https://scholars.lib.ntu.edu.tw/handle/123456789/641498
標題: | CBAP regulates the function of Akt-associated TSC protein complexes to modulate mTORC1 signaling | 作者: | Liao, Wei-Ting Chiang, Yun-Jung Yang-Yen, Hsin-Fang LI-CHUNG HSU ZEE-FEN CHANG Yen, Jeffrey J Y |
關鍵字: | Akt; Rheb; cell growth; mTORC1 activation; small GTPase; tumor cell biology | 公開日期: | 十二月-2023 | 出版社: | American Society for Biochemistry and Molecular Biology Inc. | 卷: | 299 | 期: | 12 | 來源出版物: | The Journal of Biological Chemistry | 摘要: | The Akt-Rheb-mTORC1 pathway plays a crucial role in regulating cell growth, but the mechanisms underlying the activation of Rheb-mTORC1 by Akt remain unclear. In our previous study, we found that CBAP was highly expressed in human T-ALL cells and primary tumors, and its deficiency led to reduced phosphorylation of TSC2/S6K1 signaling proteins as well as impaired cell proliferation and leukemogenicity. We also demonstrated that CBAP was required for Akt-mediated TSC2 phosphorylation in vitro. In response to insulin, CBAP was also necessary for the phosphorylation of TSC2/S6K1 and the dissociation of TSC2 from the lysosomal membrane. Here we report that CBAP interacts with AKT and TSC2, and knockout of CBAP or serum starvation leads to an increase in TSC1 in the Akt/TSC2 immunoprecipitation complexes. Lysosomal-anchored CBAP was found to override serum starvation and promote S6K1 and 4EBP1 phosphorylation and c-Myc expression in a TSC2-dependent manner. Additionally, recombinant CBAP inhibited the GAP activity of TSC2 complexes in vitro, leading to increased Rheb-GTP loading, likely due to the competition between TSC1 and CBAP for binding to the HBD domain of TSC2. Overexpression of the N26 region of CBAP, which is crucial for binding to TSC2, resulted in a decrease in mTORC1 signaling and an increase in TSC1 association with the TSC2/AKT complex, ultimately leading to increased GAP activity toward Rheb and impaired cell proliferation. Thus, we propose that CBAP can modulate the stability of TSC1-TSC2 as well as promote the translocation of TSC1/TSC2 complexes away from lysosomes to regulate Rheb-mTORC1 signaling. |
URI: | https://scholars.lib.ntu.edu.tw/handle/123456789/641498 | ISSN: | 00219258 | DOI: | 10.1016/j.jbc.2023.105455 |
顯示於: | 分子醫學研究所 |
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