Article Figures & Data
Figures
- Figure 1.
Signaling through the PI3K/mTOR and RAS/RAF/MEK/ERK pathways is controlled by negative feedback loops. Feedback loops emanate from distal elements of the same pathway (intrinsic negative loops) or from other pathways (extrinsic loops) and restrain the activity of upstream signaling nodes thereby fine-tuning the output of the signaling network. These potent negative feedback loops are indicated by the red lines and identified with numbers. Stimulatory connections are in green. See text for detailed description.
- Figure 2.
A, compensatory overactivation of signal transduction pathways induced by rapamycin-mediated suppression of negative feedback loops. Rapamycin triggers PI3K activation and AKT phosphorylation at Thr308 and Ser473 via suppression of mTORC1/S6K-mediated phosphorylation of IRS-1 and SIN1 (loop 1). mTORC2-mediated phosphorylation of AKT at Ser473 in response to rapamycin can be further enhanced by eliminating negative cross-talk from S6K (loop 2). Furthermore, mTORC2 negatively feeds back to IRS-1 via control of its stability (loop 3). In some cancer cells, rapalogs also induce MEK/ERK via the PI3K-dependent pathway that could involve RAC/PAK1 and/or PDGFR. B, compensatory overactivation of signal transduction pathways induced by active-site mTOR inhibitors. Active-site mTOR inhibitors that block both mTORC1 and mTORC2 also eliminate feedback loops that restrain PI3K/PDK1 activation. Specifically, these agents disable feedback loops 1, 2, 3, 4, 5, 6, and 10. Active-site mTOR inhibitors enhance AKT phosphorylation at the activation loop (Thr308) and consequently these agents do not completely block AKT activity. Acute exposure of a variety of cell types to active-site mTOR inhibitors induced a striking overactivation of the MEK/ERK pathway via a PI3K-independent pathway. Chronic exposure to these agents also disables the negative influence of AKT on FOXO thereby promoting expression of TRKs and adaptors. For additional details, see text. Inhibitory connections are in red. Stimulatory connections are in green. Pathways activated by suppression of negative feedback loops are highlighted in yellow.
- Figure 3.
A, compensatory overactivation of signal transduction pathways induced by dual PI3K/mTOR inhibitors. Dual PI3K/mTOR inhibitors disable feedback loops 1, 2, 3, 4, 5, 6, and 10. Acute exposure of a variety of cell types to dual PI3K/mTOR inhibitors induced overactivation of the MEK/ERK pathway via a PI3K-independent pathway, probably involving GRB2/SOS-mediated RAS activation as a result of TRK and/or IRS activation. Chronic exposure to these agents also promotes FOXO-mediated expression of TRKs and adaptors. B, compensatory overactivation of signal transduction pathways induced by MEK inhibitors. These inhibitors disable feedback loops 7, 8, and 9 leading to RAS/RAF and PI3K/AKT overactivation. See text for detailed description. Inhibitory connections are in red. Stimulatory connections are in green. Pathways activated by suppression of negative feedback loops are highlighted in yellow.
Volume 13, Issue 11
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- Article
- Abstract
- Introduction
- mTORC1 and mTORC2 Mediate Negative Feedback of PI3K/AKT Activation through Inhibition and Degradation of IRS-1
- Rapamycin-Induced ERK Overactivation
- Compensatory Activation of PI3K and ERK Signaling in Response to Active-Site mTOR Inhibitors and Dual PI3K/mTOR Inhibitors
- Mechanisms by Which mTOR and PI3K/mTOR Inhibitors Stimulate MEK/ERK Signaling
- Mechanisms by Which MEK Inhibitors Stimulate PI3K/AKT Signaling
- Chronic Exposure to PI3K/PDK1/AKT Inhibitors Suppresses a Feedback Loop That Mediates Repression of TRK and Survival Protein Expression
- Metformin Inhibits mTORC1 but Does Not Elicit AKT or ERK Overactivation: Role of AMPK
- Concluding Remarks and Clinical Implications
- Disclosure of Potential Conflicts of Interest
- Grant Support
- References
- Figures & Data
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