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. 2022 Jul 20;14(14):3528. doi: 10.3390/cancers14143528

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© 2022 by the authors.

Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/).

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Upstream Autophagy Regulation. Extracellular growth factors and cytokines activate KRAS and PI3K. GAP and GEF regulate KRAS activity which begins the MAPK cascade of activating RAF, MEK and ERK. ERK can inhibit pro-apoptotic function and support anti-apoptotic function via Bcl-2. ERK can also inhibit mTORC1 which facilitates autophagic initiation. PI3K phosphorylates PIP3 which is regulated by PTEN dephosphorylation. PIP3 activates AKT causing the destabilization of TSC2-TSC1 complex. This supports mTORC1 activity and suppresses autophagic initiation. mTORC1 can also regulate AKT via a feedback loop and suppress cytoskeleton activity involving SGK1 and mTORC2. Created with BioRender.com (accessed on 28 March 2022).