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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 徐立中(Li-Chung Hsu) | |
| dc.contributor.author | Yen-Kai Chen | en |
| dc.contributor.author | 陳彥剴 | zh_TW |
| dc.date.accessioned | 2021-06-15T12:26:37Z | - |
| dc.date.available | 2021-08-26 | |
| dc.date.copyright | 2016-08-26 | |
| dc.date.issued | 2016 | |
| dc.date.submitted | 2016-08-10 | |
| dc.identifier.citation | Alwan, H. A. and J. E. van Leeuwen (2007). 'UBPY-mediated epidermal growth factor receptor (EGFR) de-ubiquitination promotes EGFR degradation.' J Biol Chem 282(3): 1658-1669.
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/49947 | - |
| dc.description.abstract | 表皮生長因子受體(EGFR)是一種受體酪胺酸激酶(RTK)，並且參與在許多細胞代謝的過程當中，包括細胞的增生、分化與存活。表皮生長因子受體在細胞當中表現量的異常，以及訊息傳遞過度的活化會導致許多的疾病，例如：癌症；所以準確的調控表皮生長因子受體在細胞內的運輸與降解是相當重要的。有許多的證據指出表皮生長因子受體的磷酸化(phosphorylation)與泛素化(ubiquitination)會和它的運輸與降解的過程有關係，但是詳細的分子機制到目前為止還不清楚。最近我們發現了一個E3泛素接合酶ZNRF1蛋白，它可以在肺癌細胞當中去調控表皮生長因子受體的降解，因此我們想要進一步去探討ZNRF1是如何去調控表皮生長因子受體的運輸與降解。首先，我們在非小細胞肺癌細胞株A549中利用CRISPR/ Cas9的技術剔除ZNRF1基因，然後在這樣的細胞當中加入會促使表皮生長因子受體開始降解的表皮生長因子配體(EGF)，我們發現表皮生長因子受體的降解會因此而減緩。然而，在這樣的細胞當中重新表現野生型(wild-type)的ZNRF1會使得表皮生長因子受體原本減緩的降解速率得到回復，但如果是表現酵素活性受到突變的ZNRF1則無法達到回復的效果；這樣的結果顯示ZNRF1的酵素活性對於調控表皮生長因子受體的降解是必須的。此外，我們發現ZNRF1會與表皮生長因子受體的酪胺酸激酶結構區(tyrosine kinase domain; TKD)有交互作用，並且會調控受體的泛素化。接著，我們發現了第五號銜接蛋白複合體(AP-5)的其中一個成員SPG11也會參與在表皮生長因子受體的降解過程，因為當我們在肺癌細胞中降低SPG11蛋白表現量的時候，同樣會減緩表皮生長因子受體的降解。雖然我們還需要許多的研究才能更全面性的了解ZNRF1調控表皮生長因子受體運輸和降解的機制；但總體而言，我們的實驗結果指出ZNRF1會與表皮生長因子受體(EGFR)產生交互作用，並且可能是藉由調控第五號銜接蛋白複合體(AP-5)來協助受體的運輸與降解，以達到調控表皮生長因子受體降解與訊息傳遞的平衡。 | zh_TW |
| dc.description.abstract | Epidermal growth factor receptor (EGFR) is a receptor tyrosine kinase (RTK) that plays roles in numerous cellular processes, including cell proliferation, survival and differentiation. Downregulation or overactivation of EGFR has been associated with many human diseases, such as cancer. Endosomal trafficking and degradation of EGFR is crucial for controlling its downstream signaling. Mounting evidence suggests that ubiquitination and phosphorylation of EGFR are important for its trafficking and degradation, but the molecular mechanism remains unclear. We recently found an E3 ubiquitin ligase, ZNRF1, mediate EGFR degradation in lung cancer cell lines. Here, we aim to elucidate how ZNRF1 mediates EGFR trafficking and degradation. We first generated ZNRF1-/- A549 cells using the CRISPR/Cas9 system, and confirmed that EGF-triggered EGFR degradation was decreased in these cells. Reconstitution of wild-type, but not the catalytically inactive E3 ligase, ZNRF1 to ZNRF1-deleted cells restored the effect of ZNRF1-mediated EGFR degradation, suggesting a requirement of the E3 ubiquitin ligase in the ZNRF1-mediated EGFR trafficking. In addition, we found that ZNRF1 physically associated with the tyrosine kinase domain (TKD) of EGFR and regulated its ubiquitination. Depletion of SPG11, a component of the adaptor protein-5 (AP-5) complex, in A549 cells decreased ligand-induced EGFR degradation, suggesting also its involvement in EGFR degradation. Together, our data suggest that ZNRF1 interacts and controls EGFR trafficking and degradation possible through the AP-5 complex. Nevertheless, more studies are needed to completely understand the underlying mechanism by which ZNRF1 regulates EGFR trafficking and degradation. | en |
