Receptor tyrosine kinases (RTKs) are often overexpressed or mutated in cancers and drive tumor growth and metastasis. In the current model of RTK signaling, including that of MET, downstream phosphatidylinositol 3-kinase (PI3K) mediates both cell proliferation and cell migration, whereas the small guanosine triphosphatase (GTPase) Rac1 mediates cell migration. However, in cultured NIH3T3 and glioblastoma cells, we found that class I PI3K mediated oncogenic MET–induced cell migration but not anchorage-independent growth. In contrast, Rac1 regulated both processes in distinct ways. Downstream of PI3K, Rac1 mediated cell migration through its GTPase activity, whereas independently of PI3K, Rac1 mediated anchorage-independent growth in a GTPase-independent manner through an adaptor function. Through its RKR motif, Rac1 formed a complex with the kinase mTOR to promote its translocation to the plasma membrane, where its activity promoted anchorage-independent growth of the cell cultures. Inhibiting mTOR with rapamycin suppressed the growth of subcutaneous MET-mutant cell grafts in mice, including that of MET inhibitor–resistant cells. These findings reveal a GTPase-independent role for Rac1 in mediating a PI3K-independent MET-to-mTOR pathway and suggest alternative or combined strategies that might overcome resistance to RTK inhibitors in patients with cancer.

受体酪氨酸激酶 (RTK) 在癌症中通常过度表达或突变，并促进肿瘤生长和转移。在当前的 RTK 信号传导模型中，包括 MET 信号传导模型，下游磷脂酰肌醇 3 激酶 (PI3K) 介导细胞增殖和细胞迁移，而小鸟苷三磷酸酶 (GTPase) Rac1 介导细胞迁移。然而，在培养的 NIH3T3 和胶质母细胞瘤细胞中，我们发现 I 类 PI3K 介导致癌 MET 诱导的细胞迁移，但不介导不依赖锚定的生长。相比之下，Rac1 以不同的方式调节这两个过程。在 PI3K 下游，Rac1 通过其 GTP 酶活性介导细胞迁移，而独立于 PI3K，Rac1 通过适配器功能以不依赖 GTP 酶的方式介导不依赖贴壁的生长。通过其 RKR 基序，Rac1 与激酶 mTOR 形成复合物，促进其易位至质膜，其活性促进细胞培养物的贴壁依赖性生长。用雷帕霉素抑制 mTOR 可抑制小鼠皮下 MET 突变细胞移植物的生长，包括 MET 抑制剂耐药细胞的生长。这些发现揭示了 Rac1 在介导不依赖于 PI3K 的 MET 至 mTOR 通路中的不依赖于 GTP 酶的作用，并提出了可能克服癌症患者对 RTK 抑制剂耐药性的替代或组合策略。