Figure 8.

Feedback inhibition of the phosphatidylinositol 3—kinase (PI3K) pathway. Activated AKT regulates cellular growth through mammalian target of rapamycin (mTOR), a key player in protein synthesis and translation. mTOR forms part of two distinct complexes known as mTORC1 (which contains mTOR, Raptor, mLST8, and PRAS40) and mTORC2 (which contains mTOR, Rictor, mLST8, and mSIN1). mTORC1 is sensitive to rapamycin and controls protein synthesis and translation, at least in part, through p70S6K and eukaryotic translation initiation factor 4E—binding protein 1 (4E-BP1). AKT phosphorylates and inhibits tuberous sclerosis complex 2 (TSC2), resulting in increased mTORC1 activity. AKT also phosphorylates PRAS40, thus relieving the PRAS40 inhibitory effect on mTOR and the mTORC1 complex. mTORC2 and 3-phosphoinositide-dependent kinase (PDK1) phosphorylate AKT on Ser473 and Thr308, respectively, rendering it fully active. mTORC1-activated p70S6K can phosphorylate insulin receptor substrate 1 (IRS1), resulting in inhibition of PI3K activity. In addition, PDK1 phosphorylates and activates p70S6K and p90S6K. The latter has been shown to inhibit TSC2 activity through direct phosphorylation. Conversely, LKB1-activated AMP-activated protein kinase (AMPK) and glycogen synthase kinase 3 (GSK3) activate the TSC1/TSC2 complex through direct phosphorylation of TSC2. Thus, signals through PI3K as well as through LKB1 and AMPK converge on mTORC1. Inhibition of mTORC1 can lead to increased insulin receptor—mediated signaling, and inhibition of PDK1 may lead to activation of mTORC1 and may, paradoxically, promote tumor growth.