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Role of guanine‐binding protein inhibitory alpha in activation of the Akt/mTORC1 pathway by growth factors

The Akt/mTOR pathway is essential for cell growth, migration and survival mediated by growth factors. Although it has been known that growth factor receptors called receptor tyrosine kinases (RTKs) and adaptor proteins including Grb2, Gabs, IRSs as well as FRSs are critical for activation of this pathway, it is still not well understood how these adaptor proteins are activated. We have found that the heterotrimeric guanine‐nucleotide binding protein (G protein) alpha inhibitory (Gia) is critical for mediating this activation. In Gi1a and Gi3a double knockout mouse embryonic fibroblasts (Gia1/3 DKO MEFs), the activation of the Akt/mTORC pathway was largely impaired by epidermal growth factor (EGF), EGF family members, fibroblast growth factors, and low doses of platelet derived growth factor (PDGF). In contrast, Gia1 and Gi3a double deficiency had no profound defect in activation of this pathway by insulin and insulin‐like growth factors. Mechanistic study results indicated that Gia proteins are important for the association of adaptor proteins and PI3K regulatory subunit p85. Further analysis revealed that loss of Gia proteins impaired MEFs migration and proliferation in response to growth factors. In addition, Gia proteins are important for cancer cell growth and migration. Overall, our results suggest that Gia proteins are new players in growth factor signaling and the pathogenesis process of cancer.