Fig. 6

The PAM signaling pathway and its downstream functions. A PAM pathway downstream functions in normal cells. PI3K activation occurs by growth factor-induced receptors or through interaction with scaffolding adaptors, including IRS1/2 proteins. PI3K is then recruited to its substrate PIP2, promoting generation of PIP3. Inactive AKT in the cytoplasmic matrix binds to PIP3 on the cell membrane, allowing phosphorylation by PDK1 and mTORC2, leading to complete activation of AKT, which subsequently phosphorylates several downstream targets, including multiple sites on TSC2, which forms a functional complex with TSC1 (TSC Complex). AKT-induced phosphorylation on TSC2 hampers the ability of TSC Complex to act as a GAP toward the small GTPase Rheb, endorsing Rheb-GTP accumulation. As a result, Rheb-GTP remarkably activates mTORC1, which phosphorylates and activates S6K. In the negative PAM feedback loop, mTORC1 and S6K1 directly phosphorylate IRS1/2, impeding PI3K activation. In addition, mTORC1 blocks GRB10-mediated growth factor-induced receptor signaling to PI3K. Conversely, in the positive PAM feedback loop, AKT phosphorylates IKKα, which indirectly activates transcription factor NF-κB, allowing PTEN phosphatase inhibition. Besides, PRL-3 phosphatase can also inhibit PTEN phosphatase. PAM downstream functions include cell survival, metabolism, anabolism, catabolism, and cell cycle progression. B PAM pathway downstream functions in cancer cells. Mutations in RTK, PI3K, AKT, PTEN, and possibly other genes, may occur. Overactivation of AKT strongly enhances phosphorylation on TSC2, which further hampers the ability of the TSC Complex to act as a GAP toward the small GTPase Rheb, thereby remarkably endorsing Rheb-GTP accumulation. Thus, dysregulation of PAM pathway signal transduction, due to mutations and/or inevitable alterations in the negative feedback loop or positive feedback loop, can possibly lead to cancer onset and/or progression. This results in enhanced PAM downstream functions, such as increased cell survival, boosted metabolism, enhanced anabolism, reduced catabolism, and increased cell cycle progression. Activation (phosphorylation or non-phosphorylation) is shown with arrowhead lines or dotted-arrowhead lines, inhibition (phosphorylation or non-phosphorylation) is indicated with blocked lines, and dephosphorylation is displayed with roundhead lines. Red lightning symbol shows mutation for a particular gene in the PAM pathway. Red crosses emphasise signaling blockage, whereas green dash-dotted lines (adjacent to arrowhead lines or blocked lines) highlight signaling enhancement. Red upper-arrows show increases, whereas blue lower-arrows indicate reduction. Red upper-arrows show increases, whereas blue lower-arrows indicate reduction. P: phosphoryl group