Fig. 9
From: PI3K/AKT/mTOR signaling transduction pathway and targeted therapies in cancer
Simplified overview of PAM signaling pathway location among other major signal transduction pathways in the network circuit of a cancer cell. Each component of a signaling pathway is termed according to the role it plays with respect to the initial stimulus, such as ligands (e.g. IGF1), receptors (e.g. RTK), and effectors (e.g. PI3K). In cancer cells, mutations in RTK, Ras, PI3K, PTEN protein phosphatase, AKT, and/or other proto-oncogenes, may occur, resulting in PAM signaling pathway overexpression. This condition can lead to stronger AKT-induced inhibition of pro-apoptotic proteins such as FOXO, BAD, BAX, BAK, NOXA, PUMA, as well as enhanced activity of anti-apoptotic proteins such as XIAP, and amplified activity of mTORC1, IKKα, PKC, CDC42, Rac, GSKβ, and MDM2, with consequently uncontrolled survival, proliferation, growth and boosted metabolism. Signaling cross-talk between PAM pathway and other pathways play a major role in the dysregulation of functions in a cancer cell. PI3K pathway, NF-κB pathway, G-Protein pathway, MEK pathway, Integrin pathway, Wnt pathway, Gli pathway, SMAD pathway, extrinsic apoptotic pathway, intrinsic apoptotic pathway, STAT pathway, Estrogen pathway, p53 pathway, and Rb pathway are shown. Nuclear membrane is delimited by a long-dashed circular dotted line. Arrowhead lines: activation (phosphorylation or non-phosphorylation). Blocked lines: inhibition (phosphorylation or non-phosphorylation). Continuous lines: interaction. Dotted arrowhead lines: cross-talk activation (phosphorylation or non-phosphorylation) between pathways. Dotted blocked lines: cross-talk inhibition (phosphorylation or non-phosphorylation) between pathways. Red lightning symbol shows mutation for a particular gene in the PAM pathway. Red crosses: signaling blockage. Green dash-dotted lines (adjacent to arrowhead lines or blocked lines or dotted arrowhead lines): signaling enhancement. PI3K: PI3K/Ras complex. MEKs: MEK1/2. ERKs: ERK1/2. TFs1: Transcription factors Jun, ATF2, RNPK, p53, NFAT4, Shc. TFs2: Transcription factors CHOP, ATF2, MNK, MSK, MEF2, Elk-1. TFs3: Transcription factors Elk-1, Ets-2, RSK, MNK, MSK, cPLA2, Fos, Myc. FAK: FAK/Src complex. Fyn: Fyn/Shc complex. Dsh: Dishevelled. Cyclin:CDKs1: Cyclin A:CDK1, Cyclin A:CDK2, Cyclin B:CDK1, Cyclin E:CDK2. Cyclin:CDKs2: Cyclin D:CDK4, Cyclin D:CDK6. CKIs: Cyclin-dependent kinase inhibitors (p16, p18, p19)