期刊
SCIENCE SIGNALING
卷 13, 期 637, 页码 -出版社
AMER ASSOC ADVANCEMENT SCIENCE
DOI: 10.1126/scisignal.aba8627
关键词
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资金
- CR-UK studentship [C236/A11795]
- Bayer4Target grant
- ICR
- Pancreatic Cancer Research Fund
- UK Medical Research Council (MRC) studentship
- MRC Centenary Award
- Rosetrees Trust [M314, M346]
- Barts and The London Charitable Foundation [RAB 05/PJ/07]
- Breast Cancer Now [2008NovPR10]
- CR-UK grant [C309/A11566]
- MRC [MR/R009732/1]
- MRC [G0501003, MR/R009732/1] Funding Source: UKRI
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.
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