Networking of the PI3K/Akt/mTOR signaling pathway. PI3K/Akt/mTOR pathway is a central regulator of metabolism, survival, and proliferation in normal tissues and in cancers. Second only to the p53 pathway, this pathway is the one most frequently dysregulated in cancers. In addition to extrinsic activation from upstream growth factor receptors or via crosstalk from RAS, the pathway can be intrinsically and constitutively up-regulated due to activating mutations or amplifications in the positive effectors of the pathway (e.g., PIK3CA/PI3Kp110, Akt, and mTORC1) or via inactivating mutations or the loss of negative regulators of the pathway (e.g., PTEN, PIK3R1, TSC, and LKB1). In the setting of selective mTORC1 inhibition, mTORC2 activates Akt via Ser473 phosphorylation. PI3K, phosphatidylinositol 3 kinase; mTOR, mammalian target of rapamycin; PIK3CA/PI3Kp110, phosphatidylinositol-4,5-biphosphate 3-kinase, catalytic subunit alpha; mTORC1, mTOR complex-1; PTEN, phosphatase and tensin homolog; TSC, tuberous sclerosis complex; LKB1, liver kidney kinase B1; EGF, epidermal growth factor; IGF-1R, insulin growth factor 1 receptor; HER, v-erbB2 avian eryhtorblastic leukemia viral oncogene homolog 2; EGFR, epidermal growth factor receptor; PIP2, phosphatidylinositol 4,5-bisphosphate; PDK1, pyruvate dehydrogenase kinase 1; MDM2, mouse double minute 2 homolog; NF-κB, nuclear factor-κB; CREB, cAMP response element-binding protein; GSK3, glycogen synthase kinase 3; 4EBP1,4E binding protein 1.