State Key Laboratory of Membrane Biology, New Cornerstone Science Laboratory, Institute of Molecular Medicine, College of Future Technology, Peking University, Beijing, 100871, China.
Peking-Tsinghua Center for Life Sciences, Academy for Advanced Interdisciplinary Studies, Peking University, Beijing, 100871, China.
Nat Commun. 2023 Dec 20;14(1):8464. doi: 10.1038/s41467-023-44241-8.
The mechanistic target of rapamycin complex 1 (mTORC1) is a crucial regulator of cell growth. It senses nutrient signals and adjusts cellular metabolism accordingly. Deregulation of mTORC1 has been associated with metabolic diseases, cancer, and aging. Amino acid signals are transduced to mTORC1 through sensor proteins and two protein complexes named GATOR1 and GATOR2. In this study, we identify VWCE (von Willebrand factor C and EGF domains) as a negative regulator of amino acid-dependent mTORC1 signaling. Knockdown of VWCE promotes mTORC1 activity even in the absence of amino acids. VWCE interacts with the KICSTOR complex to facilitate the recruitment of GATOR1 to the lysosomes. Bioinformatic analysis reveals that expression of VWCE is reduced in prostate cancer. More importantly, overexpression of VWCE inhibits the development of prostate cancer. Therefore, VWCE may serve as a potential therapeutic target for the treatment of prostate cancers.
雷帕霉素复合物 1（mTORC1）的作用机制靶点是细胞生长的关键调节因子。它感知营养信号并相应地调整细胞代谢。mTORC1 的失调与代谢疾病、癌症和衰老有关。氨基酸信号通过传感器蛋白和两个名为 GATOR1 和 GATOR2 的蛋白复合物转导到 mTORC1。在这项研究中，我们发现 VWCE（血管性血友病因子 C 和 EGF 结构域）是氨基酸依赖性 mTORC1 信号的负调节因子。VWCE 敲低即使在没有氨基酸的情况下也能促进 mTORC1 活性。VWCE 与 KICSTOR 复合物相互作用，促进 GATOR1 向溶酶体的募集。生物信息学分析显示 VWCE 在前列腺癌中的表达降低。更重要的是，VWCE 的过表达抑制了前列腺癌的发展。因此，VWCE 可能成为治疗前列腺癌的潜在治疗靶点。
