氨基酸刺激的Rag GTP酶通路是调节机械靶向雷帕霉素复合物1 (mTORC1) 激活和功能的主要途径之一，但生长因子对Rag GTP酶介导的mTORC1激活的影响很少被研究。在这里，鉴定和表征了一种高度保守的胰岛素敏感磷酸化位点——卵泡素（FLCN）的Ser62，这种位点由AKT1磷酸化。mTORC2-AKT1定位于溶酶体上，而发现在胰岛素-AKT1介导的FLCN磷酸化过程中，RagD特异性招募mTORC2-AKT1至溶酶体是必不可少的步骤。此外，FLCN磷酸化抑制了RagC GTP酶的活性，并且对于胰岛素诱导的mTORC1激活是至关重要的。从功能上讲，磷酸化的FLCN促进了细胞的生存能力和诱导自噬，还以mTORC1依赖的方式调节体内肿瘤生长。它的表达也与结肠癌、透明细胞肾癌和脊索瘤中的mTORC1活性呈正相关。这些结果表明，FLCN是氨基酸和生长因子途径之间交流的重要中介体。此外，FLCN磷酸化可能是以mTORC1失调为特征的疾病的一种有前途的治疗靶点。© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH。

The amino acid-stimulated Rag GTPase pathway is one of the main pathways that regulate mechanistic target of rapamycin complex 1 (mTORC1) activation and function, but little is known about the effects of growth factors on Rag GTPase-mediated mTORC1 activation. Here, a highly conserved insulin-responsive phosphorylation site on folliculin (FLCN), Ser62, that is phosphorylates by AKT1 is identified and characterized. mTORC2-AKT1 is localized on lysosomes, and RagD-specific recruitment of mTORC2-AKT1 on lysosomes is identified as an essential step in insulin-AKT1-mediated FLCN phosphorylation. Additionally, FLCN phosphorylation inhibits the activity of RagC GTPase and is essential for insulin-induced mTORC1 activation. Functionally, phosphorylated FLCN promotes cell viability and induces autophagy, and also regulates in vivo tumor growth in an mTORC1-dependent manner. Its expression is also positively correlated with mTORC1 activity in colon cancer, clear cell renal cell carcinoma, and chordoma. These results indicate that FLCN is an important intermediate for cross-talk between the amino acid and growth factor pathways. Further, FLCN phosphorylation may be a promising therapeutic target for diseases characterized by mTORC1 dysregulation.© 2023 The Authors. Advanced Science published by Wiley-VCH GmbH.