Figure 2.

Mechanisms of activation of PI3K and downstream effectors. GCPRs and RTKs are upstream signals that control PI3K activation through direct interaction with the regulatory subunit of PI3K. Further, RTK can activate PI3K indirectly through Ras activation that in turn activates PI3K in a p110-dependent manner. Once activated, PI3K generates PIP₃ that promotes AKT phosphorylation, which subsequently phosphorylates a large number of downstream targets to control cell survival, proliferation and apoptosis. Other PI3K effectors are TEC family tyrosine kinase, such as BTK, and GTPases of the Rho/Rac/cdc42 family. Activation of PI3K-AKT pathway is an important mechanism in the development of resistance to chemotherapy (through protection of drug-induced apoptosis [79]) and radiotherapy (through repair of radiation-induced DSBs [80,81]).