| dc.description.provenance | Made available in DSpace on 2021-06-15T12:26:37Z (GMT). No. of bitstreams: 1 ntu-105-R02448013-1.pdf: 3343179 bytes, checksum: 97d656edeff375a4f3632b37fa1038a1 (MD5) Previous issue date: 2016 | en |
| dc.description.tableofcontents | Contents
口試委員會審定書 I 致謝 II 摘要 III Abstract IV Contents 1 Introduction 4 Epidermal Growth Factor Receptor (EGFR) and cancer 4 EGFR trafficking 5 The role of EGFR ubiquitination in trafficking 7 EGFR signaling 9 Zinc and RING finger protein 1 (ZNRF1) 12 Other members of ZNRF protein family 14 Specific aim 16 Materials and Methods 17 Antibodies and Reagents List 17 Plasmids 18 Primer list 20 Cell line, Cell culture and Transfection 20 Preparation of pseudo-typed lentiviruses and Infection 21 Generation of stable single cell clone 22 Preparation of whole cell lysate 22 Immunoblotting 23 Immunoprecipitation 24 RNA extraction and Reverse Transcription Quantitative PCR (RT-qPCR) 25 Cell Proliferation assay 25 Wound healing assay 26 Statistic analysis 26 Results 27 ZNRF1 regulates EGFR degradation in A549 cells 27 ZNRF1 deficiency enhances EGFR activation and signaling in A549 cells 28 ZNRF1 controls EGFR degradation requires its E3 ubiquitin ligase 29 ZNRF1 regulates cell proliferation and migration 30 ZNRF1 regulates ligand-triggered EGFR degradation in different lung cancer cells 31 EGFR interacts with ZNRF1 via its tyrosine kinase domain (TKD) 32 ZNRF1 regulates EGFR ubiquitination 33 SPG11 is involved in ligand-induced EGFR degradation 34 Discussion 35 Figures 41 Figure 1 41 Figure 2 43 Figure 3 45 Figure 4 46 Figure 5 48 Figure 6 50 Figure 7 52 Figure 8 53 Figure 9 55 Figure 10 57 Figure 11 58 Figure 12 60 Figure 13 61 Supplementary Figures 62 Supplementary Figure 1 62 Supplementary Figure 2 64 Supplementary Figure 3 65 Supplementary Figure 4 66 Supplementary Figure 5 67 References 68 | |
| dc.language.iso | en | |
| dc.title | ZNRF1在表皮生長因子受體的運輸與降解所扮演之角色 | zh_TW |
| dc.title | The role of ZNRF1 in EGFR trafficking and degradation | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 104-2 | |
| dc.description.degree | 碩士 | |
| dc.contributor.oralexamcommittee | 李明學(Ming-Shyue Lee),潘思樺(Szu-Hua Pan) | |
| dc.subject.keyword | 表皮生長因子受體,表皮生長因子配體,受體酪胺酸激?,泛素化, | zh_TW |
| dc.subject.keyword | ZNRF1,EGFR,EGF,RTK,ubiquitination, | en |
| dc.relation.page | 74 | |
| dc.identifier.doi | 10.6342/NTU201602044 | |
| dc.rights.note | 有償授權 | |
| dc.date.accepted | 2016-08-10 | |
| 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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