mTORC2途径在人类结直肠癌（CRC）中促进肿瘤进展方面发挥着关键作用，对该信号通路的调控机制仅部分了解。我们以前在CRC中鉴定了UBXN2A作为一种新型肿瘤抑制蛋白，并假设UBXN2A通过抑制mTORC2途径来抑制CRC生长和转移。我们首先使用小鼠模型显示，在UBXN2A的半合子不足的情况下，结直肠肿瘤发生显著增加。诱导UBXN2A可减少mTORC2途径下游的AKT磷酸化，这对于一系列细胞过程包括细胞迁移是必要的。同时，UBXN2A的存在并不影响mTORC1活动。机制研究揭示UBXN2A靶向mTORC2复合物的关键组成成分Rictor蛋白，使其经过26S蛋白酶降解。一系列基因、药理和救援实验表明，UBXN2A在CRC中调节细胞增殖、凋亡、迁移和结肠癌干细胞（CSCs）。UBXN2A水平高的CRC患者有着显著更好的生存率，高级别CRC组织的UBXN2A蛋白表达降低。在患者来源的异种移植瘤和肿瘤器官中，UBXN2A水平高可降低Rictor蛋白并抑制mTORC2途径。这些发现揭示了一种类泛素蛋白的功能，通过抑制CRC中的优势致癌途径来提供新的见解。©2023年作者，独家许可给Springer Nature Limited。

The mTORC2 pathway plays a critical role in promoting tumor progression in human colorectal cancer (CRC). The regulatory mechanisms for this signaling pathway are only partially understood. We previously identified UBXN2A as a novel tumor suppressor protein in CRCs and hypothesized that UBXN2A suppresses the mTORC2 pathway, thereby inhibiting CRC growth and metastasis. We first used murine models to show that haploinsufficiency of UBXN2A significantly increases colon tumorigenesis. Induction of UBXN2A reduces AKT phosphorylation downstream of the mTORC2 pathway, which is essential for a plethora of cellular processes, including cell migration. Meanwhile, mTORC1 activities remain unchanged in the presence of UBXN2A. Mechanistic studies revealed that UBXN2A targets Rictor protein, a key component of the mTORC2 complex, for 26S proteasomal degradation. A set of genetic, pharmacological, and rescue experiments showed that UBXN2A regulates cell proliferation, apoptosis, migration, and colon cancer stem cells (CSCs) in CRC. CRC patients with a high level of UBXN2A have significantly better survival, and high-grade CRC tissues exhibit decreased UBXN2A protein expression. A high level of UBXN2A in patient-derived xenografts and tumor organoids decreases Rictor protein and suppresses the mTORC2 pathway. These findings provide new insights into the functions of an ubiquitin-like protein by inhibiting a dominant oncogenic pathway in CRC.© 2023. The Author(s), under exclusive licence to Springer Nature Limited.