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| DC 欄位 | 值 | 語言 |
|---|---|---|
| dc.contributor.advisor | 嚴仲陽(Jeffrey J.Y. Yen) | |
| dc.contributor.author | Wei-Ting Liao | en |
| dc.contributor.author | 廖偉廷 | zh_TW |
| dc.date.accessioned | 2023-03-19T22:45:42Z | - |
| dc.date.copyright | 2022-10-03 | |
| dc.date.issued | 2022 | |
| dc.date.submitted | 2022-08-11 | |
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| dc.identifier.uri | http://tdr.lib.ntu.edu.tw/jspui/handle/123456789/85133 | - |
| dc.description.abstract | 在正常或癌化的細胞中，Akt-Rheb-mTORC1 訊息途徑調控許多重要的生理代謝作用。然而，Akt如何透過影響Tuberous Sclerosis Complex protein complex (TSCC)的GTPase-activating protein (GAP)活性，進而調控Rheb的活性的機制，並不全然清楚。在本研究中我們提供證據描述一個訊息傳遞複合體，稱作TSC2-Akt-CBAP complexes controlling Rheb Desuppression (TACRD)，可以藉由在溶酶體的表面上的CBAP調控TSC1/TSC2的結合，進而影響到TSCC的GAPase活性，以此來控制生長激素刺激之下Rheb的活性。我們的細胞內以及試管內實驗一致顯示，CBAP可以藉由其N端的疏水區域，與TSC1競爭TSC2 的HBD片段的結合，來調節TACRD的GAPase功能。更進一步，在溶酶體的表面上高量表達的CBAP，會透過一種TSC2依賴的機制，不儘可以活化mTORC1訊息途徑, 也能導致溶酶體生成變多，與TSC2基因缺失對於細胞生理影響的表現型相似。因此我們的研究揭露了另外一種抑制TSC2活性的機制，以及更進一步顯示CBAP在mTORC1調控溶酶體生成以及細胞生長的訊號途徑中扮演一定的角色。 | zh_TW |
| dc.description.abstract | The Akt-Rheb-mTORC1 signaling axis controls many crucial pathways in normal and tumorous cells. However, how Akt regulates the GTPase-activating protein (GAP) activity of Tuberous Sclerosis Complex protein complex (TSCC) on the small GTPase Rheb is incompletely understood. We provide evidence for a signaling platform, termed TSC2-Akt-CBAP complexes controlling Rheb Desuppression (TACRD), operating on lysosomal membranes where CBAP and growth factor stimulation regulate TSC1/TSC2 association and the GAP activity of TSCC towards Rheb. Our in vitro and in vivo assays reveal that CBAP modulates TACRD function partly by competing with TSC1 for binding with the harmatin-binding domain of TSC2 via the CBAP N-terminal hydrophobic domain. Lysosomal enrichment of CBAP not only activated mTORC1 signaling pathway, but also enhanced lysosomal biogenesis via a TSC2-dependent mechanism, phenocopying TSC2-null phenotypes. Our study reveals an alternative TSC2-inactivation mechanism and underscores the importance of CBAP to mTORC1-mediated regulation and lysosomal biogenesis during cell growth and oncogenesis. | en |
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| dc.description.tableofcontents | 口試委員會審定書 i 誌謝 ii 中文摘要 iii Abstract iv Contents v List of Figures viii List of Supplementary Figure x Chapter 1 Introduction 1 1.1 AKT 1 1.2 AKT and cancers 1 1.3 TSC 2 1.4 mTORC1 3 1.5 Akt regulates mTORC1 signaling through TSC2 4 1.6 Rheb 4 1.7 Rheb mutants and cancers 5 1.8 TSCC inhibits mTORC1 via hydrolysis of Rheb-GTP 5 1.9 Lysosomes as a hub for mTORC1 signaling 6 1.10 Rheb and TSCC on lysosomes 7 1.11 Lysosomes and cancers 7 1.12 Lysosome biogenesis 8 1.13 TSC1/2 deficiency and lysosomal biogenesis 9 1.14 CBAP 9 Chapter 2 Materials and Methods 12 2.1 Materials 12 2.1.1 Cell lines 12 2.1.2 Antibodies and reagents 12 2.1.3 