Figure 2 |. Canonical PTEN–PI3K–AKT–mTOR pathway.

PTEN opposes PI3K function, leading to inactivation of AKT crucial downstream target¹. When PTEN activity is decreased or absent, products of PI3K activate AKT through the activation of its upstream kinase phosphoinositide-dependent kinase 1 (PDK1; encoded by PDPK1)¹⁷⁰. Other upstream regulators of the pathway include receptor tyrosine kinases (RTKs) such as ERBB2 and epidermal growth factor receptor (EGFR) that are important in breast and lung cancer, respectively (reviewed in REF. 171). Important downstream targets of AKT (such as p27, p21, FOXO and PAWR (also known as PAR4)) are involved in multiple functions that are crucial for tumour cell growth and survival (reviewed in REF. 8). mTOR activity is also increased when PTEN activity is lost, and mTOR itself has important targets, including AKT, as well as proteins required for protein translation such as ribosomal protein S6 kinase (S6K; encoded by RPS6KB1 and TPS6KB2) and eukaryotic initiation factor 4E binding protein (4EBP1; encoded by EIF4EBP1)¹⁷². mTOR exists in two different protein complexes, TORC1 and TORC2 (REF. 173). Inhibitors of TORC1 by drugs such as rapamycin can activate AKT by deactivating a negative-feedback loop mediated by S6K and insulin receptor substrate 1 (IRS1)^174,175. Proteins that can be targeted by drugs (as outlined in TABLE 2) are indicated in red. BAD, BCL-2-associated agonist of cell death; GSK3, glycogen synthase kinase 3; MAP3K5, apoptosis signal regulator kinase 1.