by admin ntu (admin@lib.ntu.edu.tw) on 2024-08-16T17:44:15Z No. of bitstreams: 0 | en |
| dc.description.provenance | Made available in DSpace on 2024-08-16T17:44:15Z (GMT). No. of bitstreams: 0 | en |
| dc.description.tableofcontents | 口試委員會審定書 i
Acknowledgement ii 中文摘要 iii Abstract iv 圖 次 ix Chapter 1 Introduction 1 1.1 Cell migration 1 1.1.1 Rho GTPases and Actin Dynamics 1 1.1.2 Regulation by ROCK 2 1.1.3 PI3K/Akt Pathway 4 1.1.4 Calcium Regulation 5 1.1.5 TOR Signaling 7 1.1.6 MAPK/ERK Pathway 8 1.1.7 Integrin Signaling and Focal Adhesions 9 1.1.7.1 Focal adhesion dynamics in cell locomotion 11 1.1.8 Endocytic Recycling Pathways 13 1.1.9 Guanine Nucleotide Exchange Factors (GEFs) 14 1.1.10 YAP Regulation 15 1.2 Collective cell migration 17 1.2.1 Research Methodologies 19 1.2.2 Key Findings 23 1.2.3 Experimental Data Insights 27 1.3 Cancer Metastasis 31 1.4 Rationale for a two-hit migration screen 35 1.4.1 Concept of synthetic lethality 35 1.4.2 two-hit migration screen 37 1.5 STK40: A multifaceted regulator of cellular processes 39 1.6 SLK and Ezrin: partners in cellular architecture and signaling 40 1.6.1 SLK: a versatile regulator of cellular processes 41 1.6.2 Ezrin: a key regulator of cellular dynamics 42 Chapter 2 Materials and methods 44 2.1 Cell culture 44 2.2 Constructs 44 2.3 Lentivirus 45 2.4 “Two-hit” migration screen 46 2.5 Single-cell tracing migration assays 47 2.6 Double-inhibition experiment 49 2.7 Immunofluorescent staining 50 2.8 In vitro permeability assay 52 2.9 YAP activity assay 52 2.10 Real-time reverse transcription PCR 53 2.11 FA analysis 53 2.12 FA dynamic assay 54 2.13 Western blotting 56 2.14 Antibodies 58 2.15 Myofibroblastic differentiation assay 59 2.16 Flow cytometry 61 2.17 YAP analysis 61 2.18 Cycloheximide assay 61 2.19 Statistical analysis 62 Chapter 3 Results 63 3.1 Synthetic Impairment Screen Reveals a Coordinated STK40-YAP-MAPK Network Promoting Cellular Movement 63 3.1.1 Dual-Target Screen to Decipher Signaling Interactions in Cellular Mobility 63 3.1.2 STK40 Modifies Cellular Movement Through Regulation of Adhesion Cytoskeletons 65 3.1.3 STK40 Partners with MAPK in YAP-Driven Focal Adhesion Remodeling 69 3.2 Cooperative influence of SLK and ROCK on sheet migration dynamics in cellular assays 72 3.2.1 SLK did not directly regulate ROCK activities 73 3.2.2 Distinct roles of SLK and ROCK in cell adhesion modules 73 3.3 Synthetic immobility screening exposes a phosphorylation-independent aspect of the SLK-Ezrin-F-actin signaling pathway 74 3.3.1 Differential effects of SLK and Ezrin knockdown on actin configurations relative to Ezrin dephosphorylation 75 3.3.2 Double inhibition studies uncover a new phosphorylation-independent SLK-EZR pathway in actin remodeling 76 3.3.3 Ezrin facilitates remodeling of contractile actin fibers via phosphorylation-independent routes 77 3.3.4 The knockdown of SLK or Ezrin led to an increase in contractile actin fibers by modifying actin dynamics, as opposed to altering actin presentation. 77 Chapter 4 Discussion 78 4.1 Cooperative regulation of YAP signaling by STK40 and MAPK 78 4.2 How does STK40 regulate YAP? 79 4.2.1 Hypothesis 1: STK40 Prevents YAP Degradation by Direct Binding 79 4.2.2 Hypothesis 2: STK40 Modulates Importin and Exportin Activity 80 4.2.3 Hypothesis 3: STK40 Inhibits E3 Ubiquitin Ligase Activity 80 4.2.4 Hypothesis 4: STK40 Modulates MST1/2 or LAST1/2 Activity 81 4.2.5 Integrative Insights from Recent Research 81 4.3 Working hypothesis: SLK-Ezrin regulation of contractile actin bundles via unphosphorylation mechanism 82 Chapter 5 Figures 86 Chapter 6 References 111 Chapter 7 Appendix 126 | - |
| dc.language.iso | en | - |
| dc.subject | 細胞骨架重塑 | zh_TW |
| dc.subject | 細胞遷移 | zh_TW |
| dc.subject | 合成阻動 | zh_TW |
| dc.subject | MAPK | en |
| dc.subject | EZR | en |
| dc.subject | SLK | en |
| dc.subject | synthetic dysmobility | en |
| dc.subject | YAP | en |
| dc.subject | STK40 | en |
| dc.subject | contractile actin bundles | en |
| dc.title | 訊息互擾與模組協作：使用合成阻動篩選揭示了兩種不同的細胞骨架重塑模式 | zh_TW |
| dc.title | Signaling crosstalk versus modular collaboration: two distinct modes of cytoskeletal remodeling unveiled by the synthetic dysmobility screen | en |
| dc.type | Thesis | - |
| dc.date.schoolyear | 112-2 | - |
| dc.description.degree | 博士 | - |
| dc.contributor.coadvisor | 蔡丰喬 | zh_TW |
| dc.contributor.coadvisor | Feng-Chiao Tsai | en |
| dc.contributor.oralexamcommittee | 徐立中;李建國;郭津岑;曾炳輝 | zh_TW |
| dc.contributor.oralexamcommittee | Li-Chung Hsu;Chien-Kuo Lee;Jean-Cheng Kuo;Ping-Hui Tseng | en |
| dc.subject.keyword | 合成阻動,細胞骨架重塑,細胞遷移, | zh_TW |
| dc.subject.keyword | STK40,MAPK,YAP,synthetic dysmobility,SLK,EZR,contractile actin bundles, | en |
| dc.relation.page | 148 | - |
| dc.identifier.doi | 10.6342/NTU202403384 | - |
| dc.rights.note | 同意授權(限校園內公開) | - |
| dc.date.accepted | 2024-08-05 | - |
| dc.contributor.author-college | 醫學院 | - |
| dc.contributor.author-dept | 免疫學研究所 | - |
| dc.date.embargo-lift | 2029-08-05 | - |
| 顯示於系所單位： | 免疫學研究所 | |
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