RIT1 是一种罕见且尚未得到充分研究的肺癌癌基因。尽管与其他 RAS GTPase 蛋白（例如 KRAS）结构相似，但致癌 RIT1 活性似乎不受核苷酸交换或水解的严格调节。相反，人们越来越认识到 RIT1 的蛋白质丰度对其调节和功能很重要。我们之前将去泛素酶 USP9X 鉴定为 RIT1 突变细胞中的 RIT1 依赖性。在这里，我们证明 RIT1 的野生型和突变型都是 USP9X 的底物。 USP9X 的消耗会导致 RIT1 蛋白稳定性和丰度降低，并使细胞在体外和体内对表皮生长因子受体 (EGFR) 酪氨酸激酶抑制剂重新敏感。我们的工作扩展了目前对 RIT1 蛋白调控的理解，并将 USP9X 视为 RIT1 驱动的致癌表型的关键调控因子。© 2024 作者。

RIT1 is a rare and understudied oncogene in lung cancer. Despite structural similarity to other RAS GTPase proteins such as KRAS, oncogenic RIT1 activity does not appear to be tightly regulated by nucleotide exchange or hydrolysis. Instead, there is a growing understanding that the protein abundance of RIT1 is important for its regulation and function. We previously identified the deubiquitinase USP9X as a RIT1 dependency in RIT1-mutant cells. Here, we demonstrate that both wild-type and mutant forms of RIT1 are substrates of USP9X. Depletion of USP9X leads to decreased RIT1 protein stability and abundance and resensitizes cells to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors in vitro and in vivo. Our work expands upon the current understanding of RIT1 protein regulation and presents USP9X as a key regulator of RIT1-driven oncogenic phenotypes.© 2024 The Author(s).