A PI3K- and GTPase-independent Rac1-mTOR mechanism mediates MET-driven anchorage-independent cell growth but not migration

Menée à l'aide de cellules de glioblastome, d'une lignée de fibroblastes et d'un modèle murin, cette étude met en évidence dans les cellules exprimant une forme mutée de MET un mécanisme par lequel une interaction non catalytique (indépendante de la kinase PI3K et de l'activité GTPase de Rac1) entre Rac1 et mTOR au niveau de la membrane plasmique favorise une croissance cellulaire indépendante du processus d'ancrage induit par MET

Résumé en anglais

Anchorage-independent proliferation and cell migration are critical to primary tumor growth and metastatic spread. These behaviors are promoted by growth factor signaling, which is generally mediated by the kinase PI3K to downstream effectors that include the kinase mTOR and the GTPase Rac1. In both cultured cells and in tumor grafts in mice, Hervieu et al. found that anchorage-independent growth by cells expressing a mutant form of the growth factor receptor MET was mediated not by PI3K or the GTPase activity of Rac1, but rather by a noncatalytic, plasma membrane–localized interaction between Rac1 and mTOR. These findings refine our understanding of MET-driven signaling in tumor growth and may also explain why PI3K inhibitors must often be combined with mTOR inhibitors to effectively suppress tumor growth.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.