Plasmids 12 2.2 Methods 13 2.2.1 Starvation and insulin re-stimulation 13 2.2.2 Transient transfection of plasmids 14 2.2.3 Cell lysis, subcellular fractionation, immunoprecipitation and immunoblotting 14 2.2.4 Immunofluorescence staining, confocal microscopy and quantification of colocalization 15 2.2.5 Proximity Ligation Assay (PLA) 16 2.2.6 Calf intestinal alkaline phosphatase (CIP) treatment 16 2.2.7 Measurement of Rheb-GTP loading status 16 2.2.8 Affinity purification of GST-Rheb and in vitro GAP assay 17 2.2.9 Lysosome purification by Lyso-IP method 18 2.2.10 Lysosome Enrichment 18 Chapter 3 Result 20 3.1 CBAP, Rheb and Akt all display widespread intracellular distributions 20 3.2 Akt-TSCC-CBAP-Rheb forms a supramolecular complex 21 3.3 Oncogenic and insulin signals regulate the Akt•TSCC•CBAP•Rheb supramolecular complex 22 3.4 TSC2-Akt-CBAP Complex Controlling Rheb Desuppression (TACRD) regulates the GAP activity of TSCC 24 3.5 CBAP directly interacts with the harmatin-binding domain of TSC2 26 3.6 CBAP scaffolding is important to the biological function of TACRD 27 3.7 Lysosomal-anchored CBAP phenocopies the effects of TSC2 deficiency in terms of lysosome biogenesis and cell proliferation 29 Discussion 33 Figures 37 Appendix 73 TABLE 98 References 100 | |
| dc.language.iso | en | |
| dc.subject | mTORC1 activation | zh_TW |
| dc.subject | Akt | zh_TW |
| dc.subject | Rheb small GTPase | zh_TW |
| dc.subject | TSC2 deficiency | zh_TW |
| dc.subject | CBAP | zh_TW |
| dc.subject | 細胞生長調控 | zh_TW |
| dc.subject | TFEB | zh_TW |
| dc.subject | cell growth control | en |
| dc.subject | mTORC1 activation | en |
| dc.subject | TFEB nuclear localization | en |
| dc.subject | oncogenesis | en |
| dc.subject | Akt | en |
| dc.subject | Rheb small GTPase | en |
| dc.subject | TSC2 deficiency | en |
| dc.subject | CBAP | en |
| dc.title | 探討 CBAP 在 Akt/TSCC/Rheb/mTORC1 胰島素的刺激及活化中的角色 | zh_TW |
| dc.title | Study on the role of CBAP in insulin stimulated activation of the Akt/TSCC/Rheb/mTORC1 signaling pathway | en |
| dc.type | Thesis | |
| dc.date.schoolyear | 110-2 | |
| dc.description.degree | 博士 | |
| dc.contributor.oralexamcommittee | 楊性芳(Hsin-Fang Yang-Yen),李芳仁(Fang-Jen Lee),張智芬(Zee-Fen Chang),徐立中(Li-Chung Hsu) | |
| dc.subject.keyword | Akt,Rheb small GTPase,TSC2 deficiency,CBAP,細胞生長調控,TFEB,mTORC1 activation, | zh_TW |
| dc.subject.keyword | Akt,Rheb small GTPase,TSC2 deficiency,CBAP,cell growth control,oncogenesis,TFEB nuclear localization,mTORC1 activation, | en |
| dc.relation.page | 109 | |
| dc.identifier.doi | 10.6342/NTU202202252 | |
| dc.rights.note | 同意授權(限校園內公開) | |
| dc.date.accepted | 2022-08-11 | |
| dc.contributor.author-college | 醫學院 | zh_TW |
| dc.contributor.author-dept | 分子醫學研究所 | zh_TW |
| dc.date.embargo-lift | 2025-08-01 | - |
| 顯示於系所單位： | 分子醫學研究所 | |
文件中的檔案：
| 檔案 | 大小 | 格式 | |
|---|---|---|---|
| U0001-1008202213344000.pdf 授權僅限NTU校內IP使用（校園外請利用VPN校外連線服務） | 5.2 MB | Adobe PDF |
系統中的文件，除了特別指名其著作權條款之外，均受到著作權保護，並且保留所有的權利。