PI3K/Akt/mTOR signaling pathway

The PI3K/Akt/mTOR signaling pathway. GPCRs, RTKs, and Ras activate PI3K. PI3K generates PtdIns (3,4,5)P3 from PtdIns (4,5)P2. PtdIns (3,4,5)P3 attracts to the plasma membrane PDK1 which phosphorylates Akt on Thr308. Full Akt activation requires Ser473 phosphorylation which is effected by mTORC2. Most of the Akt substrates are inactivated by phosphorylation. Active Akt inhibits TSC2 activity through direct phosphorylation. TSC2 is a GAP that functions in association with TSC1 to inactivate the small G protein Rheb. Akt-driven TSC1/TSC2 complex inactivation allows Rheb to accumulate in a GTP-bound state. Rheb-GTP then activates the protein kinase activity of mTORC1. mTORC1 targets p70S6K and 4E-BP1 which are critical for translation. 4E-BP1 phosphorylation by mTORC1 results in the release of eIF4E, while p70S6K phosphorylates ribosomal S6 protein. The TSC1/2 complex is required to activate also mTORC2. However, other signaling cascades impinge on mTORC1, including GSK3β, the Ras/Raf/MEK/ERK1/2/p90RSKpathway, and the LKB1/AMPK network which is sensitive to the ADP/ATP ratio. Arrows indicate activating events, whereas perpendicular lines indicate inhibitory events.

Publication

The phosphatidylinositol 3-kinase/Akt/mTOR signaling network as a therapeutic target in acute myelogenous leukemia patients. (2010) Alberto M. Martelli, et al. Oncotarget. 2010 Jun;1(2):89-103. Figure: F1. All organisms Drosophila melanogaster Homo sapiens

Disease mentions